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Purpose: In early-stage, triple-negative breast cancer (TNBC), immune cell infiltration contributes to cancer cell survival, tumor invasion, and metastasis. High TNBC glucocorticoid receptor (GR) expression in early-stage TNBC is associated with poor long-term outcomes; it is unknown if high GR expression is associated with an immunosuppressed tumor microenvironment. We hypothesized that high tumor GR expression would be associated with an immune-suppressed tumor microenvironment, which could thus account for the poor prognosis observed in GR-positive TNBC., Methods: Formalin fixed-paraffin embedded tissue (n = 47) from patients diagnosed with early-stage TNBC from The University of Chicago (2002-2014) were evaluated for both tumor cell anti-GR immunohistochemistry and for infiltrating immune cells by immunofluorescence. Multiplexed antibodies were used to enumerate CD8+, FOXP3+, and BATF3+ immune cells infiltrating within pan-cytokeratin positive tumor cell regions of interest, and nonparametric tests compared absolute counts of each of these tumor-infiltrating immune cell types., Results: The average age of patients represented in this study was 52 years, and 63% self-identified as Black. There was no significant association between tumor GR expression and age, race, or clinical stage at diagnosis. Compared to GR-low tumors, high GR expression in early-stage, treatment-naïve TNBC was associated with relatively increased numbers of immunosuppressive FOXP3 + regulatory T cells (p = 0.046) and BATF3+immune cells (p = 0.021). While there was a positive correlation with high GR expression and CD8+ cell infiltration, it was not significant (p = 0.068). The ratio of CD8+/FOXP3+cells was also not significant (p = 0.24)., Conclusions: These data support the hypothesis that in early-stage TNBC, high GR expression is significantly associated with infiltration of immunosuppressive regulatory T cells, suggesting a tumor-intrinsic role in shaping the immunosuppressive immune cell milieu. Furthermore, suppression of GR activity may regulate the tumor immune microenvironment and improve long-term outcomes in GR-high TNBC., Competing Interests: Declarations. Competing interests: Margarite Matossian, Christine Shiang, Deniz Nesli Dolcen, Ken Hatogai, Katie Hall, Theodore Karrison and Anna Biernacka, Poornima Saha declare they have no financial interests. Randy F. Sweis reports consulting fees from, Astellas, AstraZeneca, Aveo, BMS, EMD Serono, Editas, Exelixis, Gilead, Eisai, Janssen, Loxo, Lilly, Mirati, Pfizer, Silverback, and Seattle Genetics. Randy F. Sweis reports research support (to institution) from Ascendis, ALX Oncology, Astellas, AstraZeneca, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, Scholar Rock, QED Therapeutics. Randy F. Sweis reports the following patents: Neoantigens in Cancer, PCT/US2020/031357. Rita Nanda has served on advisory boards for Astrazeneca, BeyondSpring, Daiichi Sankyo, Exact Sciences, Fujifilm, GE, Gilead, Guardant Health, Infinity, iTeos, Merck, Moderna, Novartis, OBI, Oncosec, Pfizer, Sanofi, Seagen, Stemline, and she has research funding from Arvinas, AstraZeneca, BMS, Corcept Therapeutics, Genentech/Roche, Gilead, GSK, Merck, Novartis, OBI Pharma, OncoSec, Pfizer, Relay, Seattle Genetics, Sun Pharma, Taiho. Nan Chen has received consultant fees from Stemline Therapeutics, Guardant Health, Novartis, and Seagen. Nan Chen has received institutional research funding from Eli Lilly. S.D. Conzen is a co-inventor of patents issued to The University of Chicago for methods and compositions related to GR antagonists and breast cancer., (© 2024. The Author(s).)

