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BackgroundPembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.Patients and methodsPatients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).ResultsKEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.ConclusionsThis 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.Clinical trial registryClinicalTrials.gov, NCT01295827.

During the past decade, new insights into the mechanisms by which T-cell activation and proliferation are regulated have led to the identification of checkpoint proteins that either up- or down-modulate T-cell reactivity. In the presence of active malignancy, pathophysiologic inhibition of T-cell activity may predominate over stimulation. A number of antibodies have been generated that can block inhibitory checkpoint proteins or promote the activity of activating molecules. In murine models, their use alone or with a vaccine strategy has resulted in regression of poorly immunogenic tumors and cures of established tumors. The prototypical immune regulatory antibodies are those directed against cytotoxic T-lymphocyte antigen-4, a molecule present on activated T cells. In this review, the preclinical rationale and clinical experience with 2 anticytotoxic T-lymphocyte antigen-4 antibodies are extensively discussed, demonstrating that abrogation of an immune inhibitory molecule can result in significant regression of tumors and long-lasting responses. The unique kinetics of antitumor response and the characteristic immune-related side effects of ipilimumab are also discussed. This clinical efficacy of this promising antitumor agent has been evaluated in 2 randomized phase III trials, whose results are eagerly awaited. Programmed death (PD)-1 is another immune inhibitory molecule against which an abrogating human antibody has been prepared. Initial preclinical testing with anti-PD-1 and anti-PD-L1 has shown encouraging results. Stimulatory molecules such as CD40, 41-BB, and OX-40 are also targets for antibody binding and activation, not blockade, and early dose ranging trials with antibodies against all 3 have shown that they can mediate regression of tumors, albeit with their own spectrum of side effects that are different from those that occur with abrogation of immune inhibition. [ABSTRACT FROM AUTHOR]

Background: : Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T lymphocyte antigen-4, a negative regulator of the immune system. The authors report on advanced refractory melanoma patients treated in a compassionate use trial of ipilimumab at the Memorial Sloan-Kettering Cancer Center.Methods: : Patients with advanced refractory melanoma were treated in a compassionate use trial with ipilimumab 10 mg/kg every 3 weeks for 4 doses. Those with evidence of clinical benefit at Week 24 (complete response [CR], partial response [PR], or stable disease [SD]) then received ipilimumab every 12 weeks.Results: : A total of 53 patients were enrolled, with 51 evaluable. Grade 3/4 immune-related adverse events were noted in 29% of patients, with the most common immune-related adverse events being pruritus (43%), rash (37%), and diarrhea (33%). On the basis of immune-related response criteria, the response rate (CR + PR) was 12% (95% confidence interval [CI], 5%-25%), whereas 29% had SD (95% CI, 18%-44%). The median progression-free survival was 2.6 months (95% CI, 2.3-5.2 months), whereas the median overall survival (OS) was 7.2 months (95% CI, 4.0-13.3 months). Patients with an absolute lymphocyte count (ALC) > micro =1000/microL after 2 ipilimumab treatments (Week 7) had a significantly improved clinical benefit rate (51% vs 0%; P = .01) and median OS (11.9 vs 1.4 months; P < .001) compared with those with an ALC <1000/microL.Conclusions: : The results confirm that ipilimumab is clinically active in patients with advanced refractory melanoma. The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated. Cancer 2010. (c) 2010 American Cancer Society. [ABSTRACT FROM AUTHOR]

The survival rate of patients diagnosed with late-stage melanoma is poor-only 5%-10%. Enlisting the immune systemin the fight against cancers such as melanoma could help improve the prognosis ofthese patients. Data have shown that melanocyte proteins make good targets for immune system-based therapy in this disease. However, self-tolerance, which develops to inhibit autoimmune attack, makes this strategy difficult. Two proteins on the surface ofT cells-CD28 and cytotoxic T-Iymphocyte antigen 4 (CTLA-4)-play important roles in the regulation of immune activation and tolerance. CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using antiCTLA-4 monoclonal antibody therapy has greatappeal because suppression of inhibitory signals results in the generation of an antitumorT-cell response. Both clinical and preclinical data indicate that CTLA·4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma. Interestingly, the occurrence of adverse events among patients treated with CTLA-4 blockade helps shed light on the mechanism of action of antiCTLA-4 monoclonal antibodies. Most adverse events involve immune-related toxicity to the skin and gastrointestinal tract. Major gastrointestinal toxicity develops inup to21%oftreated patients,and whileanobjective response occurs in approximately 36% of melanoma patients who develop enterocolitis with treatment, an objective response is found in only 11% ofpatients who do not experience this adverse reaction. [ABSTRACT FROM AUTHOR]

The article presents an introduction to this periodical.

Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions., Methods: We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response., Results: With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab., Conclusions: The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: To investigate the predictive value of RECIST response within 3, 6, or 12 months on long-term survival, and explore differences between nivolumab+ipilimumab and nivolumab monotherapy, we analyzed pooled 5-year data of 935 responder and non-responder patients at various time points after treatment initiation in CheckMate 069, 066, and 067 studies., Patients and Methods: Treatment-naive advanced melanoma patients received nivolumab+ipilimumab or nivolumab monotherapy. To decrease immortal time bias, 3-, 6-, or 12-month overall survival (OS) and progression-free survival (PFS) landmark analyses were performed. Association between characteristics and response was evaluated by univariate and multivariate analyses., Results: Response rates at any time were 58 % (239/409) for nivolumab+ipilimumab and 44 % (230/526) for nivolumab monotherapy. In 12-month landmark analyses, 5-year OS rates for responders versus non-responders were 82 % versus 40 % with nivolumab+ipilimumab (HR=0.23 [95 % CI, 0.15-0.35]) and 76 % versus 32 % with nivolumab monotherapy (HR=0.22 [95 % CI, 0.16-0.31]). PFS rates were 83 % versus 32 % and 69 % versus 46 %, respectively. Similar strong associations between response at 3 and 6 months and 5-year OS and PFS were also observed with more than 70 % of the responses observed in the first 3 months. Response rates correlated with baseline LDH and PD-L1 status by multivariate analysis but the association between response and long-term survival was maintained in landmark analyses even among patients with high LDH and low PD-L1 expression., Conclusion: Clinical response evaluated in the first months of therapy is a strong predictor of long-term survival, even in patients with poor prognostic biomarkers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. C. Robert disclosed medical writing support from Bristol Myers Squibb and received personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Regeneron, Roche, and Sunpharma (consulting fees); Bristol Myers Squibb, Pierre Fabre, and Sanofi (honoraria); and Regeneron and Ultimovacs (safety monitoring or advisor board). G.V. Long received consulting fees from Agenus Inc, Amgen Inc, Array Biopharma, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA Inc, Merck Sharp & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Australia, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, and Regeneron Pharmaceuticals and received honoraria from Bristol Myers Squibb and Pierre Fabre. J. Larkin received consulting fees from Apple Tree, Bristol Myers Squibb, Debipharm, Eisai, Incyte, iOnctura, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Philogen, and Telix; grants or contracts to his institution from Achilles, AVEO, Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Nektar, Pfizer, Pharmacyclics, and Roche; honoraria from Agence Unik, Bristol Myers Squibb, Eisai, GCO, Immatics, Incyte, Insighter, Merck, Novartis, Pfizer, Royal College of Physicians, TouchEXPERTS, TouchIME, and VJOncology; and discloses participation in a data safety monitoring or advisory board for IKCC. J.D. Wolchok disclosed support for the current manuscript to self as well as grant support to his institution from Bristol Myers Squibb; disclosed leadership or fiduciary role with AACR, SITC, and Ludwig Institute for Cancer Research; disclosed stock or stock options with Apricity, Ascentage Pharma, ArsenalIO/CellCarta, Georgiamune, Imvaq, Maverick, Psioxus, Tizona, and Xenimmune; received royalties and/or licenses for Xenogenic DNA Vaccines, Newcastle Disease viruses for Cancer Therapy, Myeloid-derived suppressor cell assay, Prediction of Responsiveness to treatment with immunomodulatory, anti-PD1 antibody, Anti-CTLA4 antibody, and anti-GITR antibodies and methods thereof; received consulting fees from Apricity, Ascentage Pharma, AstraZeneca, CellCarta, Bicara Therapeutics, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Imvaq, Psioxus, Takeda, Tizona, Trishula Therapeutics, Xenimmune;. J.C. Hassel received honoraria from Amgen, Bristol Myers Squibb, Delcath, GlaxoSmithKline, Immunocore, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sunpharma; advisory board support from GSK, Onkowissen, Pierre Fabre, and Sunpharma; and travel support from Bristol Myers Squibb, Iovance, and Sunpharma. D. Schadendorf disclosed personal interest as an invited speaker for Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, and Sanofi; personal interest for advisory board participant for Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, and Sanofi/Regeneron; received institutional grant support from Bristol Myers Squibb, and Merck Sharp & Dohme; disclosed no financial interest as an institutional primary investigator for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre, and Sanofi; disclosed interest as a. F.S. Hodi disclosed support for the current manuscript from Bristol Myers Squibb; royalties or licences from Bristol Myers Squibb and from Novartis (both to institution), leadership or fiduciary role as well as stock options for Apricity and Biocara; and receipt of gifts or services from Bristol Myers Squibb and Merck; received grants from 7 Hills, Amgen, Apricity, Bicara, Bioentre, Catalym, Checkpoint Therapeutics, Compass, Gossamer, Immunocore, Iovance, Merck, Novartis, Rheos, Solu Therapeutics, Surface, and Zumutor; received honoraria from George Washington University; and has patents planned, issued or pending for Methods for Treating MICA-Related Disorders (#20100111973), Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603), Therapeutic peptides (#20160046716), Tumor antigens and uses thereof (#7250291), Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407), METHODS OF USING PEMBROLIZUMAB AND TREBANANIB, Vaccine compositions and methods for restoring NKG2D pathway function against cancers (#10279021), Antibodies that bind to MHC class I polypeptide-related sequence A (#10106611), ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES (# 20170343552), and Antibodies against EDIL3 and methods of use thereof. C. Lebbe received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre; grants from Bristol Myers Squibb, Melbase project, Melbase and PREDIMEL projects, and Pierre Fabre; travel expenses from Pierre Fabre; and has participated on a data safety or advisory board for Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. J.