Résumé
Colorectal cancer (CRC) is the 2nd cause of cancer-related death worldwide. Recent tremendous progress has installed immunotherapy as a treatment option and opened multiple ways to address therapeutic challenges for CRC patients. Accordingly, Brenus-Pharma developed a therapeutic cancer vaccine, based on stimulating tumor cells (STC) technology with physical (irradiation and heat shock) or chemical (chemotherapy) stress, coupled to haptenization making vaccine more immunogenic. We first validated STC technology using a “one cell line” mouse surrogate vaccine in CT26 mouse model showed an efficacy of the combination of stress plus haptenization. We next prepared a mouse surrogate vaccine using three murine tumoral cell lines the mSTC-1010 (CT26, CMT93 and LTPA), and confirmed the value of using 3 cell lines to increase the antigenicity. In addition, mSTC-1010 associated with immunostimulant (cyclophosphamide and mGM-CSF), combined or not with chemotherapy (FOLFOX or FOLFIRI) led to a significant decrease of tumor volume, a M1-oriented macrophage response (immunohistochemical, iNOS/CD163 >1), and an increase of T lymphocyte infiltration. Following, we confirmed these proofs-of-concept with the human vaccine, STC-1010, composed of 6 drug substances (DS) derived from 3 CRC human cell lines (HCT116, HT29 and Lovo), stressed physically or chemically and then haptenized. Transcriptomic analysis showed the induction of stress-related pathways with a certain specificity for each DS, allowing their quantification in the STC-1010 by deconvolution strategy. Moreover, proteomic analysis showed specific protein expression modification of each DS and confirmed the rationale of using 3 cell lines with 2 stresses to cover the CRC heterogeneity. More than 200 cancer-related proteins from the Atlas proteins’ database were identified in theSTC-1010 including CRC-specific proteins, tumor plasticity and tumor-associated antigens. In ex vivo model, the efficacy of the vaccine was shown, through that CD8+ T cells primed by the STC-1010 treated DCs (versus control), induced massive apoptosis of cancer cells (p<0,001). In chicken embryo Chorio-Allantoid Membrane (CAM) model, STC-1010 significantly increased IL-12, IL-2 and IFN-gamma expression (versus control p<0.02). Results from this immune reactive model showed a significant increase of tumor necrosis (p=0,0267), metastasis regression (-49%), and increased infiltration of CD4+, CD8+ (versus control). The good tolerability and reproducible efficiency of the STC-1010 vaccine in these different clinical models allow to plan a first-in-human phase I/II clinical trial for metastatic CRC(mCRC) patients. A dose-escalation and cohort extension phase I followed by a phase IIa with STC-1010 plus immunostimulant, associated to mFOLFOX6 w/o bevacizumab, will be performed for MSS mCRC patients to evaluate the safety and preliminary effectiveness in human.
Citation Format: George Alzeeb, Céline Gongora, Corentin Richard, Romain Boidot, Tanguy Fortin, Yan Wang, Alban Bessede, Benoit Pinteur, Lionel Chalus, Corinne Tortorelli, Paul Bravetti, François Ghiringhelli. Efficacy of the STC-1010 a new allogenic cancer vaccine in different colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5003.