Id-neoantigen vaccine induces therapeutic CD8(+) T cells against multiple myeloma: H chain-loss escapees cause FLC MM

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.