Session: 703. Cellular Immunotherapies other than CAR-T Cells: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Diseases, Lymphoid Malignancies, Myeloid Malignancies
CD1d-restricted invariant Natural Killer (iNK) T cells are rare but powerful innate T cells that influence the adaptive immunity toward tumor surveillance or immune-tolerance via the production of Th1- or Th2-type cytokines and exert anti-tumor effects via iNK T cell receptor (TCR) or NK receptor (NKR)-mediated cytolysis or facilitating the cross-priming of antigen-specific T cells. Finally, iNK T cells can mediate antiviral immunity through NK-like properties and facilitate the immune-reconstitution in a humanized mouse model. Thus, we hypothesied that iNK T cells can play as a master-regulator to improve the outcome of ASCT by preventing GVHD while promoting GVT effects, anti-viral immunity, and donor immune-reconstitution in ASCT.
Here, we report an effective strategy to preferentially expand human iNK T cells from adult donor (AD) and cord blood (CB) to a clinically meaningful number in an extremely high purity via a single antigenic stimulation. CB-derived iNK T cells were highly enriched with IL-10 producing neuropilin1 (NRP1)+Th2+CD4+ iNK T cells (NKT10) and displayed superior in vitro and in vivo anti-GVH effects compared with AD-iNK T cells. Despite superb regulatory properties, CB-iNK T cells expressed a variety of NK receptors and exerted direct anti-tumor activity against CD1dhigh B lymphoblastic cells when pulsed with agonist glycolipid antigen. Further, the cytotoxicity of CB-iNK T cells can be re-directed against HLA-A2+ myeloid leukemia cells via an expression of 8F4CAR, chimeric antigen receptor targeting PR1/HLA-A2 myeloid antigen. Moreover, CB-iNK T cells facilitated the expansion of antigen-specific donor T cells in vitro when co-activated and enhanced donor GVT effects in xenogenic GVHD/GVT model. Lastly, CB-iNK T cells promoted the xenograft engraftment in a humanized murine model. Mechanistically, we demonstrated that NRP1, highly expressed on NKT10 subset, inhibited Th1 cytokine production by iNK T cells during antigenic stimulation leading to Th2 functional polarization.
In conclusion, NKT10-enriched CB-iNK T cells maintain a prototypical multi-functionality and are suitable candidate as off the shelf cell therapy platform engineered to prevent/treat GVHD and relapse, and to promote donor immune-reconstitution after ASCT, improving the transplantation outcome.
Disclosures: Shpall: FibroBiologics: Other: Scientific Advisor; Zelluna Immunotherapy: Other: Scientific Advisor; Axio Research: Current Employment, Other: Scientific Advisor; Adaptimmune Limited: Other: Scientific Advisor; National Marrow Donor Program: Other: Board of Directors/Management.