Cellular therapy against public neoantigens

Abstract

Neoantigen-targeted therapies have typically been based upon personalized neoantigen-specific vaccines; however, in this issue of JCI, van der Lee et al. describe the development of a potential cellular immunotherapy targeting a "public" neoantigen derived from nucleophosmin 1 (NPM1), which is mutated in approximately 30% of acute myeloid leukemias (AMLs). The authors use reverse immunology to predict, and biochemically confirm, NPM1-derived neoepitopes (ΔNPM1) and then generate high-avidity T cell clones and retrovirally transduced T cell populations that kill NPM1-mutated AML. This study provides a general approach to adoptive cellular therapy that can be applied to targeting other tumors with public neoantigens.

Figure 1. Developing neoantigen-specific T cells by reverse immunology.

For a “public” neoantigen, a common mutation is identified. In the case of NPM1, this is a 4 base pair insertion. The translational result of the mutation is predicted, which for NPM1 is an out of frame amino acid sequence at the C terminus. The new peptide sequences are tested for predicted binding to an HLA type of interest to determine the most likely neoepitopes. Targeted mass spectrometry is performed to compare peptide epitope sequences from a biological sample (e.g., cell line or primary tumor) to a synthetic peptide standard. High-avidity antigen-specific T cell clones are generated, and their T cell receptors are sequenced. The T cell receptor is incorporated into a viral vector into subsequent generation of T cell populations for use in ACT.