-J. Grob received consulting fees from Bristol Myers Squibb and Novartis; and participated on advisory boards for Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Philogen, Pierre Fabre, Roche, and Sanofi. J.R. Hyngstrom disclosed institutional trial support from Amgen, Bristol Myers Squibb, Iovance, Lyell, Merck, Natera, Philogen, Regeneron, Skyline, and Takara. J. Wagstaff has no conflicts to disclose. J. Chesney disclosed medical writing support and article processing and charges from Bristol Myers Squibb for the current manuscript. M.O. Butler received consulting fees from Adaptimmune, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, Ideaya Bio, Instil Bio, IOVANCE, LaRoche Possey, Medison, Merck, Novartis, Pfizer, Regeneron, Sanofi, and Sun Pharma; grants from Merck, Novartis, and Takara Bio; honoraria from Bristol Myers Squibb, Merck, Novartis, Pfizer, and Sanofi; and participated on safety review committees for Adaptimmune and GlaxoSmithKline. O. Bechter disclosed medical writing support from Bristol Myers Squibb for the current manuscript. I. Márquez-Rodas received consulting fees from Amgen, Astra Zeneca, BiolineRx, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Highlight Therapeutics, Immunocore, Merck Serono, Merck Sharp & Dohme, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, and Sun Pharma; received travel fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Highlight Therapeutics, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sun Pharma; and discloses a leadership or fiduciary role for Spanish Melanoma Group. A.C. Pavlick received consulting fees and honoraria from Bristol Myers Squibb, Merck, and Replimune. P. Durani disclosed employment and stock or stock options with Bristol Myers Squibb. M. Pe Benito disclosed employment and stock or stock options with Bristol Myers Squibb. P. Wang disclosed employment and stock or stock options with Bristol Myers Squibb. M.A. Postow received support for the current manuscript from Bristol Myers Squibb, grants from Bristol Myers Squibb, Infinity, Merck, Novartis, and RGenix, consulting fees from Bristol Myers Squibb, Chugai, Eisai, Merck, Nektar, Novartis, Pfizer, and Replimune; travel support from Bristol Myers Squibb and Pfizer; and also participated in a data safety monitoring or advisory board for Bristol Myers Squibb and Pfizer. P.A. Ascierto received consulting fees from Bayer, Bio-Al Health, Bristol Myers Squibb, Italfarmaco, Lunaphore, Merck Serono, Merck Sharp & Dohme, Nektar, Novartis, Pfizer Medicenna, Philogen, Pierre-Fabre, Replimmune, Roche-Genentech, Sandoz, Sanofi, Sun Pharma, and ValoTx; participated on a safety monitoring or advisory board for AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, Italfarmaco, iTeos, Lunaphore, Merck Serono, Merck Sharp & Dohme, Nektar, Nouscom, Novartis, Oncosec, Pfizer Medicenna, Philogen, Pierre-Fabre, Regeneron, Replimmune, Roche-Genentech, Sandoz, Sanofi, Seagen, Sun Pharma, and ValoTx; received grants from Bristol Myers Squibb, Pfizer, Roche-Genentech, and Sanofi; and received travel fees from Bio-Al Health, Merck Sharp & Dohme, Pfizer, and Replimmune., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neurofibromin (NF1) is a negative regulator of RAS signaling, frequently mutated in cancer. NF1-mutant melanoma is a highly malignant tumor for which targeted therapies are lacking. Here, we use biochemical and pharmacological assays on patient-derived models and isogenic cell lines to identify potential pharmacologic targets, revealing that NF1-null melanomas are dependent on RAS activation and that MEK inhibition relieves ERK-dependent negative feedback, increasing RAS signaling. MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited. However, concurrent inhibition of MEK and SOS1 abrogates ERK activation, induces cell death, and suppresses tumor growth. In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells., Competing Interests: Declaration of interests M.H.H., D.G., and F.S. are employees of Boehringer Ingelheim. T.M. is a consultant for Immunos Therapeutics, Daiichi Sankyo Co, TigaTX, Normunity, and Pfizer; is a cofounder of and equity holder in IMVAQ Therapeutics; has received research grants funding from Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics; currently receives research funding from Bristol Myers Squibb, Enterome SA, and ReAlta Life Sciences; and is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, BeiGene, Bicara Therapeutics, Bristol Myers Squibb, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Takeda, Tizona, Trishula Therapeutics, Immunocore (on their data safety board), and Scancell; received grant/research support from Bristol Myers Squibb and Enterome; has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and XenImmune; and is an inventor on the following patents: Xenogeneic DNA Vaccines, Newcastle Disease Viruses for Cancer Therapy, Myeloid-Derived Suppressor Cell Assay, Prediction of Responsiveness to Treatment with Immunomodulatory Therapeutics and Method of Monitoring Abscopal Effects During Such Treatment, Anti-PD1 Antibody, Anti-CTLA4 Antibodies, and Anti-GITR Antibodies and Methods of Use Thereof. Z.Y. is a past scientific advisory board (SAB) member of MapKure and currently an employee of Loxo Oncology at Lilly. D.S. reports personal fees from Pfizer, Vividion Therapeutics, BridgeBio, FogPharma, FORE Therapeutics, Scorpion Therapeutics, and Rain Therapeutics outside the submitted work. S.M. reports grants from Boehringer Ingelheim and Daiichi Sankyo outside the submitted work and is a SAB member of Bionseek. N.R. is on the SAB and owns equity in BeiGene, Zai Labs, MapKure, Ribon, and Effector; is also on the SAB of AstraZeneca and Chugai and a past SAB member of Novartis, Millennium-Takeda, Kura, and Araxes; and is a consultant to Revolution Medicines, Tarveda, Array-Pfizer, Boehringer Ingelheim, and Eli Lilly. He receives research funding from Revolution Medicines, AstraZeneca, Array Pfizer, and Boehringer Ingelheim and owns equity in Kura Oncology and Fortress., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Melanoma arising in association with a blue nevus (BN) is rare but has molecular similarities to uveal melanoma (UM), including GNAQ/11 mutations. Tebentafusp was recently approved for UM based on improved overall survival in a phase 3 study. We hypothesized that tebentafusp may be active in BN-associated melanoma. Here, we present a case of metastatic BN-associated melanoma with rapid response and ~1 year of disease control on tebentafusp. We also explore molecular and histological features of secondary resistance. Our case highlights that PD-1-resistant melanomas should be screened for GNAQ/11 mutations, as tebentafusp may be a treatment option in this extremely rare disease., Competing Interests: Competing interests: ANS reports grants and personal fees from Bristol-Myers Squibb, Immunocore, Novartis, and Castle Biosciences, and institutional grants from Bristol-Myers Squibb, Immunocore, Novartis, Targovax, Pfizer, Mural Oncology, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linnaeus Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics, Obsidian Therapeutics. PF reports equity in GE Healthcare, Iovance, Gilead. JDW is a consultant for Apricity, Ascentage Pharma, Bicara Therapeutics, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Takeda, Tizona, Trishula Therapeutics, Immunocore (on their Data Safety Board), Scancell. JDW received grant/research support from Bristol Myers Squibb, Enterome. JDW has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, Xenimmune. JDW is an inventor on the following patents: Xenogeneic DNA Vaccines, Newcastle Disease viruses for Cancer Therapy, Myeloid-derived suppressor cell (MDSC) assay, Prediction of Responsiveness to Treatment with Immunomodulatory Therapeutics and Method of Monitoring Abscopal Effects During Such Treatment, Anti-PD1 Antibody, Anti-CTLA4 antibodies, Anti-GITR antibodies and methods of use thereof. The remaining authors declare no 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.)

