免疫检查点抑制剂联合个体化树突状细胞疫苗用于转移性黑色素瘤患者

Metastatic melanoma patients treated with monoclonal antibody immune checkpoint inhibitors (ICI) have a response rate of 35% to 50% and a 5-year overall survival (OS) of about 50%. Personal DC-ATA vaccines are a promising investigational immunotherapy consisting of autologous dendritic cells (DCs) loaded ex vivo with autologous tumor antigens (ATA) from self-renewing autologous cancer cells. In metastatic melanoma clinical trials conducted in the pre-ICI era, DC-ATA was associated with increased 5-year OS compared to historical and contemporary randomized patients. NCT03743298 is a phase IB trial testing the combination of ICI + DC-ATA. Eligible patients have advanced melanoma, at least one resectable lesion, and a treatment plan that includes an anti-programmed death molecule (PD-1) regimen that does not include an anti-CTLA-4 antibody. A cell suspension from fresh resected metastatic melanoma tissue is incubated in liquid media containing growth factors that favor stem cells and progenitor cell proliferation. A lysate of irradiated tumor cells (ITC) from the short-term cell line serves as ATA. Patients' peripheral blood mononuclear cells are enriched for monocytes that are differentiated into DC by culturing with interleukin-4 and granulocyte-macrophage colony-stimulating-factor. DC and ATA lysate are co-incubated for antigen loading. During the 8-9 weeks while DC-ATA is being manufactured, patients receive standard ICI-based therapy, then DC-ATA is injected s.c. for six months at weeks 1, 2, 3, 8, 12, 16, 20, and 24 concurrently with ICI-based treatment. Patients are monitored for adverse events (AEs); objective tumor response is determined in patients with measurable disease. 8 patients have completed treatment: 3 males, 5 females, mean age 75 years (62 to 89 years). At the time of enrollment, clinical stages were stage 3 regional recurrence (n=2), M1A (n=1), M1B (n=2), and M1C (n=3). Before starting concurrent DC-ATA, 3 patients received the anti-PD-1 pembrolizumab, 4 received opdualag (anti-PD-1 nivolumab + anti-LAG3 relatlimab), and 1 received pembrolizumab followed by opdualag. 61 of 64 possible DC-ATA doses were injected. One patient discontinued DC-ATA because of persistent rash and pruritus that began during pembrolizumab. All patients experienced local injection site reactions. No patient experienced grade 3 or 4 AEs; the highest-grade AEs experienced were 1 or 2 (both n=4). All patients experienced local injection site reactions. The RECIST response rate for the 6 patients with measurable disease is 100% (54% to 100% 95% CI), 2 complete and 4 partial. OS from enrollment is 56+, 36+, 30+, 19+, 17+, 14+, 14, and 11+ months. DC-ATA can be safely administered concurrently with ICI without increased toxicity and may increase efficacy over what might be expected with ICI alone. Additional testing of sequential/concurrent ICI + DC-ATA combination immunotherapy is warranted.