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Purpose: In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs., Methods: We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed., Results: Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression., Conclusion: This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.

Background: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy., Methods: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete., Findings: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy., Interpretation: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting., Funding: The US National Institutes of Health and the Dana-Farber Cancer Institute., Competing Interests: Declaration of interests JDS declares research support paid to their institution from Merck, BMS, Regeneron, Debiopharm, and the NCI; consulting or participation on a scientific advisory board, and travel fees and payment for lectures from Genentech, Immunitas, Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, Astellas, Stimit, and Merck; expert witness fees from Pearson Doyle Mohre and Pastis, Kline and Specter, and Heidell, Pittoni, Murphy and Bach; stock options from Immunitas; and equity in Doximity. SMA declares research support paid to her institution from Merck, Exilixis, Abbvie, Kura Oncology, Amgen, and Nektar. RDG declares support for the present manuscript from a grant from the NCI of the National Institutes of Health (NIH); grants or contracts (to his institution) from Pfizer, Mirati, Daiichi Sankyo, Jounce Therapeutics, Helsinn, BMS, Merck, Janssen, and Takeda; honoraria from Rockpointe CME, Targeted Oncology, OncLive, and the Society for Immunotherapy of Cancer; reimbursement for travel for meetings from Pfizer and AstraZeneca; participation on advisory boards for Mirati, Daiichi Sankyo, AstraZeneca, Sanofi, Oncocyte, Jazz Pharmaceuticals, BluePrint Medicines, and Pfizer; and that he is co-chair of the Hoosier Cancer Research Network Thoracic Clinical Trial Working Group. CL declares honorarium for chairing the data and safety monitoring board for Delcath. JH declares participation on advisory boards for Bayer and Merck, and research funding from Merck, Boston Biomedical, Treos Bio, Senhwa Biosciences, Bayer, Incyte, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, Taiho Pharmaceutical, Effector Therapeutics, and G1 Therapeutics. JLA declares research support from Pfizer; scientific advisory board membership for the Lustgarten Foundation, Stand Up to Cancer, Moleculin Biotech, Bessor Pharma, and Fujifilm; stock options from Bessor Pharma and Moleculin Biotech; and honoraria for data and safety monitoring board membership from Panbela Therapeutics and the Pancreatic Cancer Action Network. SKJ declares grant funding to her institution from the NCI and the Cancer Therapy Evaluation Program, and is a consultant and adjudication committee member for Merck, IMX Medical, and Syntactx. NVU has consulted for QED, Ipsen, Taiho, Incyte, AstraZeneca, and Astellas, and declares research funding from Taiho, Eli Lilly, Ipsen, and EMD Serono, and long position holdings in Natera and Exact Sciences. KLS is a member of the data and safety monitoring committee for the Case Comprehensive Cancer Center. JMJ declares consulting for Foundation Medicine. HP declares research grants or funding to their institution from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics, ArrayBioPharma, Bayer, BeiGene, BJ Bioscience, BMS, Daiichi Pharmaceutical, Eli Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-LaRoche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, Mabspace Biosciences, MacroGenics, Medimmune, Medivation, Merck, Millennium, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, RePare Therapeutics, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, TurningPoint Therapeutics, Vedanta Biosciences, and Xencor, and reimbursement for meetings or travel from Daiichi Sankyo and Vedanta. LCV declares consulting fees for Janssen, BMS, Takeda, Jazz, and Daiichi Sankyo. JLW declares research support from the NCI of the NIH. RHM declares research support from ViewRay and AstraZeneca; scientific advisory board participation for ViewRay and AstraZeneca; and expert witness fees from the US Attorney's Office Northern District of New York. MarMA has consulted for Genentech, BMS, Merck, AstraZeneca, Maverick, Blueprint Medicine, Syndax, Ariad/Takeda, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono, and Panvaxal/NovaRx; declares research funding (to their institute) from AstraZeneca, Lilly, Genentech, BMS, and Merck; and declares participation on a data safety monitoring board and advisory board for BMS and Apollomics. SJR declares research support from BMS, Merck, Affimed, and KITE/Gilead, is on the Scientific Advisory Board of Immunitas Therapeutics, and has equity in Immunitas Therapeutics. AMM declares research support from Merck, BMS, Transgene, Incyte, Trisalus, Genentech, and the NIH; consulting fees from Zosano; advisory board participation for BMS, AstraZeneca, Incyte, and Dynavax; and stock options in MultiplexThera. CJW declares equity in BioNTech, U24 research support from the NCI of the NIH, and research funding from Pharmacyclics. FSH declares 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 the methods for treating MHC class I polypeptide-related sequence A disorders (number 20100111973; with royalties paid), tumour antigens and uses thereof (number 7250291; issued), angiopoiten-2 biomarkers predictive of anti-immune checkpoint response (number 20170248603; pending), compositions and methods for the identification, assessment, prevention, and treatment of melanoma using PD-L1 isoforms (number 20160340407; pending), therapeutic peptides (number 20160046716; pending), therapeutic peptides (number 20140004112; pending), therapeutic peptides (number 20170022275; pending), therapeutic peptides (number 20170008962; pending), therapeutic peptides (number 9402905; issued), methods of using pembrolizumab and trebananib (pending), vaccine compositions and methods for restoring NKG2D pathway function against cancers (number 10279021; issued), antibodies that bind to MHC class I polypeptide-related sequence A (number 10106611; issued), and anti-galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses (number 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. AL is currently an employee of Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade., Patients and Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink., Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1-7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3-4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3-5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8 + and CD8 + /PD-1 + /Ki-67 + T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood., Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies., (©2021 American Association for Cancer Research.)

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Expression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage-IV melanoma patients treated with or without anti-CTLA4 (ipilimumab). The screen identified an array of peptides that predominantly induced CD4 + T cell responses. XIAP epitope-specific CD4 + T cells revealed proliferative responses to melanoma cells that express XIAP. Humoral responses to XIAP were also explored. Cellular and humoral responses to XIAP were associated with beneficial clinical outcomes after ipilimumab-based treatment, supporting XIAP as a potential therapeutic target.