Tailor-made adoptive cell therapy for advanced cancers: detection, enrichment, and isolation of neoantigen-reactive T cells

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) or gene-engineered T cells can lead to tumor regression in metastatic cancer patients. However, selecting specific targets, that can prevent on-target off-tumor toxicity, is still a hurdle for the development of effective and safe cell therapy. Developments in genomic analyses and bioinformatical tools allowed the mapping of patient-specific tumor-associated neoantigens, mutated genes targeted by immune cells, that subsequently led to the development of several cancer immunotherapies. In the Surgery Branch, a clinical pipeline was developed for ACT of neoantigen-reactive T lymphocytes for chemotherapy-resistant metastatic cancer patients. Yet, effectively identifying and harnessing neoantigen-reactive T cells for patient treatment remains a challenge. Thus, we developed sensitive methods for identifying, enriching and/or isolating neoantigen-reactive T cells from tumor samples or, alternatively, from peripheral blood of the patients. These methods rely on the enrichment of T cells based on activation markers from tumor digests or memory T cell subsets from peripheral blood followed by expansion of the cells in unique conditions that allow the enrichment of neoantigen-reactive precursors. In summary, these approaches allowed us to identify new T cell reactivities that were missed by conventional neoantigen screening methods and to isolate neoantigen-reactive T cell receptors for ACT.