Neoantigen-Specific Adoptive Cell Therapies for Cancer: Making T-Cell Products More Personal

Abstract

Mutation-derived neoantigens are taking central stage as a determinant in eliciting effective antitumor immune responses following adoptive T-cell therapies. These mutations are patient-specific, and their targeting calls for highly personalized pipelines. The promising clinical outcomes of tumor-infiltrating lymphocyte (TIL) therapy have spurred interest in generating T-cell infusion products that have been selectively enriched in neoantigen (or autologous tumor) reactivity. The implementation of an isolation step, prior to T-cell in vitro expansion and reinfusion, may provide a way to improve the overall response rates achieved to date by adoptive T-cell therapies in metastatic cancer patients. Here we provide an overview of the main technologies [i.e., peptide major histocompatibility complex (pMHC) multimers, cytokine capture, and activation markers] to enrich infiltrating or circulating T-cells in predefined neoantigen specificities (or tumor reactivity). The unique technical and regulatory challenges faced by such highly specialized and patient-specific manufacturing T-cell platforms are also discussed.

Keywords: adoptive cell therapy (ACT); cancer immunotherapy; enrichment; neoantigens; tumor-infiltrating lymphocyte (TIL).

Figure 1

General workflow for personalized enrichment of antigen-specific T-cells from bulk tumor-infiltrating lymphocyte (TIL) [or peripheral blood lymphocyte (PBL)] cultures. T-cells can be isolated from the patient's infiltrating or circulating lymphocyte populations. Following neoantigen discovery and validation, antigen-specific T-cells are enriched by bulk cultures and expanded in vitro to meet the numbers required for reinfusion. FACS, fluorescence-activated cell sorting; MACS, magnetic bead-activated cell sorting; WES, whole-exome sequencing; MS, mass spectrometry.

Figure 2

Toolset for personalized enrichment of T-cell infusion products. Current technologies can be grouped into neoantigen-specific purification strategies, which rely on predictions and predefined epitope selection, and agnostic enrichment strategies based on coculture with autologous tumor or a priori identification of tumor-reactive T-cells. The main advantages and disadvantages of each approach are listed. CD8⁺ (and CD4⁺) T-cells of interest can be isolated starting from tumor infiltrating lymphocyte (TIL) or peripheral blood lymphocyte (PBL) cultures by fluorescence-activated (FACS) or magnetic bead-activated (MACS) cell sorting.