Résumé
BACKGROUND: Metastatic colorectal cancer (mCRC) is one of the major causes of death worldwide. The relative therapeutic resistance of these populations to I/O drives the need for new treatment. STC-1010 (Brenus Pharma) therapeutic vaccine is developed by tumor cells stimulation to induce overexpression of TAA and neoantigens to mimic mCRC resistant cancer cells allowing education of the immune system to target the patient’s tumor cells harboring the same resistance factors. We report results of a study evaluating efficacy and safety of a 3 cell lines-based product namely “3CL-SH” (made of CT26, CMT93 and LTPA) physical stimulated (S=irradiation and heat shock) and haptenized (H) with immunostimulant in an anti-PD1 resistant MC38 colorectal tumor model grafted with its TME.
METHODS: Female C57BL/6 mice bearing MC38 tumor model grown in vivo under anti-PD1 selection pressure (anti-PD1; 12.5 mg/kg; qw) to obtain MC38 resistant to anti-PD1 treatment (MC38 antiPD1R). Two sampled tumors from these mice were cut into fragment of 2 mm2 and reimplanted in the right flank of naïve syngenic mice. 5 groups (15 mice per group) were allocated to: G1) Control group: Isotype/placebo/vehicle G2) Anti-PD1/placebo/vehicule G3) Anti PD1/placebo-GM-CSF/endoxan G4) Isotype/3CL-SH-GM-CSF/endoxan G5) Anti-PD1/3CL-SH-GM-CSF/endoxan. Endoxan, vehicule and antibodies were administered by IP, vaccine or placebo subcutaneously. Overall survival (OS) and tumour growth (TG) were recorded until 1600 mm3 or safety endpoint. 5 mice per group were euthanized and sampled for immunophenotyping. In parallel, we conducted the identification and relative quantification of proteins expressed in 3CL-SH by LC-MS/MS and flow cytometry.
RESULTS: Flow cytometry analysis shows that HSP-70 expression was significantly upregulated in each of the three cell lines of the 3CL-SH compared to untreated cells. LC-MS/MS analysis demonstrated that cell lines of 3CL-SH display overexpression of membrane proteins of interest such as Lamp 1, MDR1A/B and Fas Receptor. The group treated with 3CL-SH significantly improves the survival of mice bearing MC38PD1R tumor model vs the control group (Log-rank Mantel-Cox test, pvalue=0.0368) and we observed a non-benefit of the combination of 3CL-SH and anti-PD1 drug in concomitant injections. The immunophenotyping data show statistical increase in the infiltration of anti-tumor populations (CD8+ T cells, M1) in the tumors treated with 3CL-SH but also an increase in M2. No side effect or inflammatory reaction towards the 3CL-SH is evidenced.
CONCLUSION: The 3CL-SH treatment presents a promising antitumor efficacy on the aggressive MC38 PD1R model, resulting in a significative gain of survival and anti-tumoral changes in the immune infiltrate of treated animals. More studies are needed to evaluate the benefit of a combination with ICI.
Citation Format: Céline Gongora, Elsa Kress, Claudine Vermot-Desroches, Lionel Chalus, Jeremy Forget, Benoît Pinteur, Paul Bravetti, Charles Dumontet, Antoîne Italiano. Antitumor activity of a novel allogeneic colorectal cancer vaccine in C57BL/6 mice bearing MC38 anti-PD1 resistant colon carcinoma syngeneic model with TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2051.