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple-drug regimen may be considered a viable option in fit patients. This case highlights the potential for long-term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses., (©2024 American Association for Cancer Research.)

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Despite therapeutic efficacy observed with immune checkpoint blockade in advanced melanoma, many tumors do not respond to treatment, representing a need for new therapies. Here, we have generated chimeric antigen receptor (CAR) T cells targeting TYRP1, a melanoma differentiation antigen expressed on the surface of melanomas, including rare acral and uveal melanomas. TYRP1-targeted CAR T cells demonstrate antigen-specific activation and cytotoxic activity in vitro and in vivo against human melanomas independent of the MHC alleles and expression. In addition, the toxicity to pigmented normal tissues observed with T lymphocytes expressing TYRP1-targeted TCRs was not observed with TYRP1-targeted CAR T cells. Anti-TYRP1 CAR T cells provide a novel means to target advanced melanomas, serving as a platform for the development of similar novel therapeutic agents and as a tool to interrogate the immunobiology of melanomas., Competing Interests: C.S.H., D.H., T.J.P., S.R., J.D.W., T.M., and R.J.B. are inventors on multiple patents filed by MSK covering CAR T cell technology, including the CAR T cells discussed in this manuscript. S.R. serves on the Scientific Advisory Board of Celyad Oncology. R.J.B. has licensed intellectual property to and collects royalties from BMS, Caribou, and Sanofi. R.J.B. received research funding from BMS. R.J.B. is a consultant to BMS, Atara Biotherapeutics Inc., and Triumvira, and was a consultant for Cargo Tx and CoImmune but ended in the past 3 months, and Gracell Biotechnologies Inc. but ended employment in the past 24 months. R.J.B. is a member of the scientific advisory board for Triumvira and was a member of the scientific advisory board for Cargo Tx and CoImmune, but that ended in the past 6 months. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, BeiGene, Bicara Therapeutics (ending 4/1/2024), Bristol Myers Squibb, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Psioxus, Recepta, Takeda, Tizona, Trishula Therapeutics, and Sellas. J.D.W. received grant/research support from Bristol Myers Squibb and Enterome. J.D.W. has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and Xenimmune. J.D.W. is an inventor on the following patents: Xenogeneic DNA Vaccines, Newcastle Disease viruses for Cancer Therapy, Myeloid-derived suppressor cell (MDSC) assay, Prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment, Anti-PD1 Antibody, Anti-CTLA4 antibodies, Anti-GITR antibodies and methods of use thereof. T.M. is a consultant for Immunos Therapeutics, Daiichi Sankyo Co, TigaTX, Normunity, and Pfizer. T.M. is a cofounder of and equity holder in Imvaq Therapeutics. T.M. receives research grant funding from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4., (© 2024 The Author(s). Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy.)

Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported., Patients and Methods: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel., Results: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months., Conclusions: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response., (©2024 American Association for Cancer Research.)

Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade., Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed., Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery., Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT., Competing Interests: TM is a consultant for Immunos Therapeutics, Daiichi Sankyo Co, TigaTx, Normunity and Pfizer; is a cofounder of and equity holder in IMVAQ Therapeutics; receives research funding from Bristol-Myers Squibb, and Realta; is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neo antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. JW is a consultant for: Apricity; Ascentage Pharma; AstraZeneca; BeiGene; Bicara Therapeutics; Bristol Myers Squibb; Daiichi Sankyo; Dragonfly; Imvaq; Larkspur; Takeda; Tizona; Trishula Therapeutics; Immunocore is on their Data Safety board. JW received Grant/Research Support from: Bristol Myers Squibb; Enterome. JW has Equity in: Apricity, Arsenal IO/CellCarta; Ascentage; Imvaq; Linneaus, Larkspur; Georgiamune; Maverick; Tizona Therapeutics; Xenimmune. The remaining 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 Budhu, Kim, Yip, La Rosa, Jebiwott, Cai, Holland, Thomas, Preise, Somma, Gordon, Scherz, Wolchok, Erinjeri, Merghoub and Coleman.)

