Sensitizing potential of a novel stimulated and haptenized vaccine in immunotherapy resistant metastatic colorectal cancer
Colorectal cancer (CRC) is the second most common solid organ cancer. Immunotherapy has recently emerged as a promising treatment for the MSI-H/dMMR metastatic CRC. However, MSS patients still cannot benefit from this therapy. STC therapeutic 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. This educates the immune system to recognize and target the patient’s tumor cells expressing the same resistance factors. We report results of the transcriptomic changes induced by the different treatment and culture conditions on each cell line; highlighting the potential of this three cell lines vaccine to sensitize immunotherapy-resistant tumors to anti-PD1 therapy.
STUDY DESIGN and METHODS
In this study, three cell lines have been cultured: HCT116, HT29, and LoVo. Each of these cell lines has been subjected to four growth conditions: RCB) the parental cell line cultured in standard medium 10% SVF or MCB) 2% SVF; DSA) MCB condition plus low-dose irradiation and heat shock or DSB) cultured with chemotherapy exposure. STC-1010 vaccine (DP) is the mix of the haptenized DSA and DSB culture conditions of these three cell lines. Total RNA of all those samples have been extracted and sequenced on Illumina NextSeq 500. Sequences have been aligned against the GRCh38 reference genome using Kallisto v0.46.1 software. Differential abundance and enrichment analyses have been performed with DESeq2 v1.34.0 and clusterProfiler v4.2.0 R packages, respectively.
A first overview of the whole-transcriptome shows that each cell line has its very own profile and that the DP condition reflects a balanced mixture of the three transcriptomes. HT29-DSA condition displays 1048 differentially expressed genes (DEG) compared to MCB condition and altered 59 pathways, whereas the HT29-DSB condition shows 1288 DEG and altered 46 pathways. Both conditions show an overexpression of DNA repair pathways. LoVo-DSA condition displays 1044 DEG compared to MCB condition and altered 59 pathways, especially DNA repair pathways. HT29-DSB condition shows 1791 DEG and altered 130 pathways, mostly impacting the tumor immunity. HCT116-DSA condition displays 407 DEG compared to MCB condition and altered 72 pathways, especially DNA repair pathways. HCT116-DSB condition shows 1824 DEG and altered 51 pathways. Both conditions show an overexpression of pathways involved in tumor immunity.
Brenus STC vaccine based on physical and chemical stimulations and haptenization reveals a promising potential to sensitize MSS CRC immunotherapy resistant tumors to immune checkpoint inhibition therapy. Further studies are ongoing to profile and analyze the proteosurfaceome of each cell line.
Corentin Richard, Sandy Chevrier, Lionel Chalus, Jeremy Forget, Benoît Pinteur, Paul Bravetti, Romain Boidot; Abstract 3566: Sensitizing potential of a novel stimulated and haptenized vaccine in immunotherapy resistant metastatic colorectal cancer. Cancer Res 15 June 2022; 82 (12_Supplement): 3566. https://doi.org/10.1158/1538-7445.AM2022-3566