Journal Article

Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma

Chelvanambi, Manoj, Rose, Amy, Fecek, Ronald J, Butterfield, Lisa H, Lowe, Devin, Taylor, Jennifer L, Ding, Fei, Tarhini, Ahmad, Kirkwood, John M, Storkus, Walter J, Bose, Anamika, Kalinski, Pawel, Miller, Lauren, Maurer, Deena, Linch, Elizabeth, Lin, Yan, Looney, Timothy J, DeMark, Melissa, Lowman, Geoffrey M, Filderman, Jessica N, Tawbi, Hussein, Karapetyan, Lilit

2021

نظرة عامة

BackgroundA 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.MethodsPatient 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-γ 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.ResultsSixteen 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.ConclusionsCombined 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 numberNCT01876212.

• الناشر: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• موضوع: Antigens / Antigens, Neoplasm - therapeutic use / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biopsy / Blood vessels / Cancer / Cancer Vaccines - pharmacology / Cancer Vaccines - therapeutic use / cellular / Clinical trials / Clinical/Translational Cancer Immunotherapy / Dasatinib - pharmacology / Dasatinib - therapeutic use / Dendritic cells / Dendritic Cells - metabolism / Enzymes / Female / Flow cytometry / Gene expression / Humans / Immune response / immunity / Immunotherapy / Lymphocytes / Male / Melanoma / Melanoma - drug therapy / Melanoma - pathology / Patients / Peptides / Pilot Projects / Prospective Studies / T cell receptors / tumor microenvironment / Tumors / vaccination / Vaccines