Article
Author: Thomson, Timothy ; Benítez-Ribas, Daniel ; Cid, Joan ; Foguet, Carles ; Ginés, Angels ; García-Criado, Angeles ; Torres, Ferràn ; Cabezón, Raquel ; Pagés, Mario ; Fernández-Martos, Carlos ; Cuatrecasas, Miriam ; Rodríguez, Nuria ; Oliveres, Helena ; Lozano, Miquel ; Pineda, Estela ; Cascante, Marta ; Maurel, Joan ; Ruiz-Casado, Ana ; Ayuso, Juan Ramon ; Elez, Elena ; Pedrosa, Leire ; Español-Rego, Marta
Background:Immune check-point blockade (ICB) has shown clinical benefit in mismatch repair-deficient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-proficient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic effects.
Methods:This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor effects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efficacy of the combination. The primary end-point was 40% progression-free survival at 6 months with a 2 Simon Stage.
Results:A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design first-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1–5.3 months] and overall survival was 12.2 months [3.2–23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted significant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, inflammation and oxidative stress pathways.
Conclusions:The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the first-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapy-induced tumor vulnerabilities.