Peptides derived from genomic variants in allogeneic melanoma vaccine induce T cell activation

CARRI, IBEL; SCHWAB, ERIKA; NIELSEN, MORTEN; MORDOH, JOSÉ; BARRIO, MARÍA MARCELA

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2023

VACCIMEL is a recently approved cancer vaccine composed of four allogeneic human cell lines rationally selected to cover a wide range of tumor-associated antigens (TAA) in melanoma. T-cells reactive to TAA and private neoantigens increased during vaccination. However, the immune response (IR) to vaccine antigens arising from somatic mutations and polymorphisms remains unexplored. To study this, we performed whole-exome sequencing of paired tumor/ normal samples from a responsive patient (pt#32) and the vaccine cells; also RNAseq and MHC typing were carried out. Variant calling was performed by comparing the vaccine and patient’s exomes with MuTect2, and annotation with VEP. Non-synonymous coding variants were used to predict T-cell epitope candidates using MuPeXI. Similarly, we predicted pt#32 tumor neoantigens. In both cases, immunogen candidates were ranked based on allele and expression in the vaccine, predicted peptide-MHC (pMHC) affinity, and stability. IR to 103 candidates was evaluated with pt#32 PBMCs post-treatment by ELISPOT. Comparison of the vaccine and pt#32’s germinal exomes revealed 10,566 coding variants, 62% of which were reported in COSMIC and 20% were shared with pt#32’s tumor. After vaccination, we found 18 ELISPOT+/46 candidate peptides expressed in pt#32’s tumor; 20 ELISPOT+/44 not expressed in the pt#32’s tumor, and 4 ELISPOT+/11 only expressed in the patient’s tumor. This analysis reveals that VACCIMEL offers a large panel of antigen candidates that may stimulate a therapeutic antitumor IR in melanoma. The computational approach successfully identified antigens in allogeneic cell lines, evidencing the relevance of protein expression and pMHC stability in immunogenicity. Besides, our results demonstrate that the immune system simultaneously responds to a high number of antigens, either vaccinal or private, proving that the IR against epitopes not expressed in the patient’s tumor, was not detrimental to the relevant IR against neoantigens and TAA.