Socializing Individualized T-Cell Cancer Immunotherapy Richard G Vile  Molecular Therapy  Volume 24, Issue 7, Pages 1170-1173 (July 2016) DOI: 10.1038/mt.2016.132 Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 How to become a neoantigen. (a) A normal self-protein (NSP) is expressed in antigen-presenting cells (APCs) in the thymus. Processing generates short epitopes, some of which (red line) bind with high affinity to major histocompatibility complex (MHC) molecules. These MHC–epitope complexes are sampled by T cells with different T-cell receptors (TCRs). In the thymus, any T cell with a TCR that binds well to the MHC–epitope complex (TCR 1) is activated to die, is lost, and will not recognize NSPs in the periphery on normal tissues. Any T cells with a TCR that does not recognize the MHC–epitope complex (TCR 2) will not be activated, will pass into the circulation, and will not recognize NSPs presented by normal tissues. (b) In a developing tumor that expresses NSPs, mutation can occur in the nsp gene, changing the conformation of the epitope (red arrow). A subpopulation (“branch”) of tumor cells develops within a population with normal NSPs, but expressing the neoantigen (NSP*). (c) The altered epitope of NSP* binds with high affinity to MHC molecules. T cells with a TCR that previously did not recognize NSPs (TCR 2; see a) now bind well to the MHC–altered epitope complex, and are potentially antitumor effectors. However, because of the immunosuppressive activities of chronic tumor growth in vivo, these T cells are heavily suppressed, exhausted, or even deleted. Therefore, although the number of potential neoantigens may be large (~50–100), T-cell reactivity against only a very small proportion can be detected in the patient's T-cell repertoire. (d) Deep sequencing of the cancer genomes identifies the mutated NSP* epitope and predicts it to be a high-affinity binder. Presentation of the predicted epitope by APC in vitro to (patient T cells or) normal healthy donor-derived T cells activates T cells with a TCR that recognizes the mutated epitope (TCR 2 from the patient or TCR 3 from a healthy donor). TCR 3 can then be cloned from these normal T cells and (e) expressed in peripheral blood mononuclear cells (PBMCs). Adoptive transfer of TCR-transduced PBMCs into a patient will lead to killing of tumor cells expressing the neoantigen NSP* but not of tumor cells that did not acquire the nsp* mutation. PD-L1, programmed death ligand 1; TGF-β, transforming growth factor-β. Molecular Therapy 2016 24, 1170-1173DOI: (10.1038/mt.2016.132) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions