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Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4 + and/or CD8 + T cells, in 71% of patients, most of them undetectable at baseline. Responses were detectable up to 23 months after treatment initiation. CD8 + T cells specific for several neoantigens constituted a median of 7.3% of circulating CD8 + T cells, reaching up to 23% in some patients. Autogene cevumeran-induced T cells were found within tumor lesions constituting up to 7.2% of tumor-infiltrating T cells. Clinical activity was observed, including one objective response in monotherapy dose escalation and in two patients with disease characteristics unfavorable for response to immunotherapy treated in combination with atezolizumab. These findings support the continued development of autogene cevumeran in earlier treatment lines. ClinicalTrials.gov registration: NCT03289962 ., Competing Interests: Competing interests: J.L. reports research funding to their institution from Roche-Genentech, Basilea, Astex, Merck, GSK, Eisai, Seagen, Immunocore, BicycleTx, AstraZeneca, Genmab, Bayer, Jansenn, Gilead, Anaveon, Affimed, Appollomics, Avacta, Byondis, Chugai, CellCentric, Daiichi, Iteos, Merck Serono, REDX, and Amgen, and a consulting and advisory role for Basilea, Roche-Genentech, Ellipses, Eisai, Pierre-Faber and GSK. T.P. reports a consulting and advisory role for Astellas Pharma, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup Ltd, Merck Serono, MSD, Novartis, Pfizer, Roche and Seattle Genetics; travel, accommodation or expenses from Ipsen, MSD, Pfizer and Roche; and research funding from Astellas Pharma, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, Seattle Genetics. F.B. reports speaking engagements and advisory boards for Roche/Genentech, BMS, Lilly, EMD Serono, AstraZeneca and Regeneron, Merck, Seagen, Jazz Pharmaceuticals, Taiho, Incyte Deciphera and Astellas. L.L.S. reports a consulting and advisory role for Merck, Pfizer, AstraZeneca, Roche, GlaxoSmithKline, Voronoi, Arvinas, Navire, Relay, Daiichi Sankyo, Coherus, Amgen, Marengo, Medicenna, Tubulis, LTZ Therapeutics and Pangea; grants or support for clinical trials to their institution from Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Mirati, BioNTech, 23Me and EMD Serono; stock ownership (spouse) of Agios; and leadership (spouse) at Treadwell Therapeutics. P.L. has served on the advisory boards of Abbvie, GenMab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Inc, Zentalis Pharmaceuticals, Molecular Templates, STCube Pharmaceuticals, Bayer, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials and Actuate Therapeutics; on the data safety monitoring board for Agios, Five Prime, Halozyme and Tyme; and as a consultant for Roche-Genentech, SOTIO, SK Life Science and Roivant Sciences. C.F.F. reports a consulting and advisory role (self) for Seagen, Aadi Biosciences, Genentech/MyPathway (uncompensated) and Merck/LYNK-002 (uncompensated), and institutional funding from Bristol Myers Squibb, Daiichi, Hotspot Therapeutics, Marengo, AstraZeneca, Genentech/Roche, Immunocore, Seagen and Merck. A.S.B. reports serving on a speakers bureau for Genentech, BMS, Mirati, AstraZeneca, Regeneron and Merck and consulting for Pfizer and Abbvie, and is on a steering committee for Janssen. M.G. reports clinical trial support to their institution from Genentech/Roche, GSK, Abbvie, Merck Serono, Medimmune, Incyte, Pfizer, Amgen, Gilead Sciences, Zai Labs, Adanate, Fog Pharma, PEEL, Orionis, SQZ, YMABS, Iovance, Vincerx, Werewolf, Endocyte, Seattle Genetics, Plexxicon/Daiichi, Celldex, Tracon, Deciphera, Fujifilm, Minnemarita, Nektar, Novita, Biosplice, Corcept, Novartis, Toray, Genzada, Salarius, Agenus, Inhibrx, AADI, Revolution Medicine, Blueprint, Astellas, BioNTech, Helix, IgM Biosciences, ImmuneSensor, Bioeclipse, Bioline, Black Diamond, Codiak, Dracen, Elevation Oncology, Famewave, Forma Therapeutics, IntraImmun SG, Pionyr, Trishula, Tolero, Vedanta Biosciences, Coordination Therapeutics, Ideaya Biosciences, I-Mab, NiKang, Nimbus Therapeutics, OncoResponse, Riboscience, Rubius Therapeutics, Simcha Therapeutics, Siranomics, Synthorx and Theseus Pharmaceuticals; consulting fees from Pfizer, Imaging Endpoints and Curio; honoraria from Lisa Stearns Academy; a patent with Sphinx Health Solutions; and advisory boards for Daiichi, Qualigen, Springworks, Cardinal Healthcare, IQVIA and Medtronics. I.K. reports consulting fees from and serving in a speakers bureau for Delcath Inc., Immunocore Ltd and Pierre Fabre Inc; educational grants from BMS and Novartis; and travel grants from Delcath Inc, Genentech Inc, BMS and Merck Serono. G.A.F. reports serving on a data safety monitoring board for AstraZeneca and Hutchison Pharma and advisory boards for Bristol Myers Squibb and Merck. M. Schmidt reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and SeaGen outside the submitted work; institutional research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre and SeaGen; and a patent for EP 2390370 B1 filed for EP 2951317 B1 filed. M. Schuler received consulting fees from Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda and Tacalyx; honoraria from Amgen, Bristol Myers Squibb, Janssen, MSD, Novartis, Roche and Sanofi; and research funding to their institution from AstraZeneca, Bristol Myers Squibb and Janssen. R.J.S. served as a consultant and in advisory boards for Marengo, Merck, Novartis, Pfizer and Replimune and has received research funding to their institution from Merck. H.B. reports research funding to their institution from AbbVie, Agios, ARMO Biosciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, BioTheryX, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, Celgene, CicloMed, Coordination Pharmaceuticals, eFFECTOR Therapeutics, Lilly, EMD Serono, Roche/Genentech, GlaxoSmithKline, Gossamer Bio, Harpoon Therapeutics, Hengrui Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicines, Ryvu Therapeutics, Foundation Medicine, SeaGen, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals, Xbiotech and Zymeworks; consulting (uncompensated) for Bristol Myers Squibb, Novartis and TG Therapeutics; consulting (payments to institution) for AstraZeneca, GRAIL, Incyte, Roche and Vincerx Pharma; and stock ownership in HCA Healthcare. V.G. reports institutional support from Seagen Inc., SOTIO Biotech AG, Shattuck Labs, Inc., T-knife GmbH, F. Hoffmann-La Roche Ltd, Janssen Research & Development, LLC, Novartis, Affimed GmbH, Anaveon AG, BioNTech SE, BicycleTx Ltd, Epizyme, Inc., Regeneron Pharmaceuticals, Inc., Boehringer Ingelheim, Genmab, Pieris Pharmaceuticals, Inc., Celgene Corporation, Debiopharm International S.A., F-star Therapeutics Limited, ImCheck Therapeutics, Gilead Sciences, Inc and Sanofi-Aventis Recherche & Développement. B.S.H. reports a consulting and advisory role for AstraZeneca, Ideaya, Jazz Pharmaceuticals, Sorrento Therapeutics, Genentech-Roche, OncLive, Veeva, Athenium, Boxer Capital, SAI-Med and DAVA Oncology, and research funding to their institution from NexImmune, Genentech-Roche, Johnson & Johnson, BMS Foundation/VCU, Stand Up 2 Cancer, V Foundation and National Cancer Institute. P.A.O. reports consulting for Array, Bristol Myers Squibb, Celldex, CytomX, Evaxion, Genentech, Imunon, Merck, MyNEO, Neon Therapeutics, Novartis, Pfizer, Phio, TRM Oncology and Servier, and grant and research support to their institution from Agenus, AstraZeneca/MedImmune, Bristol Myers Squibb, Celldex, CytomX, Genentech, Merck, Neon Therapeutics, Novartis and Pfizer. G.J. received consulting fees from Novartis, Amgen, Roche, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, Abbvie, Seagen and Diaccurate; honoraria from Novartis, Amgen, Roche, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, Abbvie and Seagen; and travel support from Novartis, Roche, Pfizer, Lilly, Amgen, Bristol Myers Squibb and AstraZeneca; served on a board for Novartis, Roche, Pfizer, Lilly, Amgen, Bristol Myers Squibb and AstraZeneca; and received materials or services from Novartis, Roche, Lilly, Amgen, Bristol Myers Squibb and AstraZeneca. L.F. reports research support from Abbvie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck and Roche/Genentech, and ownership interests in Actym, Atreca, Bioatla, Bolt, Immunogenesis, Nutcracker, RAPT, Scribe and Senti. N.S. provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte and Luszana, and received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho and Takeda (all outside the submitted work; payment was made to the Netherlands Cancer Institute). R.S.L. reports research and grant funding from Bristol Myers Squibb, Clinigen, Celldex, Incyte and Ubivac, and consulting and advisory roles for Bristol Myers Squibb, Merck, CDR-Life and Vir. A.R. was a consultant and advisor for AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Daichi Sankyo, Eli Lilly, GSK, MSD, Novartis, Pfizer and Roche/Genentech. S.A.L. reports funding to their institution from Roche/Genentech. R.A. is a primary investigator on S1933 (atezolizumab). I. Melero reports grants from Roche, BMS, Genmab and AstraZeneca, and was a consultant for Roche, BMS, Genmab, AstraZeneca, Biontech, Pharmamar, F-Star, Numab, Mestag, Curon and Bright Peaks. R.L.S., I.R., M.R.M., L. Muller, G.D.F., M.Y., L.K., V.J.P.L., A.R., M.D., T.Q., J. Zhu, J. Zhang, P.T., G.K.R., D.W.L., C.P., A.A.L., J.M.S., L.D. and I. Mellman are or were employees of Genentech, Inc. and are or were Roche stockholders. L. Muller is now an employee and shareholder of Gilead Sciences. G.D.F. reports stock ownership in CARGO Therapeutics. F.M., E.D., A.C., L. Manning, D.M., S.B., V.L., T.O., E.G., D.B., C.H., C.W., C.A., C.K., A.D.T., J.D., M.V., A.J., A.P., J.B., O.H., A.N.K., U.S. and Ö.T. are employees of BioNTech, a company developing immunotherapies against cancer and other diseases, and may hold securities in the company. U.S. and Ö.T. are management board members of BioNTech SE (Mainz, Germany). M.L., M.V., A.D.T., J.D., A.N.K., U.S. and Ö.T. are co-authors on various issued or pending patents that cover parts of this Article. D.R.C. served on advisory boards and consulted for Roche/Genentech. J.Y., S.R., L.D., D.J., K.M.W., A.S. and E.G. report no competing interests., (© 2025. Genentech, Inc. and the Author(s).)

Introduction: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with disease progression on/after osimertinib and platinum-based chemotherapy are limited., Methods: CHRYSALIS-2 Cohort A evaluated amivantamab+lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on/after osimertinib and platinum-based chemotherapy. Primary endpoint was investigator-assessed objective response rate (ORR). Patients received intravenous amivantamab 1050 mg (1400 mg if ≥80 kg) plus oral lazertinib 240 mg., Results: In Cohort A (n=162), investigator-assessed ORR was 28% (95% CI, 22-36). Blinded independent central review (BICR)-assessed ORR was 35% (95% CI, 27-42), with median duration of response (DoR) of 8.3 months (95% CI, 6.7-10.9) and clinical benefit rate of 58% (95% CI, 50-66). At a median follow-up of 12 months, 32/56 responders (57%) achieved a DoR ≥6 months. Median progression-free survival by BICR was 4.5 months (95% CI, 4.1-5.8); median overall survival was 14.8 months (95% CI, 12.2-18.0). Preliminary evidence of central nervous system-anti-tumor activity was reported among 7 patients with baseline brain lesions and no prior brain radiation/surgery. Exploratory biomarker analyses using circulating tumor DNA next-generation sequencing showed responses in patients with and without identified EGFR/MET-dependent resistance. Most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). Most common grade ≥3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%)., Conclusions: For patients with limited treatment options, amivantamab+lazertinib demonstrated anti-tumor activity with a safety profile characterized by EGFR/MET-realated adverse events, which were generally manageable., (Copyright © 2024. Published by Elsevier Inc.)

Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells., Competing Interests: Competing interests: All authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The uniqueness in each person's cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through release of innate adjuvants. The extranuclear DNA that can result from radiation damage of cells can result in production of the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) by cyclic GMP-AMP synthase (cGAS). In turn, cGAMP can activate the innate sensor stimulator of interferon genes (STING), resulting in innate immune activation. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is a phosphodiesterase that can be expressed by cancer cells that can degrade cGAMP, thus can decrease or block STING activation following radiation therapy, impairing the innate immunity that is critical to support adaptive immune control of tumors. We observed that many human and murine cancer cells lack Enpp1 expression, but that Enpp1 is expressed in cells of the tumor stroma where it limits tumor control by radiation therapy. We demonstrate in preclinical models the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. This mechanism requires STING and type I interferon (IFN) receptor expression by non-cancer cells and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1. This broadens the potential patient base for whom Enpp1 inhibitors can be applied to improve innate immune responses following radiation therapy., Competing Interests: Declarations. Competing interests: The work was funded in part by a sponsored research agreement with VIR Biotechnology Inc. In addition, the research was funded in part by NCI R01CA182311, NCI R01CA244142, R01CA208644, R21CA277250, and by the Providence Foundation. MJG receives research funding from Bristol Myers Squibb. MRC receives consulting fees from Roche. Authors listed as employees of VIR Biotechnology Inc. and may own stock or other interests in VIR Biotechnology. Authors have no additional conflicts to declare., (© 2024. The Author(s).)

Abstract: Myelofibrosis (MF) in the chronic phase is a challenging disease to treat, and conventional treatment options are geared toward symptom palliation. In this prospective, multicenter, phase 2 trial, 21 patients with MF (18 chronic phase, 2 accelerated phase, and 1 blast phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg per day. The overall response rate was 33% (95% confidence interval, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44). A high International Prognostic Scoring System risk score, high baseline fetal hemoglobin level, and sustained decrease in circulating CD34+ cell counts were associated with response to decitabine. All patients experienced at least 1 grade 3/4 cytopenia. Nonhematologic toxicities were less frequent, with fatigue, anorexia, and hypocalcemia being the most common. Given the lack of effective therapies in MF with severe cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. This trial was registered at www.ClinicalTrials.gov as #NCT00095784., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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.)

Biomedical image analysis is fundamental for biomedical discovery. Holistic image analysis comprises interdependent subtasks such as segmentation, detection and recognition, which are tackled separately by traditional approaches. Here, we propose BiomedParse, a biomedical foundation model that can jointly conduct segmentation, detection and recognition across nine imaging modalities. This joint learning improves the accuracy for individual tasks and enables new applications such as segmenting all relevant objects in an image through a textual description. To train BiomedParse, we created a large dataset comprising over 6 million triples of image, segmentation mask and textual description by leveraging natural language labels or descriptions accompanying existing datasets. We showed that BiomedParse outperformed existing methods on image segmentation across nine imaging modalities, with larger improvement on objects with irregular shapes. We further showed that BiomedParse can simultaneously segment and label all objects in an image. In summary, BiomedParse is an all-in-one tool for biomedical image analysis on all major image modalities, paving the path for efficient and accurate image-based biomedical discovery., Competing Interests: Competing interests C.B. is a member of the scientific advisory board and owns stock in PrimeVax and BioAI; is on the scientific board of Lunaphore and SironaDx; has a consultant or advisory relationship with Sanofi, Agilent, Roche and Incendia; contributes to institutional research for Illumina, and is an inventor on US patent applications US20180322632A1 (Image Processing Systems and Methods for Displaying Multiple Images of a Biological Specimen) filed by Ventana Medical Systems, Providence Health and Services Oregon and US20200388033A1 (System and Method for Automatic Labeling of Pathology Images) filed by Providence Health and Services Oregon, Omics Data Automation. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A + CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39 + CD103 + double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A - and NKG2A + DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-β-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation., Competing Interests: Competing interests The authors declare not competing interests., (© 2024. The Author(s).)

Background: For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive., Methods: To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models., Results: Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates., Competing Interests: Competing interests: JBL has received grant funding from Merck, AstraZeneca, Precigen, ArsenalBio, Volastra, Nurix, Aminex Therapeutics through his institution and is a consultant for Verismo Therapeutics. JD is employed by Grail. SS has received grant funding from Veana, IMV Inc, and Stanford Burnham Prebys. MLD has grant funding from Precigen, Veanna, Bavarian Nordic, and Aston Sci. MLD also holds shares in Epithany and is an inventor on patents held by the University of Washington. The authors declare there are no other competing interests., (© 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.

Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy., Patients and Methods: Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point., Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively., Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Purpose: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS)., Methods: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR -mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis., Results: At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug., Conclusion: Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR -mutant NSCLC. The combination is safe and well tolerated.

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.

Purpose: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor., Patients and Methods: This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy., Results: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7-46.9), and the objective response rate as assessed by independent radiological review using RECIST version 1.1 was 72%., Conclusions: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT not amenable to surgery., (©2024 The Authors; Published by the American Association for Cancer Research.)

The thymus is the central organ involved with T-cell development and the production of naïve T cells. During normal aging, the thymus undergoes marked involution, reducing naïve T-cell output and resulting in a predominance of long-lived memory T cells in the periphery. Outside of aging, systemic stress responses that induce corticosteroids (CS), or other insults such as radiation exposure, induce thymocyte apoptosis, resulting in a transient acute thymic involution with subsequent recovery occurring after cessation of the stimulus. Despite the increasing utilization of immunostimulatory regimens in cancer, effects on the thymus and naïve T cell output have not been well characterized. Using both mouse and human systems, the thymic effects of systemic immunostimulatory regimens, such as high dose IL-2 (HD IL-2) with or without agonistic anti-CD40 mAbs and acute primary viral infection, were investigated. These regimens produced a marked acute thymic involution in mice, which correlated with elevated serum glucocorticoid levels and a diminishment of naïve T cells in the periphery. This effect was transient and followed with a rapid thymic "rebound" effect, in which an even greater quantity of thymocytes was observed compared to controls. Similar results were observed in humans, as patients receiving HD IL-2 treatment for cancer demonstrated significantly increased cortisol levels, accompanied by decreased peripheral blood naïve T cells and reduced T-cell receptor excision circles (TRECs), a marker indicative of recent thymic emigrants. Mice adrenalectomized prior to receiving immunotherapy or viral infection demonstrated protection from this glucocorticoid-mediated thymic involution, despite experiencing a substantially higher inflammatory cytokine response and increased immunopathology. Investigation into the effects of immunostimulation on middle aged (7-12 months) and advance aged (22-24 months) mice, which had already undergone significant thymic involution and had a diminished naïve T cell population in the periphery at baseline, revealed that even further involution was incurred. Thymic rebound hyperplasia, however, only occurred in young and middle-aged recipients, while advance aged not only lacked this rebound hyperplasia, but were entirely absent of any indication of thymic restoration. This coincided with prolonged deficits in naïve T cell numbers in advanced aged recipients, further skewing the already memory dominant T cell pool. These results demonstrate that, in both mice and humans, systemic immunostimulatory cancer therapies, as well as immune challenges like subacute viral infections, have the potential to induce profound, but transient, glucocorticoid-mediated thymic involution and substantially reduced thymic output, resulting in the reduction of peripheral naive T cells. This can then be followed by a marked rebound effect with naïve T cell restoration, events that were shown not to occur in advanced-aged mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Collins, Khuat, Sckisel, Vick, Minnar, Dunai, Le, Curti, Crittenden, Merleev, Sheng, Chao, Maverakis, Rosario, Monjazeb, Blazar, Longo, Canter and Murphy.)

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.)

Diabetes-related bone loss represents a significant complication that persistently jeopardizes the bone health of individuals with diabetes. Primary cilia proteins have been reported to play a vital role in regulating osteoblast differentiation in diabetes-related bone loss. However, the specific contribution of KIAA0753, a primary cilia protein, in bone loss induced by diabetes remains unclear. In this investigation, we elucidated the pivotal role of KIAA0753 as a promoter of osteoblast differentiation in diabetes. RNA sequencing demonstrated a marked downregulation of KIAA0753 expression in pro-bone MC3T3 cells exposed to a high glucose environment. Diabetes mouse models further validated the downregulation of KIAA0753 protein in the femur. Diabetes was observed to inhibit osteoblast differentiation in vitro, evidenced by downregulating the protein expression of OCN, OPN and ALP, decreasing primary cilia biosynthesis, and suppressing the Hedgehog signalling pathway. Knocking down KIAA0753 using shRNA methods was found to shorten primary cilia. Conversely, overexpression KIAA0753 rescued these changes. Additional insights indicated that KIAA0753 effectively restored osteoblast differentiation by directly interacting with SHH, OCN and Gli2, thereby activating the Hedgehog signalling pathway and mitigating the ubiquitination of Gli2 in diabetes. In summary, we report a negative regulatory relationship between KIAA0753 and diabetes-related bone loss. The clarification of KIAA0753's role offers valuable insights into the intricate mechanisms underlying diabetic bone complications., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 ., (© 2024. The Author(s).)

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy., (© 2024. The Author(s).)

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.)