-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4818 Cord-Derived Invariant Natural Killer T Cells As Novel Cell Therapy to Improve the Outcome of Hematopoietic Stem Cell Transplantation

Program: Oral and Poster Abstracts
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
Monday, December 9, 2024, 6:00 PM-8:00 PM

Abel Trujillo-Ocampo1*, Maison Grefe1*, Pamella Borges2*, Jelita Clinton3*, Hong He, MD, PhD4*, Dan Li, PhD5*, Ling Yu6*, Martiela Vaz de Freitas7*, Lisa St. John, PhD6*, Karen Clise-Dwyer, PhD8*, Gheath Alatrash, PhD, DO9, Dinler Amaral Antues10*, Qing Ma, PhD11*, Jeffrey J. Molldrem, MD12, Elizabeth J. Shpall, MD13 and Jin S. Im, MD, PhD13

1The University of Texas MD Anderson Cancer Center, Department of Hematopoietic Biology and Malignancy, Houston, TX
2University of Houston, Department of Biology and Biochemistry, Houston
3The University of Texas MD Anderson Cancer Center, Department of Hematopoietic Biology and Malignancy, Houston
4Department of Hematopoietic Biology and Malignancy, University of Texas M.D. Anderson Cancer Center, Houston, TX
5University of Texas M.D. Anderson Cancer Center, Department of Hematopoietic Biology and Malignancy, Houston, TX
6Department of Hematopoietic Biology and Malignancy, University of Texas M. D. Anderson Cancer Center, Houston, TX
7the University of Houston, Department of Biology and Biochemistry, Houston, TX
8Department of Hematopoietic Biology & Malignancy, The University of Texas M.D. Anderson Cancer Center, Houston
9Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Pearland, TX
10The University of Houston, Department of Biology and Biochemistry, Houston, TX
11Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX
12Departments of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX
13Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX

Allogeneic stem cell transplantation (ASCT) is a curative immunotherapy for patients with hematologic malignancies and performed more than 7000 per year in the US. Here, patients receive the conditioning chemo-radiation to eradicate the residual blood cancer, followed by donor stem cells to reconstitute the donor immunity. However, only 30-40% patients with high-risk leukemia survive long-term due to the relapse of disease from the insufficient graft versus tumor (GVT) effects of donor T cells and treatment-related complications including Graft-Versus-Host-Disease (GVHD) due to dysregulated donor T cells and life-threatening infections from the poor graft function. Thus, there is an unmet need for the innovative strategy to mitigate the major causes of the treatment failure - the relapse, GVHD, infection, and poor graft function, leading to the better transplant outcome.

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.

*signifies non-member of ASH