Genetically Modified T-Cell-Based Adoptive Immunotherapy in Hematological Malignancies

Figure 3

Identification of neoantigens and engineered neoantigen-specific TCR-T-cell-based adoptive immunotherapy in hematological malignancies. (a) Schematic procedures of TCR-T-cell-based adoptive immunotherapy. Both tumor cells and tumor-infiltrating lymphocytes (TIL) are isolated from a patient with hematological malignancies, respectively. The isolated tumor cells are subsequently subjected to gene sequencing (e.g., whole genome sequencing, WGS; whole-exome sequencing, WES), mass spectrometric analysis (e.g., HLA peptidome), and/or bioinformatic analysis, promoting the identification of tumor-specific neoantigens. To validate the immunogenicity of the identified neoantigens, APCs expressing the identified neoantigens are cocultured with the TILs isolated from this patient. The specific population of TILs bearing neoantigen-specific TCRs, which exhibit cell proliferation or cytokine secretion in response to the stimulation of APCs expressing tumor-specific neoantigens, can be isolated, and the neoantigen-specific TCRs can then be cloned successfully. Subsequently, the cloned neoantigen-specific TCRs are transduced into the patient-derived T-cells, generating genetically modified neoantigen-specific T-cells via ex vivo activation and expansion. The modified T-cells bearing the neoantigen-specific TCRs can be adoptively transferred to the patient and target tumor cells bearing tumor-specific neoantigens with high specificity for elimination. In addition, the intratumor heterogeneity can be dissected by the single-cell sequencing or other technologies, which can facilitate the identification of clonal neoantigens and thus improve T-cell immunoreactivity. (b) Tumor cells presenting neoantigen derived peptides can be recognized and killed by genetically modified T-cells bearing the responsible neoantigen-specific TCRs. Genome editing and gene transfer technologies and other alternative measures can be utilized to modify the components of other alternative pathways for immune enhancement, ultimately providing an optimized approach to improve TCR-T-cell-based therapeutics.

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