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

Marta Español-Rego, Carlos Fernández-Martos, Elena Elez, Carles Foguet, Leire Pedrosa, Nuria Rodríguez, Ana Ruiz-Casado, Estela Pineda, Joan Cid, Raquel Cabezón, Helena Oliveres, Miquel Lozano, Angels Ginés, Angeles García-Criado, Juan Ramon Ayuso, Mario Pagés, Miriam Cuatrecasas, Ferràn Torres, Timothy Thomson, Marta Cascante, Daniel Benítez-Ribas, Joan Maurel, Marta Español-Rego, Carlos Fernández-Martos, Elena Elez, Carles Foguet, Leire Pedrosa, Nuria Rodríguez, Ana Ruiz-Casado, Estela Pineda, Joan Cid, Raquel Cabezón, Helena Oliveres, Miquel Lozano, Angels Ginés, Angeles García-Criado, Juan Ramon Ayuso, Mario Pagés, Miriam Cuatrecasas, Ferràn Torres, Timothy Thomson, Marta Cascante, Daniel Benítez-Ribas, Joan Maurel

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.

Trial registration: ClinicalTrials.gov NCT03152565.

Keywords: Metabolism; Resistance; Vaccines.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
1A. Immune-metabolic signature (IMMETCOLS) baseline expression. 1B. Gene expression pro-immune signature (GEP) baseline expression 1C. Changes in concentrations of cytokines comparing each patient baseline serum with that obtained at day 56 after
Fig. 2
Fig. 2
Correlation of both signatures GEP and IMMETCOLS with response rate (2A and 2B), progression free survival or overall survival (2C, 2D). 2E and 2F. Kaplan–Meier curves for overall survival with GEP and IMMETCOLs signatures
Fig. 3
Fig. 3
Liver biopsies before and after therapy (2-month evaluation) analyzed in both signatures. 3A. Changes in gene expression with IMMETCOLS signature. 3B. Changes in gene expression with GEP signature. 3C. Radiological CT basally and at 2 month therapy
Fig. 4
Fig. 4
A total of 143 genes significantly changed between pre and post-therapy samples. 4A. More critically GO biological processes changed before and after therapy. 4B. Top 20 genes down-regulated in post-therapy samples compared with pre-therapy samples. 4C. Volcano plot
Fig. 5
Fig. 5
Proposed metabolic rewiring (with lipid consumption instead of only glutamine and glucose feeding). This is the first clinical evidence that this metabolic adaptation is used by colorectal cancer cells, after avelumab and ADC therapy, to boost oxidative stress and contribute to cancer progression. Oxidative stress is compensated in IMMETCOLS cluster 3 tumors with anti-oxidative pathways such as pentose-phosphate pathway

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