Patient-specific dendritic cell vaccines with autologous tumor antigens in 72 patients with metastatic melanoma.
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ABSTRACT:
SUBMITTER: Dillman RO
PROVIDER: S-EPMC6688559 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Patient-specific dendritic cell vaccines with autologous tumor antigens in 72 patients with metastatic melanoma.
Dillman Robert O RO Cornforth Andrew N AN McClay Edward F EF Depriest Carol C
Melanoma management 20190531 2
<h4>Aim</h4>Metastatic melanoma patients were treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from irradiated cells from short-term autologous tumor cell lines.<h4>Patients & methods</h4>A total of 72 patients were enrolled in a single-arm Phase I/II (NCT00948480) trial or a randomized Phase II (NCT00436930).<h4>Results</h4>Toxicity was minimal. Median overall survival (OS) was 49.4 months; 5-year OS 46%. A 5-year OS was 72% for 18 recurrent s ...[more]
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Project description:BACKGROUND:Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. METHODS:Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. RESULTS:Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to >?60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio?=?0.304, p?=?0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. CONCLUSIONS:This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. TRIAL REGISTRATION:Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.
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Project description:Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. Cancer Immunol Res; 4(8); 669-78. ©2016 AACR.
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