Résumé
BACKGROUND: Metastatic colorectal cancer (mCRC) is a major cause of death. Unmet medical need in immunotherapy is high for MSS patients and still present for MSI-H/dMMR patients. STC vaccine (Brenus Pharma) is composed of selected tumor cell lines, stimulated to overexpress TAA/TSA and neoantigens including resistant factors that are further haptenized to form immunogenic hapten-protein complex to educate the immune system to recognize and target the patient's tumor cells expressing the same resistance factors. We report results of two studies aiming to A) evaluate efficacy of a one cell line-based product (CT26) physical stimulated (S=irradiation and heat shock) and/or haptenized (H) w/o immunostimulant (IS=cyclophosphamide + mGM-CSF w/o BCG) and to B) investigate a potential increase of antitumoral effect of 3 cell lines vaccine (3CL-SH made of CT26, CMT-93, LTPA).
STUDY DESIGN and METHODS: Female BALB/c mice were subcutaneously grafted with 5.104 CT26-WT cells. In study A, 9 groups (10 mice per group) are allocated to: G1) Control group, G2) IS, G3) CT26-S, G4) CT26-H, G5) CT26-SH, G6) CT26-S+IS, G7) CT26-H+IS, G8) CT26-SH+IS, G9) CT26-SH+IS+BCG. In study B, 5 groups (20 mice per group) are allocated to: G1) Control group, G2) CT26-SH + IS, G3) 3CL-SH, G4) 3CL-SH + IS once a week for 3 weeks and G5) 3CL-SH + IS twice a week for 4 weeks. Treatments were administered subcutaneously. Overall survival (OS) and tumor growth (TG) were recorded until 1000 mm3, safety endpoint or on D41 (study A) or D50 (study B).
RESULTS: Stimulated cell-based treatments with IS (CT26-SH + IS) significantly increases OS compared to control group (Study A: G1/G8 p=0.0046 & study B: G1/G2 p=0.0023). Best mOS among groups is observed with 3CL-SH+IS (Study B: G1/G4 p<0.0001 38d vs 27d, Log-rank test). A direct comparison of 3CL-SH+IS and CT26-SH+IS confirmed a highly significant added benefit in favour of the 3 cell lines vaccine (Study B: G2/G4 p=0.0475) compared to the one cell line treatment. In addition, IS reinforced the effect of cell-based treatment, with CT26-SH (Study A: G1/G8, p<0.0001 at D20, Study B: G1/G2 p<0.0001 at D24) and with 3CL-SH (Study B: G4/G3 p=0.0004). Addition of BCG to CT26-SH+IS does not improve efficacy (Study A: G8/G9 p=NS). Results showed a significant impact on TG when cells were both physically stimulated then haptenized, such as CT26-SH (study A: G1/G5, p=0.003 at D20) or 3CL-SH (study B G1/G3 P<0.0001 at D24) compared to the control group. 3CL-SH+IS exhibits a significant efficacy on TG (Study B: G1/G4 p=0.0053 or G1/G5 p=0.0018) and OS whatever the administration schedule No side effect or inflammatory reaction towards the vaccines have been evidenced.
CONCLUSION: Brenus STC vaccine based on physical stimulation and haptenization demonstrated a significant anticancer effect in mice with immunostimulant and confirmed a better efficacy of the 3 cell lines vaccine versus a single cell line vaccine. Further studies are ongoing to test the efficacy of STC vaccine in PD1 resistant preclinical model and in combination with SOC.
Citation Format: Céline Gongora, Jacqueline Taleb, Benoît Pinteur, Lionel Chalus, Fanny De Luca, Paul Bravetti, François Ghiringhelli. Efficacy results of a novel vaccine composed of stimulated and haptenized tumors cells in Balbc mice grafted with murine colon adenocarcinoma CT26 cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P003.