Background: We evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas., Methods: This first-in-human study (NCT03249792) enrolled patients with refractory, advanced solid tumors or lymphomas. Patients received intratumoral (IT) MK-2118 100-20,000 µg (arm 1), IT MK-2118 900-15,000 µg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W; arm 2), or subcutaneous (SC) MK-2118 5000-150,000 µg plus IV pembrolizumab 200 mg Q3W (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. Primary objectives were safety/tolerability. MK-2118 pharmacokinetics were a secondary endpoint; objective responses and biomarkers were exploratory endpoints., Results: 140 patients were enrolled (arm 1, n=27; arm 2, n=57; arm 4, n=56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of patients, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 µg across the 3 arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and SC administration. Objective responses were seen in 0%, 6%, and 4% of patients, respectively. IT MK-2118 led to dose-dependent changes in STING-based blood RNA expression levels, interferon-gamma, interferon-gamma‒induced protein 10, and interleukin-6; SC MK-2118 did not generate dose-related immune responses., Conclusion: IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.

Purpose: Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (Cancer Immunotherapy Trials Network-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses., Patients and Methods: Patients with urothelial cancer after platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by the objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines., Results: CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities and lower grade 3 to 4 treatment-related adverse events compared with atezolizumab monotherapy. The ORR was 26.3% for the combination therapy versus 23.8% for atezolizumab alone (P = 0.428). The complete response rate was 10.5% for the combination therapy versus 4.8% for monotherapy. Three patients on combination therapy had responses >21 months versus one with monotherapy. CD4+ and CD8+ T-lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cells. Patients who responded to treatment exhibited elevated baseline levels of CCL4 and reduced levels of VEGFA and TNF., Conclusions: Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the complete response rate, and durable responses exceeding 2 years. However, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated., (©2024 American Association for Cancer Research.)

Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified PKCδ as a candidate. Genetic deletion of PKCδ in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of PKCδ in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ KO-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.

Background: Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. Whether pembrolizumab as adjuvant therapy would be effective in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery is unknown., Methods: In this phase 3 trial, we randomly assigned patients, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks for 1 year or to undergo observation. Randomization was stratified according to pathological stage, centrally tested programmed death ligand 1 (PD-L1) status, and previous neoadjuvant chemotherapy. The coprimary end points were disease-free survival and overall survival in the intention-to-treat population. We considered the trial to be successful if either disease-free survival or overall survival was significantly longer with pembrolizumab than with observation., Results: A total of 702 patients underwent randomization; 354 were assigned to receive pembrolizumab, and 348 were assigned to observation. As of July 5, 2024, the median duration of follow-up for disease-free survival was 44.8 months. The median disease-free survival was 29.6 months (95% confidence interval [CI], 20.0 to 40.7) with pembrolizumab and 14.2 months (95% CI, 11.0 to 20.2) with observation (hazard ratio for disease progression or death, 0.73; 95% CI, 0.59 to 0.90; two-sided P = 0.003). Grade 3 or higher adverse events (regardless of attribution) occurred in 50.6% of the patients in the pembrolizumab group and in 31.6% of the patients in the observation group., Conclusions: Among patients with high-risk muscle-invasive urothelial carcinoma after radical surgery, disease-free survival was significantly longer with adjuvant pembrolizumab than with observation. (Funded by the National Cancer Institute of the National Institutes of Health and others; Alliance A031501 AMBASSADOR ClinicalTrials.gov number, NCT03244384.)., (Copyright © 2024 Massachusetts Medical Society.)