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGE SNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGE CNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGE SNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Combined immune checkpoint blockade (ICB) for cancer exhibits good efficacy in a subset of patients but also associates with immune-related adverse events. Xue et al. use an elegant drug screening strategy to identify the antimicrobial drug clofazimine as an agent that both potentiates ICB efficacy and decreases immune-related adverse events., Competing Interests: Declaration of interests J.D.W. is a consultant for Apricity; Ascentage Pharma; AstraZeneca; BeiGene; Bicara Therapeutics; Bristol Myers Squibb; Daiichi Sankyo; Dragonfly; Imvaq; Larkspur; Psioxus, Recepta; Takeda; Tizona; Trishula Therapeutics; and Sellas (ended 3/22). J.D.W. receives grant/research support from Bristol Myers Squibb and Enterome. J.D.W. has Equity in: Apricity, Arsenal IO/CellCarta; Ascentage; Imvaq; Linneaus; Georgiamune; Maverick; Tizona Therapeutics; Xenimmune. J.D.W. is an inventor on the following patents: Xenogeneic DNA Vaccines; Newcastle Disease viruses for Cancer Therapy; Myeloid-derived suppressor cell (MDSC) assay; (prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment); Anti-PD1 Antibody; Anti-CTLA4 antibodies; Anti-GITR antibodies and methods of use thereof. T.M. is a consultant for Daiichi Sankyo Co, Leap Therapeutics, Immunos Therapeutics, and Pfizer, and a co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. D.H. and T.M. are co-inventors on patent applications related to OX40 antibodies. L.K. is an intermittent consultant with Janssen and received travel support from Sanofi., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes., Methods: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered., Results: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy., Conclusions: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy., Competing Interests: Declaration of Competing Interest LH received speaker and consultancy fees from BiomeDx, BMS, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi, SUN and Therakos. The LMU received research grants or clinical study grants from Agenus, AstraZeneca Inc., BMS, Hoffmann-La Roche AG, Huya Bioscience, Immunocore, IO Biotech, Merck, Merck Sharp & Dome GmbH, Miltenyi Biomedicine GmbH, Novartis, Pfizer, Pierre Fabre, Regeneron, Replimune, and Sanofi Aventis. AF received honoraria for presentations and travel support from: BMS, Novartis, Pierre-Fabre. AF reports on participation on Advisory Boards of MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional research grants from BMS Stiftung Immunonkologie for other financial or non-financial interests. AH reports grants and personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MerckPfizer, grants and personal fees from MSD/Merck, grants and personal fees from Philogen, grants and personal fees from Pierre Fabre, grants and personal fees from Regeneron, grants and personal fees from Roche, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Novartis Pharma, grants and personal fees from Eisai, personal fees from Immunocore, grants and personal fees from Replimune, personal fees from Seagen, personal fees from IO Biotech, personal fees from Dermagnostix, personal fees from Incyte, grants and personal fees from NeraCare, personal fees from Highlight Therapeutics, grants from Huya Biosciences, personal fees from Kyowa Kirin, personal fees from Iovance, outside the submitted work. CL received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) and travel support from: BMS, MSD Merck, Pierre-Fabre, Biontech, Almirall Hermal, Sun Pharma, KyowaKirin, Immunocore, Sanofi, Novartis. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO outside the submitted work. CR reports personal consulting fees from BMS, Roche, MSD, Sanofi, Pierre Fabre, Sunpharma, Pfizer, Regeneron. CR received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) from Pierre Fabre, Sanofi, BMS. CR reports personal fees (participation on a Data Safety Monitoring Board or Advisory Board) from Ultimovacs and Regeneron. CR reports stocks/stock options: Ribonexus. DS reports grants, personal fees, non-financial support and other from Novartis, BMS, Amgen, MSD & Array/Pfizer; personal fees and from 4SC, Agenus, Array BioPharma, Astra Zeneca, BioAlta, CureVac, Daiichi Sanyko, Erasma, Haystack, Immatics, Immunocore, InFlarX, Merck Serono, Pierre Fabre, PamGene, Philogen, Neracare NoviGenix, Ultimovacs, Sandoz/Hexal, Sanofi, Seagen, Sun Pharma, Regeneron, and Replimune. GMcA reports on grants or contracts from BMS, Genentech-Roche, Merck to his institution. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. GMcA reports on participation on Data Safety Monitoring or Advisory Board from Pierre Fabre and Pfizer (no payments) and on National Breast Cancer Foundation Board (Australia) (no payments). GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. HG reports on grants or contracts from BMS, Roche, MSD Oncology, Amgen, Novartis, Iovance Biotherapeutics to her institution. HG received consulting fees from BMS, MSD Oncology, Pierre Fabre, Sanofi/ Regeneron. HG received speakers honoraria from BMS, MSD Oncology, Pierre-Fabre, Sanofi/ Regeneron. HG received travel support from MSD, Amgen, Pfizer. JH received scientific grants from BMS, Sanofi, Sunpharma and consulting fees (for advisory boards) from GSK, MSD, Pierre Fabre, Onkowiessen, Sunpharma. JH received honoraria (talks) from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Pierre Fabre, Sanofi, Sunpharma. JH received meeting/travel support from BMS, Iovance, Sunpharma. JH reports on participation on a Data Safety Monitoring Board from Nekvax. LZ declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. MS reports on research support from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi, Novartis, Roche, Seattle Genetics, Takeda. MS reports on participation on Advisory Boards of Astra Zeneca, Avencell, Ichnos, Incyte, Janssen, Molecular Partners. MS received honoraria (speaker’s bureau) from: Amgen, BMS/Celgene, Janssen, Gilead/Kite, Novartis, Pfizer, Takeda. PA reports on grants and contracts from BMS, Roche-Genentech, Pfizer, Sanofi. PA received consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck, Sharp & Dohme, Novartis, Merck Serono, PierreFabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, Bayer. PA received travel support from Pfizer, BIO-AI Health, Replimmune. PA reports on participation on a Data Safety Monitoring or Advisory Board from BMS, Roche-Genentech, Merck, Sharp & Dohme, Novartis, AstraZeneca, BoehringerIngelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, Erasca. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. RG received honoraria for advice and lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron. Ralf Gutzmer received travel support from SUN Pharma, Boehringer Ingelheim and PierreFabre. Ralf Gutzmer received research grants from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Admiral Hermal. RK received meeting and travel support from SunPharma, Novartis, Pierre-Fabre. SG reports on clinical trials honoraria to institution from MSD, BMS, Sanofi, Pfizer, BioNTech, EORTC, I-O Biotech, Astra Zeneca, and Regeneron. SG received consulting fees from MSD and BMS and an Online Ticket for ASCO from BMS. TE received speaker and consultancy fees from BMS, Curevac, Merck, MSD, Novartis, Pierre-Fabre, Sanofi, Almiral Hermal, and SUN. TN reports on grants or contracts from NIH, BMS, Astra Zeneca to his institution. TN received consulting fees from Genentech, BMS, Roche, Sanofi, Roivant, Race Oncology. TN participated on Data Safety Monitoring Board/ Advisory Board from Genentech. TR declared speaker’s honoraria and travel grants from Therakos and SUN. AR, CE, MK, VM have declared no conflicts of interest. BR received support from BMS, Merck and Astrazeneca. BR received honoraria (for lectures, presentations, speakers bureaus, manuscript writing or educational events) from BMS, Merck and Astrazeneca. BR reports on participation on a Data Safety Monitoring Board or Advisory Board from BMS, Merck and Astrazeneca. All remaining authors have declared no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Purpose: Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma., Experimental Design: We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC)., Results: A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients., Conclusions: We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells., Significance: This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial., (© 2023 The Authors; Published by the American Association for Cancer Research.)

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8 + T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status., (© 2023 Michels et al.)

