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The study was funded by grants from the FIS PI17/00732 from Instituto de Salud Carlos III, Premi Fi de Residencia Emili Letang from Hospital Clinic Barcelona, Plan Nacional de I + D (PID-107139RB-C21 to DB-R and PID2020-115051RB-I00 to MC) and Grupo Espanol Multidisciplinar en Cancer Digestivo (GEMCAD). The study was funded with Grants from Catalan Agency for Management of University and Research Grants (AGAUR) (2014-SGR-474, 2017-SGR-1174 and 2017-SGR-1033), Fundacio la Marato de TV3 (201330.10), Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Fundacion Olga Torres (Modalitat A. 2019/2020) to JM. IMMETCOLS signature is under patent protection (EP21382772.8.); This research was financially supported by GEMCAD and (OR Avelumab was provided) by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945) and Pfizer.

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A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study

Publicated to:Cancer Immunology Immunotherapy. 72 (4): 827-840 - 2023-01-01 72(4), DOI: 10.1007/s00262-022-03283-5

Authors: Espanol-Rego, Marta; Fernandez-Martos, Carlos; Elez, Elena; Foguet, Carles; Pedrosa, Leire; Rodriguez, Nuria; Ruiz-Casado, Ana; Pineda, Estela; Cid, Joan; Cabezon, Raquel; Oliveres, Helena; Lozano, Miquel; Gines, Angels; Garcia-Criado, Angeles; Ayuso, Juan Ramon; Pages, Mario; Cuatrecasas, Miriam; Torres, Ferran; Thomson, Timothy; Cascante, Marta; Benitez-Ribas, Daniel; Maurel, Joan

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Abstract

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.

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