Importance: The oral pan-fibroblast growth factor receptor inhibitor rogaratinib previously demonstrated encouraging safety and efficacy in a phase 1 study of patients with urothelial cancer (UC) overexpressing FGFR messenger RNA (mRNA)., Objective: To evaluate the safety, pharmacokinetics, and preliminary efficacy of rogaratinib in combination with the programmed cell death 1 ligand 1 (PD-L1) inhibitor atezolizumab in cisplatin-ineligible patients with FGFR mRNA-positive, locally advanced/metastatic UC., Design Setting and Participants: The FORT-2 nonrandomized clinical trial was an open-label, single-arm, multicenter study conducted between May 15, 2018, and July 16, 2021, in 30 centers across Asia, Europe, and North America. Eligible patients had locally advanced/metastatic UC with FGFR1 / 3 mRNA overexpression and were ineligible for cisplatin-based chemotherapy. The data analysis was completed from July 2022 to September 2022., Interventions: Patients received rogaratinib 600 mg or rogaratinib 800 mg twice daily in combination with intravenous atezolizumab 1200 mg every 21 days., Main Outcomes and Measures: Primary end points included safety, tolerability, and the recommended phase 2 dose (RP2D) of rogaratinib in combination with atezolizumab., Results: Among 153 patients screened, 73 (48%) had tumors with FGFR1/3 mRNA overexpression, and 37 patients were enrolled and treated (median [range] age, 75.0 [47.0-85.0] years; 32 [87%] male). The most common treatment-emergent adverse events (TEAEs) included diarrhea in 23 patients (62%), hyperphosphatemia in 19 (51%), and fatigue in 15 (41%). Grade 3 or higher TEAEs were reported in 27 patients (73%), and 4 grade 5 TEAEs were reported, though unrelated to treatment. The RP2D was rogaratinib 600 mg in combination with atezolizumab 1200 mg. At the RP2D, the overall response rate was 53.8% in the rogaratinib 600 mg group, including 4 patients (15%) with complete responses; 12 responders (86%) did not have an FGFR3 gene alteration, and 11 (79%) had low PD-L1 expression., Conclusions and Relevance: In this phase 1b nonrandomized clinical trial, rogaratinib plus atezolizumab demonstrated a manageable safety profile, with no unexpected safety signals. Efficacy for this combination at the RP2D was observed in tumors with low PD-L1 and was not dependent on FGFR3 gene alterations, suggesting broad potential benefit for patients with locally advanced/metastatic UC and FGFR mRNA overexpression., Trial Registration: ClinicalTrials.gov Identifier: NCT03473756., Competing Interests: Conflict of Interest Disclosures: Dr Sweis reported grants paid to institution from Ascendis, AstraZeneca, Astellas, ALX Oncology, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo Oncology, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, QED, Regeneron, and Scholar Rock outside the submitted work; personal fees from AbbVie, Aveo, Eisai, Exelixis, Gilead, Janssen, and Lilly outside the submitted work; and a patent pending for Neoantigens in Cancer (PCT/US2020/031357). Dr Gajate reported personal fees from BMS, Merck, Roche, Pfizer, Astellas, Janssen, and MSD outside the submitted work. Dr Morales-Barrera reported serving in an advisory role for MSD, Pfizer, Merck, Janssen, and Astellas, as well as receiving honoraria or travel expenses from Roche, Sanofi Aventis, Astellas, Janssen, MSD, Bayer, Merck, and Pfizer. Dr de Braud reported personal fees from Pierre Fabre, Mattioli 1885, MSD, IQVIA, BMS, Indena, Incyte, Taiho, Menarini, Novartis, Roche, Sanofi, AccMed, Itanet, ESO, Dephaforum, Nadirex, Events, Fare Comunicazione, Motore Sanità, Effetti, Ambrosetti, Dynamicom Education, and AstraZeneca outside the submitted work. Dr Grünwald reported personal fees from Bristol Myers Squibb, Merck Serono, MSD, AstraZeneca, and Astellas during the conduct of the study; personal fees from AstraZeneca, Gilead, Pfizer, Novartis/AAA, Janssen-Cilag, Amgen, Ipsen, Eisai, Debiopharm, Apogepha, PCI Biotech, Synthekine, and Oncorena outside the submitted work. Dr Rosenberg reported personal fees from Bayer during the conduct of the study; personal fees from Janssen, AstraZeneca, Chugai, Merck, Seagen, Pfizer, Astellas, Genentech/Roche, EMD-Serono, Boehringer Ingelheim, Lilly/Loxo Oncology, Tyra Biosciences, QED Therapeutics, Gilead, Hengrui, Century Therapeutics, and Aktis Consultant outside the submitted work. No other disclosures were reported., (Copyright 2024 Sweis RF et al. JAMA Oncology.)

Background and Purpose: Stereotactic ablative body radiotherapy (SABR) is an effective treatment for localized renal cell carcinoma (RCC). However, the role of primary site SABR for locally recurrent or metastatic RCC is unclear. Here, we report outcomes of primary SABR across a diverse cohort of localized, recurrent, and metastatic RCC patients treated at our institution., Materials and Methods: RCC patients treated with SABR to lesions of the kidney or nephrectomy bed at our institution with at least 6 months of follow-up were included for analysis. Local control, overall survival, and freedom from distant failure were estimated using the Kaplan-Meier method. Estimated glomerular filtration rate (eGFR) was assessed at baseline and following SABR., Results: Fifty-three patients received primary site SABR. Thirty-seven (70 %) patients had localized RCC, and 16 (30 %) had metastatic RCC. Seven (13 %) had locally recurrent RCC after prior surgery or ablation. The median tumor size was 4.5 cm (IQR 3.7-6.3). At a median follow-up of 23 months (IQR 12-35), 2-year local control was 100 %, and 3-year local control was 94.4 % (95 % CI 84.4 %-100 %). Among patients with initially localized disease, the 2-year freedom from distant failure was 94.6 % (95 % CI 87.6 %-100 %), and the 2-year overall survival was 66.5 % (95 % CI 51.9 %-85.2 %). Twelve (23 %) patients experienced acute grade 1-2 treatment-related toxicity (nausea, vomiting, or small bowel). There were no acute grade 3-4 toxicities. Two (3.8 %) patients developed late grade 3 gastrointestinal toxicity. The median baseline eGFR was 51 mL/min/1.73 m 2 (IQR 38-77). At 1-year post-SABR, the median eGFR decline was 5 mL/min/1.73 m 2 (IQR -3 to 9). One patient required dialysis following SABR., Conclusion: This analysis demonstrates excellent local control rates across patients with localized, recurrent, and metastatic RCC treated with SABR. Treatment was associated with minimal eGFR decline., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Walter M. Stadler has acted as a member of the Data and Safety Monitoring Board for AstraZeneca, Merck, Pfizer, and Treadwell Therapeutics, and a consultant for AstraZeneca, Aveo, Caremark/CVS, EMA Wellness, Fortress Biotech, and XenCor. Sean P. Pitroda is co-founder and Chief Medical Officer of PersonaDx (including equity) and reports intellectual property unrelated to the current manuscript., (© 2024 The Author(s).)

Since the introduction of the first immune checkpoint inhibitor (ICI), immunotherapy has changed the landscape of molecular therapeutics for cancers. However, ICIs do not work equally well on all cancers and for all patients. There has been a growing interest in using mathematical and computational models to optimize clinical responses. Ordinary differential equations (ODEs) have been widely used for mechanistic modeling in immuno-oncology and immunotherapy. They allow rapid simulations of temporal changes in the cellular and molecular populations involved. Nonetheless, ODEs cannot describe the spatial structure in the tumor microenvironment or quantify the influence of spatially-dependent characteristics of tumor-immune dynamics. For these reasons, agent-based models (ABMs) have gained popularity because they can model more detailed phenotypic and spatial heterogeneity that better reflect the complexity seen in vivo. In the context of anti-PD-1 ICIs, we compare treatment outcomes simulated from an ODE model and an ABM to show the importance of including spatial components in computational models of cancer immunotherapy. We consider tumor cells of high and low antigenicity and two distinct cytotoxic T lymphocyte (CTL) killing mechanisms. The preferred mechanism differs based on the antigenicity of tumor cells. Our ABM reveals varied phenotypic shifts within the tumor and spatial organization of tumor and CTLs despite similarities in key immune parameters, initial simulation conditions, and early temporal trajectories of the cell populations.

Background and Objective: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC., Methods: The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously)., Key Findings and Limitations: The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients., Conclusions and Clinical Implications: Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied., Patient Summary: In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity., Results: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response., Conclusions: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response., (©2024 American Association for Cancer Research.)

The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8 + T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3 + DCs and CD8 + T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3 + DCs within the TME is associated with CD8 + T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3 + DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process., Competing Interests: Declaration of interests T.F.G. has served on scientific advisory boards for Pyxis Oncology, Jounce Therapeutics, Allogene, MAIA, Samyang, Portal Innovations, Fog Pharma, Adaptimmune, Catalym, Bicara, and Merck; is a scientific co-founder and shareholder of Jounce Therapeutics and Pyxis Oncology; and has received research support from Bristol-Myers Squibb, Merck, Pyxis, FogPharma, and Bayer. K.H. is currently working at Merck, and D.E.C.K. is currently working at Slalom., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine., Materials and Methods: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m 2 ) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method., Results: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities., Conclusion: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity., Competing Interests: Disclosure Walter M. Stadler: consultant for Astra-Zeneca, Merck, Pfizer, Treadwell Therapeutics, Caremark/CVS, EMA Wellness, Fortress Biotech; speaker's bureau for Dava Oncology, Global Academy for Medical Education, OncLive, PeerView, Research to Practice, Vindico; Grant/research support to the institution from Abbvie, Amgen, Astra-Zeneca, Astellas (Medivation), Bayer, Bristol-Myers-Squibb, Boehringer-Ingelheim, Calithera, Clovis, Corvus, Eisai, Exilixis, Genentech (Roche), Johnson & Johnson (Janssen), Merck, Novartis, Pfizer, Seattle Genetics, X4Pharmaceuticals, Xencor; stockholder in Fortress Biotech Peter H. O'Donnell: reports past research funding from the Translational Breast Cancer Research Consortium to perform pharmacogenomic studies related to capecitabine. The other authors does not have conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 that depletes tumor-associated macrophages. In this study, the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC. Eligible patients had clear cell RCC with disease progression on prior CPI either in combination or sequentially with VEGF-TKI. Patients were treated with PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days. The primary objective was to assess safety and tolerability and secondary objectives included pharmacokinetics and anti-tumor activity by RECIST v1.1. Seventeen patients were enrolled with a median age of 67 years, 82% male, 100% had prior CPI, and 76% had received three or more prior lines of therapy. The combination of PY314 and pembrolizumab demonstrated an acceptable safety profile with 47.1% any grade treatment-related adverse events (AE) (including only 5.9% grade ≥ 3), the most common being fatigue, pyrexia, nausea, and infusion-related reactions. One patient achieved a partial response (6%), and four patients had stable disease (24%) as their best response. The median PFS was 1.4 months (95% CI 1.2- 3.8). The combination of PY314 and pembrolizumab was safe, but the limited anti-tumor effect observed suggests that TREM2 targeting in conjunction with PD-1 blockade may not overcome resistance to prior CPI. Further investigation is warranted to determine if improved efficacy can be achieved in IO-naïve settings. Trial Registration: NCT04691375., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bladder cancer is an increasingly prevalent global disease that continues to cause morbidity and mortality despite recent advances in treatment. Immune checkpoint inhibitors (ICI) and fibroblast growth factor receptor (FGFR)-targeted therapeutics have had modest success in bladder cancer when used as monotherapy. Emerging data suggests that the combination of these two therapies could lead to improved clinical outcomes, but the optimal strategy for combining these agents remains uncertain. Mathematical models, specifically agent-based models (ABMs), have shown recent successes in uncovering the multiscale dynamics that shape the trajectory of cancer. They have enabled the optimization of treatment methods and the identification of novel therapeutic strategies. To assess the combined effects of anti-PD-1 and anti-FGFR3 small molecule inhibitors (SMI) on tumor growth and the immune response, we built an ABM that captures key facets of tumor heterogeneity and CD8 + T cell phenotypes, their spatial interactions, and their response to therapeutic pressures. Our model quantifies how tumor antigenicity and FGFR3 activating mutations impact disease trajectory and response to anti-PD-1 antibodies and anti-FGFR3 SMI. We find that even a small population of weakly antigenic tumor cells bearing an FGFR3 mutation can render the tumor resistant to combination therapy. However, highly antigenic tumors can overcome therapeutic resistance mediated by FGFR3 mutation. The optimal therapy depends on the strength of the FGFR3 signaling pathway. Under certain conditions, ICI alone is optimal; in others, ICI followed by anti-FGFR3 therapy is best. These results indicate the need to quantify FGFR3 signaling and the fitness advantage conferred on bladder cancer cells harboring this mutation. This ABM approach may enable rationally designed treatment plans to improve clinical outcomes., 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 Bergman, Wang, Trujillo, Fernald, Li, Pearson, Sweis and Jackson.)

Over the last decade, the composition of the gut microbiota has been found to correlate with the outcomes of cancer patients treated with immunotherapy. Accumulating evidence points to the various mechanisms by which intestinal bacteria act on distal tumors and how to harness this complex ecosystem to circumvent primary resistance to immune checkpoint inhibitors. Here, we review the state of the microbiota field in the context of melanoma, the recent breakthroughs in defining microbial modes of action, and how to modulate the microbiota to enhance response to cancer immunotherapy. The host-microbe interaction may be deciphered by the use of "omics" technologies, and will guide patient stratification and the development of microbiota-centered interventions. Efforts needed to advance the field and current gaps of knowledge are also discussed., Competing Interests: Declaration of interests B.R. received grand funding from Davolterra and Kanvas and honorarium from Merck, BMS and AstraZeneca. He is also the co-founder of Curebiota. C.K.B. is an employee and stockholder of AbbVie. M.B. sits on the scientific advisory board of Micronoma. A.B. was an employee of Genentech and is a holder of Roche stock. N.C. is CSO of MaaT Pharma. D.D. is a consultant for: ACM Bio, Ascendis Pharma, Clinical Care Options, Gerson Lehrman Group, Merck, Medical Learning Group, Xilio Therapeutics; CE Speakers’ Bureau: Castle Biosciences; and Intellectual Property: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020 and 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. L.D. sits on the scientific advisory board of EverImmune, holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota by LBP, and has been consulting for Ipsen and Sanofi. H.C.H. has filed a patent application (PCT/US2020/019038) for the commercial use of SagA-bacteria to improve checkpoint blockade immunotherapy, which is licensed by Rise Therapeutics to develop immunological-based biologics. M.I. is the founder and shareholder of Bio-Me. G.K. is a consultant for ReiThera; is on the Board of Directors of the Bristol Myers Squibb Foundation France; is a scientific co-founder of EverImmune Ltd., Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio; and is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. G.K.’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. F.M. reports honoraria from Therakos/Mallinckrodt, BMS, Sanofi, Jazz Pharmaceuticals, Gilead, Novartis, and Astellas, all outside the scope of this work. S.P. received travel reimbursement from CRISPR Therapeutics, and Ipsen. Z.R. is the founder of and a Scientific Advisor to Pangea Biomed. B.R. is the co-founder of Curebiota. G.D.S.-P. is an inventor on a US patent application (PCT/US2019/059647) submitted by The Regents of the University of California and licensed by Micronoma that covers methods of diagnosing and treating cancer using multi-domain microbial biomarkers in blood and cancer tissues; a founder of and reports stock interest in Micronoma; and has filed several additional US patent applications on cancer bacteriome and mycobiome diagnostics that are owned by The Regents of the University of California. R.F.S. reports consulting fees from Astellas, AstraZeneca, AVEO, BMS, EMD Serono, Editas, Exelixis, Gilead, Eisai, Janssen, Loxo, Lilly, Mirati, Pfizer, Silverback, and Seattle Genetics; research support (to institution) from Ascendis, ALX Oncology, Astellas, AstraZeneca, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, Scholar Rock, QED Therapeutics; equity in AbbVie; and patents: Neoantigens in Cancer, PCT/US2020/031357. M.v.d.B. has received stock options from Seres Therapeutics, Notch Therapeutics, and Pluto Therapeutics; royalties from Wolters Kluwer; consultant for and honorarium from or participated in advisory boards for Seres Therapeutics, Rheos Medicines, Ceramedix, Pluto Therapeutics, Thymofox, Garuda, Novartis (Spouse), Synthekine (Spouse), BeiGene (Spouse), and Kite (Spouse); IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). R.K.W. is a consultant for Takeda Pharmaceuticals. H.Z. sits on the scientific advisory board of EverImmune and is a consultant for MaaT Pharma. L. Zhao is a co-founder of Notitia Biotechnologies Company. J.M. received honoraria from Roche, BMS, and Merck. L. Zitvogel is a co-founder of EverImmune; the President of EverImmune scientific advisory board; holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota by LBP; has held research contracts with bioMérieux, Daiichi Sankyo, Glaxo Smith Kline, Incyte, Lytix, Kaleido, PiLeJe, Transgene, 9 Meters, Tusk Pharma, Merus, Roche, and Innovate Pharma; is on the scientific advisory board of Hookipa; and was on the Board of Directors of Transgene., (Copyright © 2023. Published by Elsevier Inc.)

