Original version
Journal for ImmunoTherapy of Cancer (JITC). 2023, 11 (8):e006944, DOI: https://doi.org/10.1136/jitc-2023-006944
Abstract
Background Multiple myeloma (MM) cancers originate from plasma cells that have passed through the germinal center reaction where somatic hypermutation of Ig V regions takes place. Myeloma protein V regions often express many mutations and are thus a rich source of neoantigens (traditionally called idiotopes (Id)). Therefore, these are highly tumor-specific and excellent targets for immunotherapy. Methods We have developed a DNA Id vaccine which as translated protein targets conventional dendritic cells (cDC) for CCL3-mediated delivery of myeloma protein V regions in a single-chain fragment variable (scFv) format. Vaccine efficacy was studied in the mouse MM model, mineral oil-induced plasmacytoma 315.BM. Results The Id vaccine protected mice against a challenge with MM cells. Moreover, the vaccine had a therapeutic effect. However, in some of the vaccinated mice, MM cells not producing H chains escaped rejection, resulting in free light chain (FLC) MM. Depletion of CD8 + T cells abrogated vaccine efficacy, and protection was observed to be dependent on cDC1s, using Batf3 -/- mice. Modifications of scFv in the vaccine demonstrated that CD8 + T cells were specific for two mutated V H sequences. Conclusions V H neoantigen-specific CD8 + T cells elicited by CCL3-containing Id vaccines had a therapeutic effect against MM in a mouse model. MM cells could escape rejection by losing expression of the H chain, thus giving rise to FLC MM.