Search

Purpose: In this first-in-human dose escalation study, the safety and efficacy of IO-108, a fully human monoclonal antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), was investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody., Methods: The study included patients with histologically or cytologically confirmed advanced and relapsed solid tumors, with measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Patients were treated with escalating doses of IO-108 every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. Safety and tolerability were the primary objectives. Secondary and exploratory objectives included: pharmacokinetics, clinical efficacy, immunogenicity and biomarkers., Results: Of 25 patients enrolled, 12 were treated with IO-108 monotherapy and 13 received combination therapy. IO-108 was well-tolerated up to the maximally administered dose of 1,800 mg every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. No dose-limiting toxicity was observed, and a maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 6 (50.0%) patients treated with IO-108 monotherapy and 6 (46.2%) patients treated with IO-108+pembrolizumab. All TRAEs were mild or moderate (Grade 1 or 2), and no TRAEs led to treatment discontinuation or death. IO-108 exhibited a dose-proportional increase in exposure. Full receptor occupancy (RO) in peripheral blood was achieved at doses ≥600 mg. The overall response rate was 9% (1/11) in the monotherapy and 23% (3/13) in the combination therapy. A patient with treatment-refractory Merkel cell carcinoma treated with IO-108 monotherapy achieved a durable complete response (CR) for more than 2 years. Pharmacodynamic gene expression changes reflecting increased tumor infiltration of T cells were associated with clinical benefits in both monotherapy and combination therapy. Additionally, baseline tumor inflammation gene signature (TIS) scores correlated with clinical benefit., Conclusion: IO-108 is well tolerated and has led to objective response as monotherapy and in combination with pembrolizumab. The complete response and the pharmacodynamic changes in the monotherapy cohort demonstrate single agent activity of IO-108 and provide proof of concept that targeting myeloid-suppressive pathways through LILRB2 inhibition may potentiate the clinical efficacy of anti-PD-1 immune checkpoint inhibitors., Trial Registration Number: NCT05054348., Competing Interests: Competing interests: HT, HX, WHL, KH, DV, TH, XMS, YZ and XCL are employees of Immune-Onc Therapeutics, Inc. PW and LC were previous employees of Immune-Onc Therapeutics, Inc. NS and RD are paid consultants to Immune-Onc Therapeutics, Inc. MHT has served as an advisory board member for and received consulting fee from Immune-Onc, Bristol Myers Squibb, Eisai Inc, Cascade Prodrug, Exelixis, Pfizer, Regeneron, and Sanofi Genzyme; MHT has served as speakers Bureau for and received payment from Bristol Myers Squibb, Eisai Inc, Blueprint Medicines, and Merck; MHT has served as data safety monitoring board member for Oncosec. MRP are paid consultant to Kura, Accutar, and Mitsubishi, and participated on a Data Safety monitor board or advisory board for Olema, Nurix, Daiichi, Kura, and Janssen; AN received research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, SOTIO Biotech AG, and GV20 Therapeutics, and served as advisory board and received consulting fees from CTI, Deka Biosciences, Janssen Biotech, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec KEYNOTE-695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Corp, Servier, Lynx Health, AbbVie, PsiOxus. JP was the founder of Caroline BioOncology Institute and BioCytic Inc; paid consultant for Terumo and Boxer Capital., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Precision therapies and immunotherapies have revolutionized cancer care, with novel genomic biomarker-associated therapies being introduced into clinical practice rapidly, resulting in notable gains in patient survival. Despite this, there is significant variability in the utilization of tumor molecular profiling that spans the timing of test ordering, comprehensiveness of gene panels, and clinical decision support through therapy and trial recommendations., Methods: To standardize testing, we designed a pathologist-directed test ordering system at the time of diagnosis using a 523-gene DNA/RNA hybrid comprehensive genomic profiling (CGP) panel and extensive clinical decision support tools. To comprehensively characterize the clinical impact of this protocol, we developed a novel natural language processing (NLP)-based approach to extract clinical features from physician chart notes. We assessed test actionability rates, therapy choice, and outcomes across a set of 3,216 patients with advanced cancer., Results: We observed 49% of patients had at least one actionable genomic biomarker-driven-approved and/or guideline-recommended targeted or immunotherapy (IO) and 53% of patients would have been eligible for a precision therapy clinical trial from three large basket trials. When assessing CGP versus an in silico 50-gene panel, 67% of tumors compared with 33% harbored actionable alterations including clinical trials. Among patients with 6 months or more of follow-up, over 52% received a targeted therapy (TT) or IO, versus 32% who received conventional chemotherapy alone. Furthermore, patients receiving TT had significantly improved overall survival compared with patients receiving chemotherapy alone ( P < .001)., Conclusion: Overall, these data represent a major shift in standard clinical practice toward molecularly guided treatments (targeted and immunotherapies) over conventional systemic chemotherapy. As guidelines continue to evolve and more precision therapeutics gain approval, we expect this gap to continue to widen.

RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively., Methods: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers., Results: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease)., Conclusions: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated., Trial Registration Number: NEON-1 (NCT04186637) and NEON-2 (NCT04920383)., Competing Interests: Competing interests: DD: Support for the present manuscript: Alpine; Grants/Research Support (institutional): Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals, Tesaro/GSK. Consultant: ACM Bio, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics. CE Speakers’ Bureau: Castle Biosciences. Stockholder: None. Patents planned, issued or pending: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, December 11, 2020; US Patent 63/208,719, “Compositions and Methods for Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. LC: Honoraria/Consultant: Pliant Therapeutics, Janssen, CDR-Life, Actuate Therapeutics. NL: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees: SK Life Sciences; Research Funding (institutional): Alexo Therapeutics, Ascentage Pharma, BeiGene, Constellation Pharmaceuticals, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron, Apexian Pharmaceuticals, Coordination Therapeutics, Symphogen, CytomX Therapeutics, InhibRx, Incyte, Jounce Therapeutics, Livzon, Northern Biologics, Tesaro, Innovent Biologics, LAM Therapeutics, Ikena, Celgene, Shattuck Labs, Alpine Immune Sciences, Genmab, Odonate, Mersana, Seagen, Alpine Biosciences, Astellas Pharma, Celgene, Helsinn, Therapeutics, Ikena Oncology, Lilly, Sapience Therapeutics, Epizyme, Gilead, Glaxo Smith Kline, Tizona, Servier, Alkermes, KSQ, Repare Therapeutics, Biosplice/Samumed, Sapience Therapeutics, SK Life Sciences, Janssen, Arcus, Artios, BioNTech SE, Alkermes/Mural Oncology. JM: Support for the present manuscript (institutional): Alpine Immune Sciences; Grants or contracts (institutional): NovoCure, Genentech, Alpine Immune Sciences, Amgen, Trishula Therapeutics, BioEclipse Therapeutics, FujiFilm, ImmuneSensor, Simcha, Repertoire Immune Sciences, Nektar Therapeutics, Synthorx, Istari Oncology, Ideaya Biosciences, Rubius, University of Arizona, Senwha, Storm Therapeutics, Werewolf Therapeutics, Fate Therapeutics, Y-Mab, Agenus, T-Scan, Lovance; Consulting Fees: BMS, Amunix, Thirona Bio, Adagene, Imaging Endpoints, Boxer Capitol, Oberland Capital, IQVIA, Genome Insight, Incyte, Novotech, Red Arrow Therapeutics; Payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events: Caris Life Sciences, Daiichi-Sankyo, TGen; Participation on a data safety monitoring board or advisory board: Topotecan Episcleral Plaque for Treatment of Retinoblastoma; Other: Board member: Caris Molecular Tumor Board, Caris Consultant; Speakers Bureau: Caris Life Sciences, Immunocore, Castle Biosciences. MMi: Support for the present manuscript (institutional): Alpine Immune Sciences; Consulting Fees (Advisory Board): The Limbic, Bristol Myers Squibb Pty Ltd, Guardant Health, Beigene Australia Pty Ltd, Merck Pte Ltd, AstraZeneca Pty Ltd, Pfizer Australia Pty Ltd; Honoraria (meeting chair): Roche Products Pty Ltd, The Limbic; Participation on a Data Safety Monitoring Board: Novartis Pharma AG (Europe); Leadership or fiduciary role on a Scientific Advisory Board: Thoracic Oncology Group Australia, Melanoma and Skin Cancer Trials Australia. MMc: Support for the present manuscript (institutional): Alpine Immune Sciences; Grants or contracts (institutional): Aadi Biosciences, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, ASCO, Astellas, Aulos Bioscience, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Bristol-Myers Squibb, C4 Therapeutics, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, GI Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therrapeutics, Nektar, Novartis, NucMito Pharmaceuticals, OncoC4, Oncorus, OnKure, PACT Pharma, Pfizer, Plexxikon, Poseida, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Xilio; Consulting Fees (institutional): Castle Biosciences, IQVIA, Merck, Moderna, Pfizer. MV: Support for the present manuscript: Alpine Immune Sciences (institutional); Honoraria: MSD; Consulting or Advisory Role: AstraZeneca, MSD; Grants or Contracts (Research Funding, institutional): AstraZeneca/MedImmune, AstraZeneca, MSD, Alpine Immune Sciences, Virocure, Hinova Pharmaceutics, Atridia, Antengene, BeiGene, Hengrui Pharmaceutical. RES: Grants and Contracts: AstraZeneca, Merck; Consulting (steering committee): GlaxoSmithKline, Janssen Oncology, Daiichi, BeiGene; Consulting (advisory board): AstraZeneca, Macrogenics, Sanofi, Gilead, Regeneron, Targeted Oncology, GI Therapeutics, GE Health Care, Lily Oncology; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (educational presentations: Illumina, GameOn!, OncLive, Binay Foundation, APP Oncology, Masters in Thoracic Oncology Summit; consulting for manuscript: EMD Serono. JSG: Grants or contracts: Novartis; Consulting: Amgen, Arcus Biosciences, AI Proteins, AstraZeneca, Beigene, Blueprint Medicines, Bristol Myers Squibb, Genentech/Roche, EMD Serono, InterVenn Biosciences, Gilead Sciences, iTeos Therapeutics, Jounce Therapeutics, Karyopharm Therapeutics, Lilly, Loxo, Merus, Mirati Therapeutics, Pfizer, Sanofi, Silverback Therapeutics, Merck, Moderna Therapeutics, Mariana Oncology, Takeda; Payment or Honoraria: Merck, Pfizer, Novartis, Pfizer, Takeda; Leadership or fiduciary role: SAB Happy Lungs; Stock or Stock Options: Immediate family member is an employee with equity in Ironwood Pharmaceuticals. AN: Payment for honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Dava Oncology. AP: Honoraria: Texas Society of Clinical Oncology (TxSCO); Consulting or Advisory Role: Bayer, Novartis, Merck, Seattle Genetics, Silverback Therapeutics, Shenzhen IONOVA Life Sciences, Gilead, Daiichi Sankyo, HalioDx, Janssen; Consulting or Advisory Role (immediate family member): Genentech/Roche, Merck, Bristol-Myers Squibb; Research Funding (institutional): Merck, Pfizer, Lilly, Plexxikon, Corvus Pharmaceuticals, Tesaro, AbbVie, Forty Seven, Five Prime Therapeutics, Infinity Pharmaceuticals, Pieris Pharmaceuticals, Surface Oncology, Livzon, Vigeo Therapeutics, Astellas Pharma, Klus Pharma, Symphogen, Syndax, Arcus, Fochon, Upsher-Smith, Exelixis, Seattle Genetics, Bolt, Ionova, Daiichi Sankyo, Sanofi, Gilead Sciences, Seagen, Shenzhen Ionova Life Science, Pionyr Immunotherapeutics, Loxo Oncology, Inc. On behalf of Eli Lilly and company, Nektar Therapeutics, Alpine Immune Sciences, Amgen, Institut de Recherches Internationales Servier (I.R.I.S.), 1200 Pharma, Arcus Biosciences, Genentech, Aadi Bioscience, Prelude, KSQ Therapeutics, Carrick Therapeutics. JFG: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristal Myers Squibb, Curio Sciences. MS: Consulting fees: Adagene, Adaptimmune, Alkermes, Alligator, Anaptys, Asher, Biond, Biontech, Boston Pharmaceuticals, Bristol-Myers, Dragonfly, Evaxion, Evolveimmune, Gilead, Glaxo Smith Kline, Ichnos, Immunocore, Incyte, Innate pharma, Iovance, iTEOS, Jazz Pharmaceuticals, Kanaph, Merck, Molecular Partners, Nextcure, Nimbus, Normunity, Numab, Ocellaris-Lilly, Oncohost, Ontario Institute for Cancer Research, Partner Therapeutics, Pfizer, Pierre-Fabre, PIO Therapeutics, Pliant, Regeneron, Rootpath, Sapience, Simcha, Sumitomo, Targovax, Teva, Turnstone, Verastem, Xilio; Leadership or fiduciary role in other board, society, committee or advocacy group: Society for Immunotherapy of Cancer, past President (unpaid); Stock options: Actym, Adaptive Biotechnologies, Amphivena, Asher, Evolveimmune, Intensity, Nextcure, Normunity, Oncohost, Thetis; Stock: Johnson and Johnson, Glaxo-Smith Kline. AE: Employee of Alpine Immune Sciences; Support for attending meetings and/or travel: Alpine Immune Sciences; Patents planned, issued, or pending: Tempest Therapeutics, University of California; Holds stock or stock options in Alpine Immune Sciences. LB: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences. HL: All support for the present manuscript: Former employee of Alpine Immune Sciences; Holds stock or stock options in Alpine Immune Sciences. HT: All support for the present manuscript: Alpine Immune Sciences biostatistician supporting work on the manuscript; Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences. MJC: Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA; Owns stock in Merck & Co, Rahway, New Jersey, USA. SLP: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences. AN: Employee of Alpine Immune Sciences; Holds stock options in Alpine Immune Sciences., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gut Akkermansia muciniphila (Akk) has been implicated in impacting immunotherapy or oncogenesis. This study aims to dissect the Akk-associated tumor immune ecosystem (TIME) by single-cell profiling coupled with T cell receptor (TCR) sequencing. We adopted mouse cancer models under anti-PD-1 immunotherapy, combined with oral administration of three forms of Akk, including live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc&#95;1100 (Amuc). We show that live Akk is most effective in activation of CD8 T cells by rescuing the exhausted type into cytotoxic subpopulations. Remarkably, only live Akk activates MHC-II-pDC pathways, downregulates CXCL3 in Bgn(+)Dcn(+) cancer-associated fibroblasts (CAFs), blunts crosstalk between Bgn(+)Dcn(+) CAFs and PD-L1(+) neutrophils by a CXCL3-PD-L1 axis, and further suppresses the crosstalk between PD-L1(+) neutrophils and CD8 T cells, leading to the rescue of exhausted CD8 T cells. Together, this comprehensive picture of the tumor ecosystem provides deeper insights into immune mechanisms associated with gut Akk-dependent anti-PD-1 immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting immune interventions to prevent or intercept premalignant lesions, before significant immune dysregulation has occurred, may be a more successful strategy. The field of cancer immune interception and prevention is nascent, and the scientific community has been slow to embrace this potentially most rational approach to reducing the global burden of cancer. This may change due to recent promising advances in cancer immunoprevention including the use of vaccines for the prevention of viral cancers, the use of cancer-associated antigen vaccines in the setting of precancers, and the development of cancer-preventative vaccines for high-risk individuals who are healthy but carry cancer-associated heritable genetic mutations. Furthermore, there is increasing recognition of the importance of cancer prevention and interception by national cancer organizations. The National Cancer Institute (NCI) recently released the National Cancer Plan, which includes cancer prevention among the top priorities of the institute. The NCI's Division of Cancer Prevention has been introducing new funding opportunities for scientists with an interest in the field of cancer prevention: The Cancer Prevention-Interception Targeted Agent Discovery Program and The Cancer Immunoprevention Network. Moreover, the Human Tumor Atlas Network is spearheading the development of a precancer atlas to better understand the biology of pre-invasive changes, including the tissue microenvironment and the underlying genetics that drive carcinogenesis. These data will inform the development of novel immunoprevention/immuno-interception strategies. International cancer foundations have also started recognizing immunoprevention and immune interception with the American Association for Cancer Research, Cancer Research UK and the Society for Immunotherapy of Cancer each implementing programming focused on this area. This review will present recent advances, opportunities, and challenges in the emerging field of cancer immune prevention and immune interception., Competing Interests: Competing interests: SES—Institutional research support: IMV Inc; Consulting fees: Margenza, Stanford Burnham Prebys. PEC—Nothing to disclose. OJF—Consulting fees: PDS Biotech, GeoVax, Invectys, Inc, Ardigen. SS—Nothing to disclose. LAE—Consulting Fees: F. Hoffmann-La Roche, Genentech, Macrogenics, Lilly, Chugai, Silverback, Shionogi, CytomX, GPCR, Immunitas, DNAMx, Gilead, Mersana, Immutep, BioLineRx; Research funding: Genentech, F. Hoffmann-La Roche, EMD Serono, Merck, AstraZeneca, Takeda, Tempest, Bolt, Silverback, CytomX, Compugen, AbbVie, BMS, NextCure, Immune-Onc; Ownership interest: MolecuVax; Other: Executive role at the Society for Immunotherapy of Cancer; Employment: Ankyra Therapeutics with potential for equity. MD, TH, OK, LW—nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies., (©2023 The Authors; Published by the American Association for Cancer Research.)

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Costimulatory members of the tumor necrosis factor receptor family, such as OX40 (CD134), provide essential survival and differentiation signals that enhance T cell function. Specifically, OX40 (CD134) agonists stimulate potent anti-tumor immunity in a variety of preclinical models but their therapeutic impact in patients with advanced malignancies has been limited thus far., Areas Covered: In this review, we discuss the current state of combination immunotherapy with OX40 agonists including preclinical studies and recent clinical trials. We also discuss the strengths and limitations of these approaches and provide insight into alternatives that may help enhance the efficacy of combination OX40 agonist immunotherapy., Expert Opinion: OX40 agonist immunotherapy has not yet demonstrated significant clinical activity as a monotherapy or in combination with immune checkpoint blockade (ICB), likely due to several factors including the timing of administration, drug potency, and selection of agents for combination therapy clinical trials. We believe that careful consideration of the biological mechanisms regulating OX40 expression and function may help inform new approaches, particularly in combination with novel agents, capable of increasing the therapeutic efficacy of this approach.

The 2022 Immunotherapy Bridge congress (November 30-December 1, Naples, Italy) featured a Great Debate session which addressed three contemporary topics in the field of immunotherapy. The debates included counterpoint views from leading experts and considered whether adoptive cell therapy (ACT) has a role in the treatment of solid tumors, the use of peripheral/blood biomarkers versus tumor microenvironment biomarkers for cancer immunotherapy and the role of chimeric antigen receptor T cell versus natural killer cell therapy. As is the tradition in the Immunotherapy Bridge Great Debates, speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect their own personal views. Audiences voted in favour of either side of the topic both before and after each debate., (© 2023. The Author(s).)

Tissue resident memory (Trm) CD8 T cells infiltrating tumors represent an enriched population of tumor antigen-specific T cells, and their presence is associated with improved outcomes in patients. Using genetically engineered mouse pancreatic tumor models we demonstrate that tumor implantation generates a Trm niche that is dependent on direct antigen presentation by cancer cells. However, we observe that initial CCR7-mediated localization of CD8 T cells to tumor draining lymph nodes is required to subsequently generate CD103 + CD8 T cells in tumors. We observe that the formation of CD103 + CD8 T cells in tumors is dependent on CD40L but independent of CD4 T cells, and using mixed chimeras we show that CD8 T cells can provide their own CD40L to permit CD103 + CD8 T cell differentiation. Finally, we show that CD40L is required to provide systemic protection against secondary tumors. These data suggest that CD103 + CD8 T cell formation in tumors can occur independent of the two-factor authentication provided by CD4 T cells and highlight CD103 + CD8 T cells as a distinct differentiation decision from CD4-dependent central memory., (© 2023. The Author(s).)

While significant evidence has established an increased rate of thrombosis in patients with cancer, the risk of occult malignancy in the setting of an unprovoked thrombosis is less clear. Despite continued interest in developing an effective screening system for occult malignancy following unprovoked venous thromboembolism (VTE), discrepancies in the literature and guideline recommendations leave providers uncertain whether to screen or perform further diagnostics for this patient population. Evidence suggests that screening for malignancy can detect cancer sooner in patients with unprovoked VTE, but there is a lack of high-quality evidence demonstrating improvements in survival who receive early detection. In the following manuscript, we summarize VTE in relation to cancer epidemiology and pathophysiology. Our literature review summarizes the spectrum of testing strategies for occult malignancy following unprovoked VTE, including biomarker detection methods and various imaging approaches. We evaluate the benefit of additional diagnostic strategies, review current guidelines on the issue, and provide guidance to the reader on the best practice for investigating undiagnosed malignancy in patients with unprovoked VTE., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The response to radiation therapy incorporates both the direct impacts of radiation on cancer cells as well as the immune consequences that can help or hinder control of residual disease. Understanding the response of an individual patient's cancer to radiation, and the impact of radiation on the immune cell subsets present in the tumor prior to radiation therapy, can help identify potential predictors of outcome. Here, we describe a methodological approach to using an explant tumor model to characterize and study the immune cell subsets in murine tumors following exposure to ex vivo radiation treatment. The broader tumor environment incorporates distinct microenvironments consisting of tumor stroma and cancer cell nests, with limited interchange between these zones. Ex vivo analysis of tumor explants ensures that these environments remain intact and allows patient-specific response assessments with a broader range of treatment conditions to find optimal conditions and immunotherapy combinations. While this protocol describes the treatment of murine tumors, with minor variations the same protocol can be used to study and characterize various immune populations following radiation therapy in human tumors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy., Methods: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab 200 mg was infused intravenously every 3 weeks. Epacadostat 100 mg was administered orally twice daily. The primary objectives of phase I were determining safety/tolerability and defining the maximum tolerated or pharmacologically active dose of epacadostat. Phase II of the study was designed to enroll efficacy-expansion cohorts and to assess changes in the tumor and tumor microenvironment via mandatory-biopsy cohorts., Results: A total of 70 patients were enrolled. Twelve patients were enrolled in the phase II mandatory-biopsy cohorts. Due to early study closure, efficacy expansion did not enroll. Grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 78.6% of patients. Neutropenia and disease progression were the only grades 3 and 4 TEAEs reported in ≥10.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups., Conclusion: The combination of epacadostat 100 mg bid with pembrolizumab and chemotherapy had an acceptable safety profile. This regimen showed antitumor activity across multiple types of advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT03085914)., (© The Author(s) 2022. Published by Oxford University Press.)

While immune checkpoint blockade has revolutionized cancer treatment, unfortunately most patients do not benefit from this treatment. Many pharmacodynamic (PD) studies have revealed essential requirements for successful cancer immunotherapy that may provide insight into how we can improve these agents. Despite enormous efforts focused on interrogating the immune system using different biospecimens (e.g. blood, primary tumor, metastatic tumor, microbiome samples), a variety of technologies (e.g. flow cytometry, bulk and single-cell RNA-sequencing, immunohistochemistry), and wide-ranging disciplines (e.g. pathology, genomics, bioinformatics, immunology, cancer biology, metabolomics, bacteriology), discovery of consistent biomarkers of response have remained elusive. Pharmacokinetics (PK) studies, however, not only provide critical information regarding safe dosing but may also reveal useful biomarkers. For example, recent studies found that trough levels of therapeutic monoclonal antibodies (mAbs) or clearance (CL) of them were associated with clinical outcome, which suggests that trough levels of mAbs may represent a new class of on-treatment cancer immunotherapy biomarker. In this review, we summarize the potential utility of trough levels of mAbs, the mechanism of varying PK, consideration for therapeutic drug monitoring, and assay attributes that will facilitate wider utilization of PK information in conjunction with PD assessments.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally., Significance: AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data. This article is highlighted in the In This Issue feature, p. 2007., (©2022 The Authors; Published by the American Association for Cancer Research.)

Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models., (© 2022. The Author(s).)

Purpose: Combination therapies targeting immunologic checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 mAb, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors., Patients and Methods: In this phase I, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every 2 weeks in combination with durvalumab (1,500 mg) or tremelimumab (75 or 225 mg) every 4 weeks, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed every 8 weeks. The primary objective was to evaluate safety and tolerability., Results: Among the 27 and 31 patients who received MEDI0562 + durvalumab or MEDI0562 + tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment-emergent AE that led to discontinuation, respectively. The MTD of MEDI0562 + durvalumab was 7.5 mg MEDI0562 + 1,500 mg durvalumab; the maximum administered dose of MEDI0562 + tremelimumab was 22.5 mg MEDI0562 + 225 mg tremelimumab. Three patients in the MEDI0562 + durvalumab arm had a partial response. The mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased by >100% following the first dose of MEDI0562 + durvalumab or tremelimumab in all dose cohorts. A decrease in OX40+FOXP3 regulatory T cells was observed in a subset of patients with available paired biopsies., Conclusions: Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated., (©2022 American Association for Cancer Research.)

In this review we consider what appears to be a paradox in immunotherapies based around radiation therapy. The paradox is based on three main points. 1. That T cells are needed for radiation's efficacy; 2. That tumor-specific T cells are enriched in the field of treatment; and 3. That radiation kills T cells in the treatment field. We discuss evidence of the effect of radiation on T cells in the field given their ongoing movement in and out of tissues and the tumor, and how the movement of T cells impacts the treated primary tumor and untreated distant metastases. Given this evidence, we revisit the paradox to understand how the extraordinary efficacy of radiation and immunity in preclinical models is dependent on this radiation sensitive cell., (Copyright © 2022. Published by Elsevier Inc.)

Abstract: The holy grail of cancer therapeutics is the destruction of cancer cells while avoiding harm to normal cells. Cancer is unique from normal tissues because of the presence of somatic mutations that accumulate during tumorigenesis. Some nonsynonymous mutations can give rise to mutated peptide antigens (hereafter referred to as neoantigens) that can be specifically recognized by T cells. Thus, the immunological targeting of neoantigens represents a safe and promising strategy to treat patients with cancer. This article reviews the clinical application of adoptive cell therapy targeting neoantigens in patients with epithelial cancers., Competing Interests: Conflicts of Interest and Source of Funding: The author is on the scientific advisory board of the following 3 companies (which all have an interest in neoantigen targeted T-cell therapy): PACT Pharma, Genocea Biosciences, and Turnstone Biologics., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Despite the efficacy of immune checkpoint blockade (ICB) immunotherapy, most cancer patients still develop progressive disease necessitating additional treatment options. One approach is ligation of the OX40 (CD134) costimulatory receptor which promotes T cell activation, effector function, and the generation of long-lived memory cells., Recent Findings: Numerous preclinical studies have demonstrated that OX40 agonists alone or in combination with ICB (e.g., anti-PD-1, anti-PD-L1, and anti-CTLA-4) augment anti-tumor immunity. In this review, we discuss the impact of OX40 agonists on T cell function and the therapeutic potential of OX40 agonists alone or in conjunction with ICB for patients with advanced malignancies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors., Patients and Methods: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D)., Results: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies., Conclusions: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Tumor cell death caused by radiation therapy (RT) triggers antitumor immunity in part because dying cells release adjuvant factors that amplify and sustain dendritic cell and T cell responses. We previously demonstrated that bempegaldesleukin (BEMPEG: NKTR-214, an immunostimulatory IL-2 cytokine prodrug) significantly enhanced the antitumor efficacy of RT through a T cell-dependent mechanism. Because RT can induce either immunogenic or tolerogenic cell death, depending on various factors (radiation dose, cell cycle phase), we hypothesized that providing a specific immunogenic adjuvant, like intratumoral therapy with a novel toll-like receptor (TLR) 7/8 agonist, NKTR-262, would improve systemic tumor-specific responses through the activation of local innate immunity. Therefore, we evaluated whether intratumoral NKTR-262 combined with systemic BEMPEG treatment would elicit improved tumor-specific immunity and survival compared with RT combined with BEMPEG., Methods: Tumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; intravenously), RT (12 Gy × 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4 + and CD8 + T cell responses in the blood and tumor 7 days post-treatment. The contribution of specific immune subsets was determined by depletion of CD4 + , CD8 + , or NK cells. CD8 + T cell cytolytic activity was determined by an in vitro CTL assay. Data are representative of 1-2 independent experiments (n=5-14/group) and statistical significance was determined by 1-way analysis of variance (ANOVA) or repeated measures ANOVA (p value cut-off of 0.05)., Results: BEMPEG+NKTR-262 significantly improved survival compared with BEMPEG+RT in a CD8 + T cell-dependent manner. Response to BEMPEG+NKTR-262 was characterized by a significant expansion of activated CD8 + T cells (GzmA + ; Ki-67 + ; ICOS + ; PD-1 + ) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, BEMPEG+NKTR-262 induced higher frequencies of GzmA + CD8 + T cells exhibiting reduced expression of suppressive molecules (PD-1 + ), compared with BEMPEG+RT (p<0.05). Further, BEMPEG+NKTR-262 treatment induced greater tumor-specific CD8 + T cell cytolytic function than BEMPEG+RT., Conclusions: BEMPEG+NKTR-262 therapy elicited more robust expansion of activated CD8 + T cells compared with BEMPEG+RT, suggesting that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared with RT. A clinical trial of BEMPEG+NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640)., Competing Interests: Competing interests: Redmond: Research support from Galectin Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, MiNA Therapeutics, Inhibrx, Veana Therapeutics, Aeglea Biotherapeutics, Shimadzu, OncoSec, and Calibr. Patents/Licensing Fees: Galectin Therapeutics. Advisory Boards: Nektar Therapeutics, Vesselon. Rubas: Former employee of Nektar Therapeutics; current employee of Sutra Biopharma. Kïvimäe: Current employee of Nektar Therapeutics. All other authors had no relevant disclosures., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted health care delivery worldwide. Cancer is a leading cause of death, and the impact of the pandemic on cancer diagnoses is an important public health concern., Methods: This cross-sectional study retrospectively analyzed the electronic medical records of 80,138 cancer patients diagnosed between January 1, 2019, and May 31, 2021. Outcome measures included weekly number of new cancer cases and trends in weekly cancer cases, before and after the pandemic; patient demographics; and positive COVID-19 test rates., Results: Beginning March 4, 2020, defined as the onset of the pandemic, weekly cancer cases declined precipitously (-110.0 cases per week [95% confidence interval, -190.2 to -29.8]) for 4 weeks, followed by a moderate recovery (+23.7 cases per week [9.1 to 38.4]) of 10 weeks duration. Thereafter, weekly cancer cases trended slowly back toward pre-COVID-19 baseline levels. Following the pandemic onset, there was a cumulative year-over-year decline in cancer cases overall of 7.3%, including a 20.2%, 14.3%, and 12.8% decline in nonmelanoma skin cancer, breast cancer, and prostate cancer, respectively. Changes in case volumes were accompanied by variations in patient characteristics, including region, age, gender, race, insurance coverage, and COVID-19 positive test rates (P < .01 for all). Among patients tested for COVID-19, 5.3% had a positive result., Conclusions: The data in this study demonstrate a substantial reduction in cancer diagnoses following the onset of COVID-19, which appear to reach expected pre-COVID norms 12 months later. The largest reduction was noted among cancers that are typically screen-detected or identified as part of a routine wellness examination., (© 2021 American Cancer Society.)

Malignancy has long been implicated with hypercoagulability, leading to an increased rate of both venous and arterial thromboembolic events (VTE and ATE). Immunotherapy has established itself as a cornerstone of modern cancer therapy by promoting antitumor immune responses, though there have been some suggestions that immune-related adverse events could include increased rates of VTE and ATE. In this review, we examine the available evidence regarding the use of immune checkpoint inhibitors (ICIs) and thrombosis. First, we describe the potential mechanisms by which ICIs might lead to thrombophilia given the overlap between the immune system, coagulation cascade, and platelet adhesion and activation. In addition, while there are some preclinical data evaluating immunotherapy-associated ATEs in animal models, there is a paucity of evidence exploring potential mechanism of VTEs in ICIs. Second, we review the incidence of ATE and VTE in patients receiving ICIs in the published literature. Finally, we discuss current limitations in understanding, areas of conflicting evidence, and approaches to further investigation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Radiation has been utilized as a direct cytotoxic tumorcidal modality, however, the effect of radiation on tumor vasculature influences response to anticancer therapies. Although numerous reports have demonstrated vascular changes in irradiated tumors, the findings and implications are extensive and at times contradictory depending on the radiation dose, timing, and models used. In this review, we focus on the radiation-mediated effects on tumor vasculature with respect to doses used, timing postradiation, vasculogenesis, adhesion molecule expression, permeability, and pericyte coverage, including the latest findings., (© 2021 Wiley Periodicals LLC.)

Background: NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors., Methods: Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1)., Results: As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1-77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8 + T cells), increased CD16 + monocytes, and increased CD163 + macrophages at injection sites., Conclusions: Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy., Trial Registration Number: NCT02452268., Competing Interests: Competing interests: AV, CB, BKF, and GNP report inventorship in issued patents of relevance to this work (licensed to Novartis; managed by the National Cancer Institute) and other support by Novartis during the conduct of this study. DGM and TAW report other support from Novartis during the conduct of the study. JT reports grants from Alpine Biosciences, other support from Novartis during the conduct of the study, other support from Pfizer, Five Prime, Merck, Trillium, Incyte and Xencor outside of the current work, and personal fees from Regeneron, Aveo, Neoleukin, Seattle Genetics, BJ Biosciences, and Calithera outside of the current work. SG reports other support from Novartis during the conduct of the study, other support from Bristol Myers Squibb, Rexahn, Incyte, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, AstraZeneca, Medimmune, Clovis, and Seattle Genetics outside of the current work, and ownership of stock in Salerius Pharmaceuticals by spouse. RL reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck, Oncolys, and Sanofi, and non-financial support from Clinigen outside of the current work. NSP, DL, SK, LHL, NRC and FB are, or were at the time of the work described, employees of Novartis Pharmaceuticals. KC, DCW, CJP, WF, ELP, MR and AW-G report nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody-drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody-drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target., Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks., Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies., Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459 ., (©2021 American Association for Cancer Research.)

Background: The yearly Think Tank Meeting of the Italian Network for Tumor Biotherapy (NIBIT) Foundation, brings together in Siena, Tuscany (Italy), experts in immuno-oncology to review the learnings from current immunotherapy treatments, and to propose new pre-clinical and clinical investigations in selected research areas. MAIN: While immunotherapies in non-small cell lung cancer and melanoma led to practice changing therapies, the same therapies had only modest benefit for patients with other malignancies, such as mesothelioma and glioblastoma. One way to improve on current immunotherapies is to alter the sequence of each combination agent. Matching the immunotherapy to the host's immune response may thus improve the activity of the current treatments. A second approach is to combine current immunotherapies with novel agents targeting complementary mechanisms. Identifying the appropriate novel agents may require different approaches than the traditional laboratory-based discovery work. For example, artificial intelligence-based research may help focusing the search for innovative and most promising combination partners., Conclusion: Novel immunotherapies are needed in cancer patients with resistance to or relapse after current immunotherapeutic drugs. Such new treatments may include targeted agents or monoclonal antibodies to overcome the immune-suppressive tumor microenvironment. The mode of combining the novel treatments, including vaccines, needs to be matched to the patient's immune status for achieving the maximum benefit. In this scenario, specific attention should be also paid nowadays to the immune intersection between COVID-19 and cancer., (© 2021. The Author(s).)

