PMID- 34782430 OWN - NLM STAT- MEDLINE DCOM- 20220111 LR - 20220716 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 11 DP - 2021 Nov TI - Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma. LID - 10.1136/jitc-2021-003675 [doi] LID - e003675 AB - BACKGROUND: A first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2(+) patients with advanced melanoma. METHODS: Patient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-gamma enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins. RESULTS: Sixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against >/=3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8(+) T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis. CONCLUSIONS: Combined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents. TRIAL REGISTRATION NUMBER: NCT01876212. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Storkus, Walter J AU - Storkus WJ AUID- ORCID: 0000-0001-8961-4444 AD - Dermatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA storkuswj@upmc.edu. FAU - Maurer, Deena AU - Maurer D AD - Translational and Regulatory Affairs, Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. FAU - Lin, Yan AU - Lin Y AD - Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA. FAU - Ding, Fei AU - Ding F AD - Biostatistics, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. FAU - Bose, Anamika AU - Bose A AD - Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India. FAU - Lowe, Devin AU - Lowe D AD - Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, Texas, USA. FAU - Rose, Amy AU - Rose A AD - Clinical Research Services, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. FAU - DeMark, Melissa AU - DeMark M AD - Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. FAU - Karapetyan, Lilit AU - Karapetyan L AD - Medicine, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. FAU - Taylor, Jennifer L AU - Taylor JL AD - Dermatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. FAU - Chelvanambi, Manoj AU - Chelvanambi M AD - Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. FAU - Fecek, Ronald J AU - Fecek RJ AD - Microbiology and Immunology, LECOM, Greensburg, Pennsylvania, USA. FAU - Filderman, Jessica N AU - Filderman JN AD - Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. FAU - Looney, Timothy J AU - Looney TJ AD - Immunology, Singular Genomics, Austin, Texas, USA. FAU - Miller, Lauren AU - Miller L AD - Molecular Biology, Thermo Fisher Scientific, Santa Clara, Carlsbad, California, USA. FAU - Linch, Elizabeth AU - Linch E AD - Molecular Biology, Thermo Fisher Scientific, Santa Clara, Carlsbad, California, USA. FAU - Lowman, Geoffrey M AU - Lowman GM AUID- ORCID: 0000-0002-1498-4165 AD - Molecular Biology, Thermo Fisher Scientific, Santa Clara, Carlsbad, California, USA. FAU - Kalinski, Pawel AU - Kalinski P AD - Medical Oncology and Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA. FAU - Butterfield, Lisa H AU - Butterfield LH AUID- ORCID: 0000-0002-3439-9844 AD - Research and Development, Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. AD - Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA. FAU - Tarhini, Ahmad AU - Tarhini A AUID- ORCID: 0000-0002-3193-9702 AD - Cutaneous Oncology and Immunology, Moffitt Cancer Center, Tampa, Florida, USA. FAU - Tawbi, Hussein AU - Tawbi H AUID- ORCID: 0000-0003-1942-851X AD - Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Kirkwood, John M AU - Kirkwood JM AD - Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. LA - eng SI - ClinicalTrials.gov/NCT01876212 GR - P01 CA234212/CA/NCI NIH HHS/United States GR - P30 CA047904/CA/NCI NIH HHS/United States GR - R01 CA169118/CA/NCI NIH HHS/United States GR - R01 CA204419/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (Cancer Vaccines) RN - RBZ1571X5H (Dasatinib) SB - IM MH - Antigens, Neoplasm/*therapeutic use MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Cancer Vaccines/pharmacology/*therapeutic use MH - Dasatinib/pharmacology/*therapeutic use MH - Dendritic Cells/*metabolism MH - Female MH - Humans MH - Male MH - Melanoma/*drug therapy/pathology MH - Pilot Projects MH - Prospective Studies PMC - PMC8593702 OTO - NOTNLM OT - cellular OT - dendritic cells OT - immunity OT - melanoma OT - tumor microenvironment OT - vaccination COIS- Competing interests: WJS, DM, YL, FD, LK, AB, DBL, AR, MD, JLT, MC, RJF, JNF and PK declare no competing interests. TJL was an employee of Thermo Fisher Scientific during the performance of this work. TJL, LM, EL and GML are/were employees of Thermo Fisher Scientific during the performance of this work. LHB declares the following unrelated advisory activities: StemImmune/Calidi Scientific and Medical Advisory Board, April 6, 2017-present; SapVax Advisory Board meetings November 15, 2017; December 6, 2018; NextCure, Scientific Advisory Board, 2018-2020; Western Oncolytics, Scientific Advisory Board, 2018-present; Torque Therapeutics, Scientific Advisory Board, 2018-2020; Khloris, Scientific Advisory Board, 2019-present; Pyxis, Scientific Advisory Board, 2019-present; Cytomix, Scientific Advisory Board, 2019-present; Vir, Scientific Advisory Board meeting, February 2020; DCprime, Scientific Advisory Board meeting, November 2020; RAPT, Scientific Advisory Board, 2020-present; Takeda, Scientific Advisor, 2020-present; EnaraBio scientific advisor, February 2021. AT declares the following unrelated advisory activities: Receipt of fees for consulting and/or advisory board participation from Partner Therapeutics, Merck, Bristol Myers Squibb, Novartis, Genentech-Roche, Array Biopharma, Sanofi-Genzyme/Regeneron, Pfizer, EMD Serono, NewLink Genetics, BioNTech, Immunocore, and Eisai; participation in a Data Safety Monitoring Board for Incyte; involvement with institution contracted research with Merck, OncoSec, Genentech-Roche, Bristol Myers Squibb, Amgen and Clinigen. HT declares the following unrelated consulting Honoraria: BMS, Novartis, Merck, Genentech, Eisai, Iovance, Boxer Capital, Karyopharm. Research Funding to Institution: BMS, Novartis, Merck, Genentech, GSK. JMK declares the following unrelated advisory activities and funding: Advisory Role: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Elsevier, Amgen, Checkmate Pharmaceuticals, Harbour BioMed, Istari Oncology, OncoSec, Scopus BioPharma, Pfizer; Speakers' Bureau: Bristol Myers Squibb unbranded IO; Research Funding: Amgen, Bristol Myers Squibb, Castle Biosciences, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapeutics, Novartis, Merck. EDAT- 2021/11/17 06:00 MHDA- 2022/01/12 06:00 PMCR- 2021/11/15 CRDT- 2021/11/16 06:13 PHST- 2021/10/17 00:00 [accepted] PHST- 2021/11/16 06:13 [entrez] PHST- 2021/11/17 06:00 [pubmed] PHST- 2022/01/12 06:00 [medline] PHST- 2021/11/15 00:00 [pmc-release] AID - jitc-2021-003675 [pii] AID - 10.1136/jitc-2021-003675 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Nov;9(11):e003675. doi: 10.1136/jitc-2021-003675.