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

Abstract

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.

Trends in Melanoma Phase 3 Clinical Trials since 2010: Is there Hope for Advanced Melanoma Therapies beyond Approved Treatment Mechanisms?

“…Despite the limited success of exploratory therapies, a slew of additional treatment mechanisms are being studied in ongoing trials and may pique the interest of patients and clinicians when approved therapies are not an option. Dendritic cell vaccine therapies, for example, have shown promise in phase 2 trials and continue on in phase 3 [ 51 ]. VEGFR blockers which are efficacious for other cancers [ 52 ] also show promising results in early phase trials in melanoma [ 53 ].…”

The construction of a hypoxia-based signature identified CA12 as a risk gene affecting uveal melanoma cell malignant phenotypes and immune checkpoint expression

“…Hypoxia has been suggested to affect immunotherapy by tumor cell anaerobic glycolysis; the metabolite adenosine secreted to the ECM suppressed T cell activation, and thus, excused the tumor cells from immune attack ( 25 ), indicating the promising therapeutic strategy developed from cancers with hypoxia. Currently, hypoxia has presented association with immunotherapy response or immune checkpoint effects in many cancers ( 26 – 28 ), whereas only a clinical trial consisting of mixed melanoma patients suggested that the PD-1 blockage responders of immunotherapy has a reduced hypoxia transcriptomic change ( 29 ). In this study, we observed many upregulated immune checkpoints in the high-risk group and C1 subtype and transcription similarity with the samples that responded to the PD-1 therapy, demonstrating the potential of hypoxia as the target to improve immunotherapeutic effects.…”

Longitudinal Modulation of Loco-Regional Immunity in Ovarian Cancer Patients Receiving Intraperitoneal Chemotherapy

“…Our study further highlights the role of B cells in ovarian cancer biology as shown by studies in other tumor types [ 35 , 38 , 39 ]. For example, a recent study demonstrated that formation of B cell-rich TLS structures is associated with epitope spreading and predicts the occurrence of clinical responses to DC vaccines in patients with advanced PD1-resistant melanoma [ 40 ]. Additionally, results from studies on humoral immunity in response to vaccines for influenza or COVID-19 in patients with solid tumors treated with cytotoxic therapies also reveal a preserved ability for seroconversion during or after treatment, further highlighting the conserved state of B cell responsiveness during chemotherapy [ 41 , 42 ].…”