Background: Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab., Methods: Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1)., Results: Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients., Conclusions: The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile., Competing Interests: Competing interests: RES: Honoraria from Amgen and AstraZeneca. Advisory boards for AstraZeneca, Blueprint Medicines, Celldex, Daiichi Sankyo, EMD Serono, Genentech/Roche, Janssen, and Seagen. Research support from AstraZeneca and Merck. OH: Consulting/advisory boards for Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, lmmunocore, ldera, lncyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Tempus, and Zelluna. Speakers’ bureau for BMS, Novartis, Pfizer, and Sanofi/Regeneron. Institutional financial support for contracted research from Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, lmmunocore, ldera, lncyte, lovance, Merck, Moderna, Merck-Serano, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Torque, and Zelluna. EGEdV: Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, G1 Therapeutics Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon. Institutional financial support for advisory boards from Daiichi Sankyo, Merck, NSABP, Pfizer, and Sanofi; all outside the submitted work. PAO: Research funding from and has advisory role for Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences and Roche/Genentech. JG-C: Speaker’s bureau for Bayer; Fees to support registration and attending scientific meetings from BMS, Novartis. VB: Consulting/advisory role for CytomX Therapeutics, Guidepoint, Ideaya Biosciences; Loxo Therapeutics, Oncoart, and Puma Biotechnology. Institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, Amgen, Astellas, AstraZeneca, BeiGene, BMS, Boehringer Ingelheim, Boston Therapeutics, CytomX Therapeutics, Daiichi, DebioPharm, Dynavax, GSK, Genentech/Roche, H3, Incyte, Innovio, Janssen, Kura, Lilly, Loxo, Mersana, Nektar, Macrogenics, Menarini, Merck, Merus, Millenium, MSD, Nanobiotix, Novartis, ORCA, Pfizer, PharmaMar, Principia, PsiOxus, PUMA, Regeneron, Rigontec, Sanofi, Seattle Genetics, Spectrum, Synthon, Taiho, Tesaro, Transgene, Takeda, and Zenith. JB: Institutional financial support for clinical trials or contracted research from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Bio, ARMO, Array, Arrys, AstraZeneca, AtlasMedx, Bayer, Beigene, Bellicum, BI, Bicycle Therapeutics, Blueprint, BMS, Boston Biomedical, CALGB, Calithera, Celgene, Celldex, Cyteir Therapeutics, Cytomx, Daiichi Sankyo, Effector, Eisai, EMD Serono, Evelo, Five Prime, FORMA, Forty Seven, Foundation Bio, Genentech / Roche, Gilead, Gossamer Bio, GSK, Harpoon, Hutchinson MediPharma, IGM Biosciences, Imclone, Incyte, Innate, Innate Pharma, Ipsen, Jacobio, Koltan, LEAP, Lilly, Mabspace, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Morphotex, Nektar, NeoImmune Tech, NGM Biopharma, Novartis, Novocare, NuMab, Oncogenex, OncoMed, Ongologie, Onyx, Pfizer, Pieris, Prelude Oncology, PureTech Health, Regeneron, Relay Therapeutics, REPARE Therapeutics, Revolution Medicines, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck Labs, Sierra, Stemcentrx, SynDevRex, Synthorx, Taiho, Takeda, Tarveda, TempestTx, TG Therapeutics, Tracon, Treadwell Therapeutics, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks. Institutional financial support for advisory boards/consulting from Array, Agios, Amgen, Apexigen, Arch Oncology, ARMO, AstraZeneca, Bayer, Beigene, BI, Bicycle Therapeutics, BMS, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Evelo, Five Prime, FORMA, Fusion Therapeutics, Genentech / Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Pfizer, Phoenix Bio, Piper Biotech, Prelude Therapeutics, Relay Therapeutics, Samsung Bioepios, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug Development), TG Therapeutics, Tizona, Tolero, and Torque. Food, beverages and/or travel expenses from ARMO, BI, BMS, Celgene, FORMA, Genentech / Roche, Gilead, Ipsen, Lilly, MedImmune, Merck, Novartis, Oncogenex, OncoMed, and Taiho. KAA: Advisory board for CytomX (unpaid). Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, CytomX, GSK, Merck, Pfizer, and Tizona. DCC: Consultant for Nektar Therapeutics, GSK, Torque, PureTech, and HUYA. RP: Honoria for attending advisory boards from Pierre Faber, Bayer, Octimet, Clovis Oncology, Novartis, Karus Therapeutics, Biosceptre, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics and Sanofi Aventis. Fees for delivery of educational talks or chairing educational meetings by AstraZeneca, Novartis, Bayer, Tesaro and BMS. Funds to support attendance at conferences from BMS and MSD. MS is a former employee and Lawrence Lu is a current employee of CytomX Therapeutics and both own stock in CytomX Therapeutics. FT: Research funding and conference registration from Novartis. Consultancy/advisory role for GSK, Achilles Therapeutics, BMS, Zelluna, Enara Bio, Bayer, T-Knife., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic, and regulatory organisations discussed the role of neoadjuvant immunotherapy for the treatment of cancer. Although the number of neoadjuvant immunotherapeutic trials is increasing across all malignancies, the Think Tank focused its discussion on the status of neoadjuvant trials in cutaneous melanoma (CM), muscle-invasive urothelial bladder cancer (MIBC), head and neck squamous cell carcinoma (HNSCC), and pancreatic adenocarcinoma (PDAC). Neoadjuvant developments in CM are nothing short of trailblazing. Pathologic Complete Response (pCR), pathologic near Complete Response, and partial Pathologic Responses reduce 90-100% of recurrences. This is in sharp contrast to targeted therapies in neoadjuvant CM trials, where only a pCR seems to reduce recurrence. The pCR rate after neoadjuvant immunotherapy varies among the different malignancies of CM, MIBC, HNSCC, and PDAC and may be associated with different reductions of recurrence rates. In CM, emerging evidence suggests that neoadjuvant immunotherapy with anti-CTLA-4 plus anti-PD1 is a game changer in patients with palpable nodal Stage III or resectable Stage IV disease by curing more patients, reducing recurrences and the need for surgical interventions, such as lymph node dissections and metastasectomies. The Think Tank panel discussed future approaches on how to optimise results across different tumour types. Future approaches should include reducing monocyte-mediated (tumour-associated macrophages) and fibroblast-mediated (cancer-associated fibroblasts) barriers in the tumour microenvironment to facilitate the recruitment of immune cells to the tumour site, to reduce immune-suppressive mediators, and to increase antigen presentation at the site of the tumour., Competing Interests: Conflicts of interest statement M.M. was a consultant/advisory board member for Bristol Myers Squibb, Roche, Astra Zeneca, Merck Sharp Dohme, Philogen, Merck Serono, Glaxo Smith Kline, Sanofi, Pierre Fabre, Eli-Lilly, Amgen, Cosmos, Alfasigma, and owns shares of Epigen Therapeutics. C.B. received commercial research grants from Novartis, Bristol-Myers Squibb, and NanoString; is a paid advisory board member for Bristol-Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, and Pierre Fabre; and holds ownership interest in Uniti Cars, Neon Therapeutics, and Forty Seven. A.N. received honoraria Roche, Merck, AstraZeneca, and Janssen Pharmaceuticals. A.M.D.G. was a consultant and/or advisor to Incyte, Pierre Fabre, Bristol Myers Squibb, Merck Sharp Dohme, and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre, and Sanofi. R.I. was a CMO at bitbio, BoD of bluebird and Surface oncology, and SAB member of Harpoon. M.L. was employed by iOnctura SA as Chief Medical Officer. B.F. received consulting fees from Turnstone Bio, PrimeVax, UltiVue, AstraZeneca, and Boehringer Ingelheim; conducted contracted research at Macrogenics, OncoSec, BMS, Akoya, NanoString, Incyte, Shimadzu, and Viralytics/Merck; was cofounder of and holds ownership interest in UbiVac. R.B.B. has received research funds from Bristol-Myers Squibb and is on the speakers bureau for Merck and Regeneron. He is an advisory board member for Macrogenics. G.T. was a consultant/advisory board member for Bristol Myers Squibb, Astra Zeneca, Merck Sharp Dohme, and Merck Serono. A.M.M.E. is/has been consultant/advisory board member for Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, GSK, ISA pharmaceuticals, Ellipses, GSK, IO Biotech, ISA pharmaceuticals, Merck&Co/MSD, Nektar, Novartis, Pfizer, Roche, Sellas, SkylineDx, RiverD, TigaTx, and TTxDiscovery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.