While many patients are treated beyond progression (TBP), the magnitude and duration of clinical benefit in these patients have not been fully quantified. Data from 799 patients with melanoma (n = 176), non-small cell lung cancer (NSCLC; n = 146), gastric cancer (GC; n = 87), head and neck squamous cell carcinoma (HNSCC; n = 112), clear-cell renal cell carcinoma (ccRCC; n = 51), and urothelial carcinoma (UC; n = 227) TBP were included. Patients had received pembrolizumab beyond confirmed progressive disease (PD) per RECIST v1.1. A subset of patients displays a 30% reduction in the sum of lesion diameters in the post-progression period (melanoma 24.4%, NSCLC 11.6%, 12.6% GC, 8.9% HNSCC, 15.7% ccRCC, and 13.2% UC). Most patients show stable target lesion dynamics in the post-progression period (melanoma, 64.8%; NSCLC, 72.6%; GC, 69.0%, 75.9% HNSCC, 72.5% ccRCC, 75.3% UC). Pembrolizumab generates meaningful efficacy in a subset of patients treated beyond RECIST v1.1 progression., Competing Interests: Declaration of interests B.G.T. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. M.C. has nothing to disclose. K.M. is a stockholder of Merck & Co., Inc., Rahway, NJ, USA, and holds a leadership role (Vice President, Clinical Pharmacology, Clinical Development) at Generate Biomedicines. DPd.A. is a stockholder of Merck & Co., Inc., Rahway, NJ, USA, and holds a leadership role (Senior Vice President, Clinical Drug Development) at Generate Biomedicines. E.R. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA; and holds a leadership role (Senior Vice President, Clinical Oncology) at Merck & Co., Inc., Rahway, NJ, USA. A.S. reports advisory/consultancy to Two River, Inc, holds a leadership role at Generate Biomedicines (CMO), and is an officer/on the board of directors for Navigating Cancer. J.D.W. reports a role of consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Bristol Myers Squibb, Celgene, Chugai, Eli Lilly and Company, F Star, Imvaq, Kyowa Hakko Kirin, Linneaus, MedImmune, Merck, Neon Therapeutics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Takara Bio, Trieza, Truvax, Serametrix, Surface Oncology, Syndax, and Syntalogic; research support from AstraZeneca and Bristol Myers Squibb; and equity in Adaptive Biotechnologies; BeiGene; Imvaq; Linneaus; Potenza Therapeutics; Tizona Pharmaceuticals; and Trieza. A.R. reports leadership for PACT Pharma, Arcus Biosciences, and Lutris; stock and other ownership interests for Compugen, CytomX Therapeutics, Advaxis, Acrus Biosciences, Tango Therapeutics, PACT Pharma, Merus, ImaginAb, Lutris Pharma, Highlight, MapKure, 4c Biomked, Kite/Gilead, Isoplexis, Appia, Synthekine, Pluto, Inspirna, RAPT Therapeutics, and ImmPACT-Bio; honoraria from Merck Sharp & Dohme, Novartis, Amgen, Chugai/Roche, Genentech/Roche, Sanofi, Vedanta Biosciences, and AstraZeneca; a consulting or advisory role for Merck, Amgen, Novartis, Chugai Pharma, and Sanofi; research funding to institution from Agilent and Bristol Myers Squibb; and patents, royalties, other intellectual property for nonviral gene editing to Arsenal Bio., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40hiCCR8hi Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA., (© 2023 Yang et al.)

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD., Competing Interests: Declaration of interests F.S. has held stock ownership in BioNTech SE and Moderna Inc; has received honoraria from Bristol Myers Squibb and RV Mais Promocao Eventos LTDS; has received institutional research funding from Amgen, Mirati Therapeutics, Boehringer Ingelheim, Merck & Co, Novartis, and Pfizer; has an immediate family member who has received research funding from AImmune Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by Tango Therapeutics, Amgen, and AstraZeneca Pharmaceuticals. T.M. is a consultant for Immunos Therapeutics, Daiichi Sankyo Co and Pfizer; is a cofounder of and equity holder in IMVAQ Therapeutics; receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics; is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neo antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Maverick Therapeutics, Psioxus, Recepta, Tizona, Trieza, Trishula, Sellas, Surface Oncology, Werewolf Therapeutics; receives Grant/Research Support from Bristol Myers Squibb, Sephora; has Equity in Tizona Pharmaceuticals, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, Georgiamune, Trieza, Maverick, Ascentage. K.K.W. is a founder and equity holder of G1 Therapeutics; has sponsored Research Agreements with MedImmune, Takeda, TargImmune, Mirati, Merus, Alkermes and BMS; has consulting & sponsored research agreements with AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono, Array. R. J. D. is a member of the Scientific Advisory Board for Agios Pharmaceuticals and Vida Ventures. J.D.M receives licensing fees from the NCI and UT Southwestern to distribute cell lines. N.I.V. receives consulting fees from Sanofi, Regeneron, Oncocyte, and Eli Lilly, and research funding from Mirati. J.F.G. has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Takeda, Loxo/Lilly, Blueprint Medicine, Gilead, Moderna, AstraZeneca, Curie Therapeutics, Mirati, Merus Pharmacueticals, Nuvalent, Pfizer, Novartis, Merck, iTeos, Karyopharm, and Silverback Therapeutics; research support from Novartis, Genentech/Roche, and Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; equity in AI Proteins, and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. A.R. receives honoraria from Adaptive Biotechnologies; is a member of advisory board for Adaptive Biotechnologies. J.V.H. is a member of advisory committees of AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, Chugai Pharmaceuticals; has research support from AstraZeneca, GlaxoSmithKline, Spectrum; has royalties and licensing fees from Spectrum. The other authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors., Patients and Methods: Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE)., Results: The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors., Conclusions: On the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study., (©2023 American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3 . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 + T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence., (© 2023. The Author(s).)

