Cancer neoantigens targeted by adoptive T cell transfer: private no more

Abstract

Effector T cell responses directed toward cancer neoantigens mediate tumor regression following checkpoint blockade or adoptive T cell immunotherapy, but are generally "private", thus requiring considerable effort for their identification. In this issue of the JCI, Malekzadeh et al. show that a fraction of patients with epithelial cancers mount antigen-specific T cell responses to "hot spot" p53 mutations that in some cases are shared among patients. This work suggests that other genes frequently mutated in human cancer can be immunogenic, thus offering a rapid way to screen for cancer neoantigens that can be targeted by subsequent T cell-based therapies.

Figure 1. Accelerated neoantigen identification pipeline.

A panel of hot spot mutations is tested by target sequencing. Should a known HLA/mutant peptide pair be identified, the patient’s own T cells can be engineered by TCR gene therapy as an off-the-shelf strategy from a previously created library of TCRs. Alternatively, the patient’s TILs can be assessed for neoantigen reactivity by using a collection of mutant peptides from genes frequently mutated in human cancer and by using IFN-γ secretion or 41BB upregulation as a readout. These approaches will decrease the time requested to produce the engineered cell products or vaccine formulations for personalized therapy. Should the patient not harbor hot spot mutations in the tumor, the standard pipeline for neoantigen identification using whole-exome/RNA sequencing and epitope prediction is applied. Assessment of candidate peptides by T cell assays in vitro may be performed as an optional validation step.