Tumor neoepitopes presented by major histocompatibility complex (MHC) class I are recognized by tumor-infiltrating lymphocytes (TIL) and are targeted by adoptive T-cell therapies. Identifying which mutant neoepitopes from tumor cells are capable of recognition by T cells can assist in the development of tumor-specific, cell-based therapies and can shed light on antitumor responses. Here, we generate a ranking algorithm for class I candidate neoepitopes by using next-generation sequencing data and a dataset of 185 neoepitopes that are recognized by HLA class I-restricted TIL from individuals with metastatic cancer. Random forest model analysis showed that the inclusion of multiple factors impacting epitope presentation and recognition increased output sensitivity and specificity compared to the use of predicted HLA binding alone. The ranking score output provides a set of class I candidate neoantigens that may serve as therapeutic targets and provides a tool to facilitate in vitro and in vivo studies aimed at the development of more effective immunotherapies., Competing Interests: Competing interests The authors declare no competing interests.

CTLA-4 blockade in combination with an agonist OX40-specific monoclonal antibody synergizes to augment antitumor immunity through enhanced T-cell effector function, leading to increased survival in preclinical cancer models. We have shown previously that anti-OX40/anti-CTLA-4 combination therapy synergistically enhances the expression of Eomesodermin (Eomes) in CD8 + T cells. Eomes is a critical transcription factor for the differentiation and memory function of CD8 + T cells. We hypothesized that Eomes hi CD8 + T cells were necessary for anti-OX40/anti-CTLA-4 immunotherapy efficacy and that further enhancement of this population would improve tumor-free survival. Indeed, CD8 + T cell-specific deletion of Eomes abrogated the efficacy of anti-OX40/anti-CTLA-4 therapy. We also found that anti-OX40/anti-CTLA-4-induced Eomes hi CD8 + T cells expressed lower levels of checkpoint receptors (PD1, Tim-3, and Lag-3) and higher levels of effector cytokines (IFNγ and TNFα) than their Eomes lo counterparts. Eomes expression is negatively regulated in T cells through interleukin-2-inducible T-cell kinase (ITK) signaling. We investigated the impact of modulating ITK signaling with ibrutinib, an FDA-approved tyrosine kinase inhibitor, and found that anti-OX40/anti-CTLA-4/ibrutinib therapy further enhanced CD8 + T cell-specific Eomes expression, leading to enhanced tumor regression and improved survival, both of which were associated with increased T-cell effector function across multiple tumor models. Taken together, these data demonstrate the potential of anti-OX40/anti-CTLA-4/ibrutinib as a triple therapy to improve the efficacy of immunotherapy., (©2021 American Association for Cancer Research.)

Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. Clinical trial registration: NCT03884101, NCT03713593, NCT03820986, NCT03776136, NCT03797326, NCT03829319, NCT03829332, NCT03976375, NCT04428151, NCT04199104, NCT03898180, NCT04246177 (ClinicalTrials.gov).

Genetic mutations lead to the production of mutated proteins from which peptides are presented to T cells as cancer neoantigens. Evidence suggests that T cells that target neoantigens are the main mediators of effective cancer immunotherapies. Although algorithms have been used to predict neoantigens, only a minority are immunogenic. The factors that influence neoantigen immunogenicity are not completely understood. Here, we classified human neoantigen/neopeptide data into three categories based on their TCR-pMHC binding events. We observed a conservative mutant orientation of the anchor residue from immunogenic neoantigens which we termed the "NP" rule. By integrating this rule with an existing prediction algorithm, we found improved performance in neoantigen prioritization. To better understand this rule, we solved several neoantigen/MHC structures. These structures showed that neoantigens that follow this rule not only increase peptide-MHC binding affinity but also create new TCR-binding features. These molecular insights highlight the value of immune-based classification in neoantigen studies and may enable the design of more effective cancer immunotherapies., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Since the publication of the Society for Immunotherapy of Cancer's (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients., Competing Interests: Competing interests: SHL – Consulting: Amgen, Merck, Genmab, Xencor, Bristol-Myers Squibb, Regeneron; Funding support: Bristol-Myers Squibb, Merck, Vaccinex; Contracted research: Astellas, Merck, Xencor, Boehringer Ingelheim, Kite Pharma, Vedanta. SB – Employee: Roche Tissue Diagnostics. SG – Funding: Bristol-Myers Squibb, Rexahn, Incyte, Novartis, LSK BioPharma, Five Prime, Mirati, QED Bioscience, Debiopharm, Merck, Pfizer, AstraZeneca, MedImmune, Clovis, and Immunocore; Spouse stock ownership: Salarius Pharmaceuticals. BAH – Research funding: Merck, GlaxoSmithKline, Tempest Therapeutics, Leap Therapeutics, A*STAR Singapore, Sanofi; Consulting fees: Novartis, Merck, G1 Therapeutics. SJ – President and owner: ZellNet Consulting, Inc. TOK – Owner: Biolab Services; Employee: Immodulon Therapeutics. YK – Travel funds: AgonOx, Beckman Coulter; Consulting: Curiox; Research and travel funding: Shimadzu Corporation; Research funding from Bristol-Myers Squibb. YDM – President and owner: FlowKnowHow LLC; Business relationship ZellNet Consulting, Inc. RDN – Shareholder: Eli Lilly, Bristol-Myers Squibb. TS – Employee: Regeneron; IP rights: Regeneron; Sockholder: Regeneron. HTM – Scientific advisory board: Cytek, Inc., Caris Life Sciences; Stockholder: BD Biosciences; Spouse employed by: AbbVie Inc. KD, JCJBG, AWL, CM, SRS, YZ – Nothing to disclose. SITC Staff: AK, BL, LL, RL, SMW – Nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated Ags. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor Ags, and migrate to the tumor draining lymph node to initiate cross-priming of tumor-reactive cytotoxic CD8 + T cells. In this study, we report that radiation therapy promotes the activation of intratumoral cDC1s in radioimmunogenic murine tumors, and this process fails to occur in poorly radioimmunogenic murine tumors. In poorly radioimmunogenic tumors, the adjuvant polyinosinic-polycytidylic acid overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1 and CD8 + T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and polyinosinic-polycytidylic acid significantly expands the proportion of proliferating CD8 + T cells in the tumor with enhanced cytolytic potential and requires T cell migration from lymph nodes for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly radioimmunogenic tumors, and coadministration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5 flox/flox (ALK5 ΔCD8 ) mice reject tumors in high proportions, dependent on CD8 + T cells. ALK5 ΔCD8 mice have more tumor-infiltrating effector CD8 + T cells, with more cytotoxic capacity. ALK5-deficient CD8 + T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5 ΔCD8 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8 + T cells, thereby limiting their trafficking into tumors.

A malignant tumor consists of malignant cells as well as a wide array of normal host tissues including stroma, vasculature, and immune infiltrate. The interaction between cancer and these host tissues is critical as these host tissues play a variety of roles in supporting or resisting disease progression. Radiotherapy (RT) has direct effects on malignant cells, but, also, critically important effects on these other components of the tumor microenvironment (TME). Given the growing role of immune checkpoint inhibitors and other immunotherapy strategies, understanding how RT affects the TME, particularly the immune compartment, is essential to advance RT in this new era of cancer therapy. The interactions between RT and the TME are complex, affecting the innate and adaptive arms of the immune system. RT can induce both proinflammatory effects and immune suppressive effects that can either promote or impede antitumor immunity. It is likely that the initial proinflammatory effects of RT eventually lead to rebound immune-suppression as chronic inflammation sets in. The exact kinetics and nature of how RT changes the TME likely depends on timing, dose, fractionation, site irradiated, and tumor type. With increased understanding of the effects of RT on the TME, in the future it is likely that we will be able to personalize RT by varying the dose, site, and timing of intervention to generate the desired response to partner with immunotherapy strategies., (Copyright © 2019. Published by Elsevier Inc.)

Immunotherapies are rapidly entering the clinic as approved treatments for diverse cancer pathologies. Radiation therapy is an integral partner in cancer therapy, commonly as part of complicated multimodality approaches that optimize patient outcomes. Preclinical studies have demonstrated that the success of radiation therapy in tumor control is due in part to immune mechanisms, and that outcomes following radiation therapy can be improved through combination with a range of immunotherapies. However, preclinical models of cancer are very different from patient tumors, and the way these preclinical tumors are treated is often very different from standard of care treatment of patients. This review examines the preclinical and clinical data for the role of the immune system in radiation therapy outcomes, and how to integrate preclinical findings into clinical trials, using ongoing studies as examples., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors., Patients and Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m 2 ) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1., Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients., Conclusions: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable., (©2019 American Association for Cancer Research.)

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Sting gt/gt mice, but not in Cgas -/- mice. Abolishing cGAMP production in Cgas -/- tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy., Competing Interests: Declaration of Interests All authors, except J.P. and H-M.H., were employees of Genentech., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Surgery remains a primary modality of treatment for the majority of solid tumor malignancies. While advancements in surgical technique and instrumentation have improved the quality of life for cancer patients, local tumor recurrence and metastasis after surgery remain challenging and result in a high rate of mortality and decrease quality of life. It is therefore urgent to explore effective methods to eliminate residual microscopic disease in the surgical site and/or circulating tumor cells (CTCs) to inhibit tumor recurrence and minimize the risk of distant metastasis. Recently, advances in bioengineering technology have facilitated the development of drug delivery systems (DDSs) for the release of chemotherapy and immunotherapy agents, which could be used to enhance the effectiveness of surgical resection. In this review, we survey the rapidly evolving fields of local and systemic controlled DDSs, utilizing a variety of formulations and devices, such as implantable wafers, injectable/sprayable hydrogels, micro/nanoparticles, and cellular particles. Opportunities and challenges for the clinical translations of these delivery systems are also discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

OX40 is a costimulatory molecule from the TNFR family. In mice, it is expressed on Foxp3 + regulatory T cells (Tregs) constitutively and on conventional CD4 (Tconv) and CD8 T cells after Ag encounter. OX40 agonists are in clinical development to enhance antitumor immune responses, and one proposed mechanism of action is loss of Treg suppressive function. Studies have postulated that agonist OX40 therapy can impair Treg suppressive function. Using tools developed since the initial studies were published, we evaluated a direct effect of OX40 agonism on Treg function. We conclude that OX40 agonist Abs do not intrinsically impair Treg function but rather enhance Tconv cell IL-2 production, increasing Treg and Tconv cell proliferation. OX40-stimulated Tregs retain suppressive function, but also gain IFN-γ, TNF-α, and granzyme B expression. These data help resolve mechanistic questions regarding OX40 agonist immunotherapy and thus are relevant to developing combination therapies that target distinct T cell functions., (Copyright © 2019 by The American Association of Immunologists, Inc.)

An enduring goal of personalized medicine in cancer is the ability to identify patients who are likely to respond to specific therapies. Our growing understanding of the biology and molecular signatures of individual tumor types has facilitated the identification of predictive biomarkers and has led to an increasing number of diagnostic tests to be performed, often as serial and distinct assays on limited tumor specimens. The biomarker diagnostics field has been revolutionized by next-generation sequencing (NGS), which provides a comprehensive overview of the genomic profile of a tumor. Many preanalytic variables can influence the accuracy and reliability of NGS results. Standardization of preanalytic variables is, however, complicated by the plethora of specimen acquisition and processing methods. Variables across the tissue journey, including specimen acquisition, specimen fixation, and sectioning, as well as postfixation processing, such as nucleic acid extraction, library preparation, and choice of sequencing methods, are critical for the reliability of NGS analysis; thus, standardization would be beneficial. In this article, each step in the tissue journey is outlined, with specific focus on preanalytic variables that can influence NGS results. Practical considerations for standardization of these variables are provided to facilitate accurate, reliable, and reproducible NGS-based molecular characterization of tumors, ultimately informing diagnosis and guiding treatment., (Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: CD4 + T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4 + T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4 + T cells in the tumor microenvironment., Methods: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4 + T cells to examine the function and mechanism of TRAPs in CD4 + T cell differentiation and function. TRAPs-elicited CD4 + T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model., Results: Heat shock protein 90α (HSP90α) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4 + T cell production of IL-6 via a TLR2-MyD88-NF-κB signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4 + T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4 + T cells inhibited CD4 + and CD8 + effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4 + T cells markedly retarded tumor growth. Furthermore, B cell or CD4 + T cell depletion impeded tumor growth by increasing effector T cell function., Conclusions: HSP90α on the surface of TRAPs programs the immunosuppressive functions of CD4 + T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90α represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.

Immune checkpoint inhibitors (ICIs) are therapeutic antibodies that target regulatory molecules on T cells and represent the most widely used FDA-approved class of immunotherapy. ICIs are associated with unique immune-mediated toxicities called immune-related adverse events. These toxicities may affect any organ system, and their precise mechanisms of action remain under investigation. Current evidence suggests that activation of T cells is involved, although other components of the immune response have been implicated. This article summarizes toxicities, potential mechanisms of action, management strategies, and other clinical considerations. Unique mechanisms of action and immune-related toxicities of other FDA-approved classes of immunotherapy are reviewed., (Copyright © 2019 Elsevier Inc. All rights reserved.)