Pluripotent Stem Cell-derived Genome-edited Sarcoma-targeted T cells for Immunotherapy
Current approaches to adoptive cell therapy (ACT) for metastatic synovial sarcomas are limited by the difficulty of obtaining sufficient numbers of less-differentiated T cells and existence of immune suppressive pathways. We and others have shown that induced pluripotent stem cells (iPSCs) can provide an unlimited source of autologous less-differentiated T cells that persist long, mediate regression of large established tumors, and establish immunological memory in vivo. Similar to other tumor-specific T cells, however, iPSC-derived T cells that express Programmed cell Death-1 (PD-1) can be inhibited by Programmed cell Death Ligand-1 (PD-L1) which is upregulated in many tumors including sarcoma. Systemic administration of anti-PD-1/PD-L1 can reinvigorate exhausted tumor-infiltrating lymphocytes, but come with immune-related adverse effects.
Genome editing in iPSCs holds great promise for biomedical research and regenerative medicine. Recently, an RNA-guided, DNA-cleaving interference pathway from bacteria [the type II bacterial clustered regularly interspaced short palindromic repeats (CRISPR)/(CRISPR-associated) Cas system] was developed as an efficient and versatile technology for genome editing in eukaryotic cells. The potential of iPSCs can be further enhanced by genome editing, which may be used to study individual gene function, to track cells or endogenous proteins, and to correct genetic defects for gene therapy.
In the proposed study, we hypothesize that effector function and survival of iPSC-derived T cells can be further enhanced by genome editing in iPSCs to generate T cells that do not express inhibitory receptor, PD-1. The rationale for this research is that confirmation of the in vivo efficacy of T cells derived from genome-edited human iPSCs in a robust preclinical model will provide the basis for using these cells as a novel treatment for cancer. The long-term goal of our research is to elicit efficient immune responses to targeted antigens and facilitate the development and application of more effective ACT. The objective of this proposal is to determine antitumor efficacy of genome-edited human iPSC-derived T cells.
We will test this hypothesis using two specific aims to ensure that: 1) generation of human iPSCs that can differentiate to T cells specific to NY-ESO-1 antigen, highly expressed in the majority of synovial sarcomas and myxoid/round cell liposarcomas and.; 2) genome-editing of human iPSCs to disrupt inhibitory checkpoint genes enhances anti-tumor reactivity of regenerated iPSC-derived T cells. Given that ACT is safe and effective in patients with sarcoma, successful completion of this proposed study will provide a solid foundation for the future development of personalized cancer treatment using autologous iPSC-derived T cells.