Immunotherapy has dramatically transformed the cancer treatment landscape largely due to the efficacy of immune checkpoint inhibitors (ICIs). Although ICIs have shown promising results for many patients, the low response rates in many cancers highlight the ongoing challenges in cancer treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms: a fast-acting, perforin-mediated process and a slower, Fas ligand (FasL)-driven pathway. Evidence also suggests that the preferred killing mechanism of CTLs depends on the antigenicity of tumor cells. To determine the critical factors affecting responses to ICIs, we construct an ordinary differential equation model describing in vivo tumor-immune dynamics in the presence of active or blocked PD-1/PD-L1 immune checkpoint. Specifically, we identify important aspects of the tumor-immune landscape that affect tumor size and composition in the short and long term. We also generate a virtual cohort of mice with diverse tumor and immune attributes to simulate the outcomes of immune checkpoint blockade in a heterogeneous population. By identifying key tumor and immune characteristics associated with tumor elimination, dormancy, and escape, we predict which fraction of a population potentially responds well to ICIs and ways to enhance therapeutic outcomes with combination therapy., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose of Review: New therapies are needed to potentiate the effects of current immunotherapies and overcome resistance. The stimulator of interferon genes genes (STING) pathway is an innate immune activating cascade that may enhance current cancer immunotherapies., Recent Findings: Preclinical data has shown that the addition of a STING agonist enhances the effect of current treatments such as immune checkpoint inhibitor antibodies and radiation therapy. Early phase trials have demonstrated modest efficacy of STING agonists and revealed new mechanistic and technical challenges. STING agonists are a new class of agents that activate the immune response to improve tumor control. A wide range of preclinical experiments, translational data, and ongoing clinical trials support the therapeutic use of STING agonists in patients. Trials to determine optimal drug combinations and novel delivery mechanisms are continuing in development., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas., Patients and Methods: Patients were treated with weekly intratumoral injections of MIW815 (50-3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks., Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity., Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen., (©2022 American Association for Cancer Research.)

Agent-based models (ABMs) are a natural platform for capturing the multiple time and spatial scales in biological processes. However, these models are computationally expensive, especially when including molecular-level effects. The traditional approach to simulating this type of multiscale ABM is to solve a system of ordinary differential equations for the molecular events per cell. This significantly adds to the computational cost of simulations as the number of agents grows, which contributes to many ABMs being limited to around 10 5 cells. We propose an approach that requires the same computational time independent of the number of agents. This speeds up the entire simulation by orders of magnitude, allowing for more thorough explorations of ABMs with even larger numbers of agents. We use two systems to show that the new method strongly agrees with the traditionally used approach. This computational strategy can be applied to a wide range of biological investigations., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

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.)

Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers., Patients and Methods: Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule., Results: A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation., Conclusions: MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study; however, evidence of systemic immune activation was seen., (©2021 American Association for Cancer Research.)