Abstract CT105: Randomized trial of dendritic vs tumor cell patient-specific vaccines: 5-year analysis

Abstract

Eltrapuldencel-T (CLBS20) consists of autologous dendritic cells loaded with antigens from irradiated, self-renewing, autologous tumor cells that potentially present the entire repertoire of unique patient-specific tumor-associated antigens resulting from nonsynonymous mutations in each patient's melanoma tumor cell line. In a single-arm phase 2 trial, metastatic melanoma patients treated with s.c. injections of CLBS20 had a 2-year overall survival (OS) of 73% (NCT00948480). In a randomized phase 2 trial (NCT00436930), 2-year OS was 72% compared to 31% for a tumor cell vaccine (TCV) consisting of irradiated cancer cells from an autologous tumor cell line. Mild local injection site reactions was the most common toxicity. This report focuses on 5-year follow up data from the randomized trial. During October 2007 to February 2011 42 patients were randomized 1:1 to receive CLBS20 or TCV. After resection of a metastatic tumor, if/when a cell line was established, patients were eligible for randomization if/when they were referred by their managing physician. Both products were mixed in 500 micrograms GM-CSF and injected s.c. weekly for three weeks, then monthly for up to 5 months. Cell lines were successfully established rapidly enough for possible clinical use for 78/183 (43%); 42/78 (54%) patients were referred for randomization. The median time from tumor submission to cell line success was 3.0 months, then 2.5 weeks for safety testing and documentation, then another 3.7 months to randomization. At the time of tumor harvest 24 patients were stage 4 and 18 were recurrent stage 3; at randomization 33 were stage 4 and 9 stage 3. Trends toward imbalances of baseline characteristics were biased against the CLBS20 arm (elevated LDH, detectable disease, brain metastases). There were no differences in tumor resection site, days in cell culture, or days to randomization. Because of leukapheresis and dendritic cell production for CLBS20, the median time from randomization to first dose was 43 days for CLBS20 vs 8 days for TCV. All patients were treated as randomized; survival was calculated from randomization date. At this analysis, 33 (79%) were dead and the 9 survivors had been followed 5 years. OS was higher in the CLBS20 arm: median 42.2 vs 19.9 months for all and 40.4 vs 16.9 for stage 4 patients, and in subsets defined by measurable disease, and serum LDH. The only variable associated with 3-year OS was randomization to CLBS20 (p = 0.018). A patient with refractory progressive measurable disease experienced a delayed complete response that was ongoing at 5 years. In an era before widespread use of anti-BRAF/anti-MEK and anti-checkpoint agents, CLBS20 monotherapy was associated with encouraging 5-year OS. Because of its unique mechanism of action, absence of toxicity, and apparent benefit regardless of tumor burden, CLBS20 is worthy of further evaluation as a monotherapy or in combination with other anti-melanoma therapies. Citation Format: Robert O. Dillman, Edward F. McClay, Thomas T. Amatruda, Carol DePriest, Denysha J. Carbonell, Andrew N. Cornforth. Randomized trial of dendritic vs tumor cell patient-specific vaccines: 5-year analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT105.

An Update on the Relevance of Vaccine Research for the Treatment of Metastatic Melanoma

“…Long-term follow-up has confirmed a more than doubling of overall survival despite no difference in progression-free survival. DCV treatment was the only variable associated with survival beyond 3 years in a multivariate analysis, at a time when all patients were dead or followed beyond 3 years with no patients lost to follow-up [43]. To date, this is the only direct comparison of a DCV versus a TCV using autologous cancer-cell-derived TAA.…”

Is there a role for therapeutic cancer vaccines in the age of checkpoint inhibitors?

“…In similar analysis of metastatic melanoma patients who were treated with dendritic cell vaccines, the response rate for defined TAA was 11/201 (5.5%) for 9 studies in which defined TAA were loaded onto DC, and 14/115 (12.2%) for 7 studies utilizing autologous DC loaded with autologous TAA (p=0.034), but only 8/116 (6.9%) for 6 studies in which DC or tumor cell sources were allogeneic 31 . In a randomized phase II trial in metastatic melanoma, patients injected with DC loaded with TAA by phagocytosis of irradiated autologous tumor cells had an improved survival at the time of initial analysis, 32 and eventually showed a median survival of 42.2 months and 3-year survival of 61%, compared to a median survival of 19.9 months and 3-year survival of 25% for patients treated with injections of the irradiated tumor cells as the source of TAA 33 . Pooled data confirmed therapeutic benefit regardless of whether patients had no evidence of disease at the time of treatment 34 .…”

Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial

“…melanoma [5]. Clinical studies utilizing autologous dendritic cells loaded with antigens from autologous tumor cells have been especially promising [6][7][8][9]. A randomized phase II trial tested two vaccines featuring autologous tumor antigens (ATA): injections of autologous dendritic cells loaded ex vivo with antigens from autologous tumor cell lines (DCV), and tumor cell vaccines (TCV) consisting of irradiated autologous proliferating tumor cells [8,9].…”

“…Clinical studies utilizing autologous dendritic cells loaded with antigens from autologous tumor cells have been especially promising [6][7][8][9]. A randomized phase II trial tested two vaccines featuring autologous tumor antigens (ATA): injections of autologous dendritic cells loaded ex vivo with antigens from autologous tumor cell lines (DCV), and tumor cell vaccines (TCV) consisting of irradiated autologous proliferating tumor cells [8,9]. An early analysis showed that DCV was associated with better survival [8], and this was confirmed when 5-year follow up showed a more than doubling of median survival and 3-year survival rate, and a 70% reduction in the risk of death [9].…”