Little is known about the long-term outcomes of anti-PD-1 treated patients with melanoma beyond 5 years, especially for patients treated off clinical trials. This retrospective cohort study includes patients with unresectable stage III/IV nonuveal melanoma treated with anti-PD-1 off-trial at Memorial Sloan Kettering Cancer Center between 2014 and 2017 who survived at least 5 years following their first anti-PD-1 dose (N = 139). We characterized overall survival (OS), melanoma-specific survival (MSS) estimates, treatment-free survival rates, and subsequent treatment courses. Median follow-up among 5-plus year survivors (N = 125) was 78.4 months (range 60.0-96.3). OS at year 7 (2 years post 5-year landmark) was 90.1% (95% CI: 83.0%-94.3%). Fourteen deaths occurred, seven due to melanoma. MSS at year 7 (2 years post 5-year landmark) was 95.0% (95% CI: 33.5%-95.2%). In patients who completed anti-PD-1 based therapy and did not require subsequent treatment by 5 years (N = 80), the probability of not requiring additional treatment for an additional 2 years was 95.7% (95% CI: 91.0%-100%). Patients treated with anti-PD-1 regimens off clinical trials who survive at least 5 years from initial anti-PD-1 treatment can be reassured of their excellent long-term prognosis, particularly if they did not require additional melanoma treatment during the first 5 years., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response., Competing Interests: Declaration of interests K.M.C. is a shareholder in Geneoscopy LLC and received consulting fees from PACT Pharma, Tango Therapeutics, Geneoscopy LLC, Flagship Labs 81 LLC, and the Rare Cancer Research Foundation. M.A. received consulting fees from PICI. J.S.W. received consulting fees from Merck, Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Nektar, Celldex, Incyte, Biond, ImCheck, Sellas, Evaxion, and EMD Serono; is or has been a member of the scientific advisory board for Bristol-Myers Squibb (BMS), CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4 and Neximmune; and holds equity in Biond, Evaxion, Instil Bio, and Neximmune. J.S.W. has been named on patents filed by Moffitt Cancer Center (ipilimumab biomarker and TIL growth method) and Biosedix (PD-1). NYU has received research support from BMS, Merck, GlaxoSmithKline, Moderna, Pfizer, Novartis, and AstraZeneca. J.D.W. received consulting fees from Apricity, CellCarta, Ascentage Pharma, AstraZeneca, Astellas, Bicara Therapeutics, Boehringer Ingelheim, BMS, Dragonfly, Georgiamune, Imvaq, Larkspur, Maverick Therapeutics, Psioxus, Recepta, Tizona, and Sellas; has received research/grant support from BMS and Sephora; and has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linnaeus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.L. has worked in a consulting/advisory role for iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, and Incyte; received honoraria from AstraZeneca, BMS, Eisai, EUSA Pharma, GlaxoSmithKline, Incyte, Ipsen, Merck, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, Merck Sharp & Dohme, Novartis, Aptitude, Pierre Fabre, Pfizer, Roche, Seagen, Inselgruppe, eCancer, Ultimovacs, Calithera, and Goldman Sachs; and received research/grant support from Achilles Therapeutics, BMS, Immunocore, Aveo, Pharmacyclics, MSD, Nektar Therapeutics, Covance, Novartis, Pfizer, and Roche. F.S.H. received research support from the NCI of the NIH, BMS, Novartis, and Genentech; royalties or licenses from BMS and Novartis; consulting fees from BMS, EMD Serono, Surface, Sanofi, Genentech, Gossamer, Trillium, Immunocore, Merck, Novartis, Compass Therapeutics, Pieris, Bioentre, Iovance, Catalym, and Amgen; patents for methods for treating MHC class I polypeptide-related sequence A disorders (20100111973, pending, with royalties paid), tumor antigens and uses thereof (7250291, issued), angiopoiten-2 biomarkers predictive of anti-immune checkpoint response (20170248603, pending), compositions and methods for the identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms (20160340407, pending), therapeutic peptides (20160046716, 20140004112, 20170022275, and 20170008962, all pending, and 9402905, issued), methods of using pembrolizumab and trebananib (pending), vaccine compositions and methods for restoring NKG2D pathway function against cancers (10279021, issued), antibodies that bind to MHC class I polypeptide-related sequence A (10106611, issued), and anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses (20170343552, pending); data safety monitoring board and advisory board participation for Aduro and Checkpoint Therapeutics; scientific advisory board leadership for Bicara and Apricity; and stock options in Checkpoint Therapeutics, Pionyr, Apricity, and Bicara. S.B., L.S., D.T., and T.T. are employees of BMS. C.N.S. received consulting fees from the Rare Cancer Research Foundation. D.K.W. is an employee, founder, and equity holder at Santa Ana Bio; holds equity in Immunai, and has received consulting fees from Rubius Therapeutics, DeepMind, Illumina, and Guardant Health. A.R. has received honoraria from consulting with Amgen, BMS, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi; is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prim, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics; and has received research funding from Agilent Technologies and BMS through Stand Up to Cancer., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8 + T cells, regulatory CD4 + T cells (Treg), and follicular helper CD4 + T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8 + T cells are clonally linked to TCF7 + SELL + progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8 + T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8 + and CD4 + T cell clones reveals persistence in the peripheral blood for years after ICB therapy., Competing Interests: Declaration of interests M.D.H. reports advisory/consulting fees from Achilles, Adagene, Adicet, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Da Volaterra, Eli Lilly, Genentech, Genzyme/Sanofi, Immunai, Instill Bio, Janssen, Mana Therapeutics, Merk, Mirati, Pact Pharma, Regeneron, Roche, and Shattuck Labs; research funding from Bristol Myers Squibb; stock interest with Arcus, Factorial, Immunai, and Shattuck Labs; a patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from Personal Genome Diagnostics (PGDx); after the completion of this work, M.D.H .began as an employee (and equity holder) at AstraZeneca. J.D.W. has Equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: Xenogeneic (Canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. The remaining authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Adjuvant anti-PD1 treatment improves relapse-free survival (RFS) but has not been shown to improve overall survival (OS) in melanoma and is associated with risks of immune-related adverse events (irAEs), some permanent. We identified factors patients consider in deciding whether to undergo adjuvant anti-PD1 treatment and assessed prospective health-related quality of life (HRQoL), treatment satisfaction, and decisional regret., Patients and Methods: Patients with stage IIIB-IV cutaneous melanoma and free of disease, were candidates for adjuvant anti-PD1 immunotherapy, and had not yet discussed adjuvant treatment options with their oncologist were eligible. Participants viewed a 4-minute informational video tailored to their disease stage which communicated comprehensive, quantitative information about the risk of relapse both with and without adjuvant treatment, and risks of each irAE before deciding whether or not to opt for adjuvant therapy. We collected data on demographics, HRQoL, and attitudes toward adjuvant treatment over 1 year., Results: 14/34 patients (41%) opted for adjuvant anti-PD1 immunotherapy, 20/34 (59%) opted for observation. Patients choosing adjuvant immunotherapy scored higher on HRQoL social well-being at pre-treatment, were more likely to endorse positive statements about adjuvant immunotherapy, and to perceive that their physician preferred adjuvant therapy. They had lower decisional regret and higher satisfaction, even if they experienced toxicity or recurrence., Conclusions: When provided with comprehensive quantitative information about risks and benefits of adjuvant anti-PD1 immunotherapy, 20/34 (59%) of patients opted for observation. Patients choosing adjuvant immunotherapy had lower decisional regret and higher satisfaction over time even if they had poorer outcomes in treatment., (© The Author(s) 2023. Published by Oxford University Press.)

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 + T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 + T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants., Competing Interests: Declaration of interests T.M. is a consultant for Daiichi Sankyo, Leap Therapeutics, Immunos Therapeutics, and Pfizer and co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq Therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. D.H. and S.B. have received royalties from Agenus. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4; has received grant support from Bristol-Myers Squibb; and is a consultant for Leap Therapeutics. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Imvaq, Larkspur, Psioxus, Recepta, Tizona, and Sellas. J.D.W. received grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, CellCarta, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and Xenimmune. J.D.W. is an inventor on the following patents: xenogeneic DNA vaccines, alphavirus replicon particles expressing TRP2, myeloid-derived suppressor cell (MDSC) assay, Newcastle disease virus for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy (with T.M.), anti-CD40 agonist mAb fused to monophosphoryl lipid A (MPL) for cancer therapy (with T.M.), CAR(+) T cells targeting differentiation antigens as a means to treat cancer, anti-PD-1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies, and methods of use thereof. D.H. and T.M. are co-inventors on patent applications related to OX40 antibodies. M.E. is a member of the research advisory board for brensocatib for Insmed, Inc.; a member of the scientific advisory board for Vividion Therapeutics, Inc.; and a consultant for Protalix, Inc. and holds shares in Agios Pharmaceuticals, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8 + T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8 + T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39 + CD8 + T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39 + CD8 + T cells. Higher baseline frequency of CD39 + CD8 + T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39 + CD8 + T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8 + T cells in human lung cancer., Competing Interests: Declaration of interests C.A.K. received research funding support from Kite/Gilead and Intima Bioscience; is on the Scientific and/or Clinical Advisory Boards of Achilles Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics, and T-knife; and has performed consulting services for Bristol Myers Squibb, PACT Pharma, and Roche/Genentech. C.A.K. is a co-inventor on patent applications related to TCRs targeting public neoantigens unrelated to the current work. M.D.H. received a research grant from BMS; personal fees from Achilles, Arcus, AstraZeneca, Blueprint, BMS, Genentech/Roche, Genzyme, Immunai, Instil Bio, Janssen, Merck, Mirati, Natera, Nektar, Pact Pharma, Regeneron, Shattuck Labs, and Syndax; and equity options from Arcus, Factorial, Immunai, and Shattuck Labs. A patent filed by MSKCC related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. J.D.W. is a consultant for Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Larkspur, Maverick Therapeutics, Merck, Psioxus, Recepta, Tizona, Trishula, Sellas, Surface Oncology, and Werewolf Therapeutics. J.D.W. receives grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: xenogeneic (canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo, and PharmaMar and is on the scientific advisory boards of Elucida, Bridge, and Harpoon. B.Y.N. and X.G. are employees and stockholders of Genentech/Roche., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600 -mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy., Patients and Methods: In a phase III trial, patients with treatment-naive BRAFV600 -mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety., Results: A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A ( P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B ( P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated., Conclusion: Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy., (© 2022. Springer Nature Limited.)

Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2., (© 2022. The Author(s).)

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

Purpose: TRX518 is a mAb engaging the glucocorticoid-induced TNF receptor-related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors., Patients and Methods: TRX518 monotherapy was dose escalated (Part A) and expanded (Part B) up to 4 mg/kg loading, 1 mg/kg every 3 weeks. Parts C-E included dose-escalation (2 and 4 mg/kg loading followed by 1 mg/kg) and dose-expansion (4 mg/kg loading) phases with gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E). Primary endpoints included incidence of dose-limiting toxicities (DLT), serious adverse events (SAE), and pharmacokinetics. Secondary endpoints were efficacy and pharmacodynamics., Results: A total of 109 patients received TRX518: 43 (Parts A+B), 30 (Part C), 26 (Part D), and 10 (Part E), respectively. A total of 67% of patients in Parts D+E had received prior anti-PD(L)1 or anti-CTLA-4. No DLTs, treatment-related SAEs, and/or grade 4 or 5 AEs were observed with TRX518 monotherapy. In Parts C-E, no DLTs were observed, although TRX518-related SAEs were reported in 3.3% (Part C) and 10.0% (Part E), respectively. Objective response rate was 3.2%, 3.8%, 4%, and 12.5% in Parts A+B, C, D, and E, respectively. TRX518 affected peripheral and intratumoral regulatory T cells (Treg) with different kinetics depending on the combination regimen. Responses with TRX518 monotherapy+anti-PD1 combination were associated with intratumoral Treg reductions and CD8 increases and activation after treatment., Conclusions: TRX518 showed an acceptable safety profile with pharmacodynamic activity. Repeated dose TRX518 monotherapy and in combination resulted in limited clinical responses associated with immune activation. See related commentary by Hernandez-Guerrero and Moreno, p. 3905., (©2022 The Authors; Published by the American Association for Cancer Research.)