Randomized phase II trial of autologous dendritic cell vaccines versus autologous tumor cell vaccines in metastatic melanoma: 5-year follow up and additional analyses

Abstract

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.

Keywords: Autologous tumor cell lines; Dendritic-cell vaccines; Metastatic melanoma; Patient-specific vaccines; Tumor-cell vaccines.

Conflict of interest statement

Authors’ information

ROD is a former president of the Society for Immunotherapy of Cancer (2000–2002, then called the International Society for the Biotherapy of Cancer) after serving two previous terms on its Board of Directors. For more than a decade he was Chairman of the Cancer Biotherapy Research Group. From 1989 to 2011 he was Medical Director of the Hoag Cancer Center, where this trial was conducted, and Scientific Director for the Hoag Cell Biology Laboratory, where the investigational products used in this trial were manufactured.

Ethics approval and consent to participate

The MACVAC clinical trial was conducted per the Declaration of Helsinki after approval by the Western Institutional Review Board (Seattle, WA), and in accord with assurances filed with and approved by the Department of Health and Human Services. All patients gave written informed consent prior to randomization. In addition to Institutional Review Board oversight, conduct of the trial was monitored by an external consultant, and Hoag Hospital’s institutional clinical research oversight committee. The protocol and manufacturing procedures were reviewed by the US Food and Drug Administration in association with BB-IND 5838 for the tumor cell vaccine, 8554 for the dendritic cell vaccine. The trial was registered on ClinicalTrials.gov (NCT00436930) on 28 July 2009.

Consent for publication

Not applicable

Competing interests

ROD is an employ of AIVITA Biomedical, Inc. ANC is an employee of TCR2. GIN is an employ of AVITIA Biomedical, Inc. ROD, ANC, and GIN are former employees of Caladrius Biosciences, Inc. and retain stock in that company. None of the other authors declared any conflicts as related to this trial.

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Figures

Fig. 1

a Overall Survival by treatment arm. Median OS was 43.4 months versus 20.5 months for DCV and TCV respectively (18.6 to > 60 vs 9.3 to 32.3 months, 95% CI) (p = 0.194 Mantel-Haenzsel; p = 0.088 Gehan’s Wilcoxon). Adjusted Cox proportional hazard model revealed a 70% reduction in risk of death in the DCV arm (HR = 0.304, 95% CI 0.131 to 0.702, p = 0.0053, Wald test). Variables in multivariate analysis included age, stage, LDH, performance status, gender, M1 category, whether patient had measurable disease, treatment with dendritic cell vaccine, and whether patient lived outside California (see Additional file 4: Table S3. b Progression free survival (PFS) by treatment arm. Median PFS was 5.4 months in the DCV arm and 3.7 months in the TCV arm (4.0 to 8.0 vs 1.0 to 5.0 months, 95% CI p = 0.498)

Fig. 2

a Baseline analysis of serum cytokines. In order to summarize data for all tests, data is expressed as change in relation to values for set of assays compared to 3 normal control volunteers. There was substantial variation in markers among patients. At baseline most markers were elevated compared to normals, especially in the DCV arm. b The post treatment analysis of cytokines one week after the third weekly vaccine injection, showing changes compared to baseline. The changes associated with the two vaccines were quite different. Levels increased for nearly all markers in the TCV arm, but decreased for eight of the 17 groupings in the DCV arm