Clinical Trials of Cancer Immunotherapies最新文献

{"title":"Abstract A010: Personalized neoantigen-targeting vaccines for high-risk melanoma generate epitope spreading","authors":"Zhuting Hu, Donna E. Leet, Siranush Sarkizova, Rebecca L. Holden, Jing Sun, Susan Klaeger, K. Clauser, S. Shukla, Wandi Zhang, S. Carr, E. Fritsch, B. Pentelute, N. Hacohen, D. Keskin, P. Ott, Catherine J. Wu","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A010","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A010","url":null,"abstract":"Cancer vaccines have been envisioned as a key tool for generating effective cancer therapy. Tumor neoantigens are ideal targets because of their exquisite tumor-specific expression (arising from somatic mutations of the tumor) and high level of immunogenicity (lacking of central tolerance against them). Recently, we and others have demonstrated that personalized neoantigen-targeting vaccines are safe, feasible and highly immunogenic in phase I trials of stage III/IV resected high-risk melanoma (Ott & Hu, Nature 2017; Sahin, Nature 2017). Our neoantigen vaccine (NeoVax), consisting of up to 20 long peptides and poly-ICLC, induced strong polyfunctional neoantigen-specific T-cells that recognized patient tumor in vitro. In addition, 2 patients who were vaccinated and received anti-PD1 checkpoint blockade (CPB) therapy upon relapse had durable complete responses (CRs). Thus far, these vaccine studies have been performed in the adjuvant setting, preventing direct assessment of on-target tumor killing in vivo due to the lack of evaluable tumor. On the other hand, the detection of epitope spreading (the broadening of the immune response from the initially targeted epitope to others) would indirectly suggest therapy-induced tumor lysis, whereby the release of additional tumor antigens leads to further tumor-specific T-cell activation. To explore the hypothesis that NeoVax+/- CPB generates epitope spreading, we evaluated the T-cell responses against neoantigens and tumor associated antigens (TAAs) that were not included in the original vaccine in 3 patients. We performed experiments for a patient with stage III melanoma who has remained disease-free (Pt.3) after vaccination and 2 patients with resected stage IV disease who recurred but achieved CR after CPB (Pts. 2&6). For the assessment of CD8+ T-cell responses, we designed 9-10 aa epitope length peptides (predicted by NetMHCpan and/or a mass spectrometry [MS]-based prediction algorithm (Abelin, Immunity 2017) or detected physically on the tumor’s surface class I complexes by MS) arising from 3 categories of antigens: (i) neoantigen peptides; (ii) TAA peptides based on high tumor gene expression; (iii) TAA peptides, detected on the tumor by MS (available for 2 of the 3 patients). For testing of CD4+ T-cell responses, we designed 15-16 aa peptides that spanned predicted neoepitopes from category i. Per patient, we designed peptides against up to 70 genes (~20 for each category). PBMCs from pre- , week 16 post-vaccination and post-CPB were stimulated with peptide pools (~10 peptides/pool) for 2 weeks, followed by restimulation with individual peptides in IFN-γ ELISPOT assays to deconvolute the peptides. Thus far, we have tested CD8+ T-cells against 71 neoantigens (category i) and 22 TAAs (ii) from Pts. 2 and 6, and CD4+ T-cells against 30 neoantigens from all 3 patients. We identified CD4+ T-cells specific for 3 peptides (mut-AGAP3 [Pt.2], -EYA3 and -P2RY4 [Pt.3]) in the week 16 samples that were not inclu","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"21 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116971273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A006: Phase 1 study to evaluate the safety and tolerability of MEDI4736 (durvalumab, durva) + tremelimumab (treme) in patients with advanced solid tumors","authors":"M. Callahan, K. Odunsi, M. Sznol, J. Nemunaitis, P. Ott, P. Dillon, R. Schneider, Andrew J. Park, P. Schwarzenberger, T. Ricciardi, M. Macri, A. Ryan, R. Venhaus, J. Wolchok","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A006","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A006","url":null,"abstract":"Durvalumab (durva) is a human IgG1 monoclonal antibody (mAb) that blocks programmed cell death ligand-1 (PD-L1). Tremelimumab (treme) is a human IgG2 mAb inhibitor of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Blocking these checkpoints can result in antitumor activity in some solid tumors. The targets for durva and treme are non-redundant, providing sound rationale for clinical testing of the combination.This is an ongoing phase 1, multicenter, open-label study (NCT01975831) with a dose escalation (3+3 design) and subsequent expansion phase. Patients with renal cell carcinoma (RCC), cervical (CC), colorectal (CRC), non-triple-negative breast (NTNBC), or ovarian (OC) cancer are included in the expansion phase. The protocol excludes patients who had prior exposure to anti-CTLA-4 or anti-PD-1/PD-L1 antibodies. Primary objectives are safety/tolerability and identification of maximum tolerated dose (MTD) of the combination. Secondary objectives include tumor response, progression-free survival (PFS), and overall survival (OS). The intent-to treat (ITT) analysis set includes all patients who received at least one dose of durva or treme and had the baseline and at least one post-baseline tumor assessment.As of 11 May 2018, 104 patients were treated (73.1% female; median age: 56 (30 to 80) years. Durva 1500 mg every 4 weeks (Q4W) X 12 and treme 75 mg Q4W X 4 was the regimen used for opening the expansion phase (n = 82 patients). The majority of treatment-related adverse events (TRAEs) for all patients were Grades 1 and 2. TRAEs ≥ Grade 3 were reported in 17 (16.3%) patients; the majority were diarrhea/colitis (n = 6) and abnormal liver function tests (n = 4) and responded to established treatment algorithms. There was 1 Grade 5 TRAE: multi-organ failure. Fifteen (14.4%) patients experienced TRAEs leading to treatment discontinuation; the majority were diarrhea/colitis (n = 6) and abnormal liver function tests (n = 5). No new toxicities were identified. Tumor response by immune-related Response Criteria (irRC) was assessed by tumor type in the ITT analysis set for all cohorts included in the expansion phase; the follow-up period was at least 12 months. Best overall responses (complete response (irCR), partial response (irPR) and stable disease (irSD)) are presented by tumor type. For OC (n = 27): irCR = 0, irPR = 2 (7.4%), irSD = 10 (37%); for CRC (n = 18): irCR = 1 (5.6%), irPR = 1 (5.6%), irSD = 2 (11.1%); for NTNBC (n = 16): irCR = 0, irPR = 1 (6.3%), irSD = 2 (12.5%); for RCC (n = 19): irCR = 0, irPR = 3 (15.8%), irSD = 11 (57.9%); and for CC (n = 16): irCR = 1 (6.3%), irPR = 3 (18.8%), irSD = 4 (25%) patients. PD-L1 status is not yet available. MSI status was collected retrospectively for patients with CRC; in this group, the patient with irPR had MSI-high status, and the MSI status of the patient with irCR is unknown. PFS and OS rates will be presented at the meeting. In conclusion, the durva and treme combination has a manageable safety","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"228 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114058338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}