Developing Novel CAR-T Cell Therapy For Hematologic Malignancies
Qing Yi
MD PhDHouston Methodist Research Institute
Project Term: July 1, 2023 - June 30, 2026
We observed that patients with many hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that can kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in vivo. In this proposal, we will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities. Completing these studies are critical for developing new and effective CAR-T therapy for patients with hematologic malignancies who are still dying from the disease.
Although B-cell tumors and myeloma patients are treated with FDA-approved monoclonal antibodies or CAR-T cells, many other types of hematologic cancer patients have no effective immunotherapy agents. Moreover, patients with myeloma or B-cell cancer relapse during or after the immunotherapy. Thus, there is an urgent and unmet need for developing more effective immunotherapy strategies for patients with hematologic cancers. We observed that patients with hematologic cancers expressed high levels of DKK1 and generated novel human DKK1-A2 CAR-T cells that recognize DKK1-A2 complex on tumor cells and kill cancer cells from HLA-A2+ patients with myeloma, lymphoma, or leukemia. We also found that Th9-polarized T cells have enhanced antitumor effects in mouse models. The goal of this proposal is to develop a new and effective CAR-T cell therapy for HLA-A2+DKK1+ patients with myeloma, lymphoma, or leukemia. We will determine 1) whether and how Th9-polarized DKK1-A2 CAR-T cells are promising effector T cells for immunotherapy of HLA-A2+DKK1+ human patients, and 2) whether Th9-polarized DKK1-A2 CAR-T cells are associated with reduced on- and off-target toxicities. Completing these studies are critical for providing important information for conducting a first-in-human phase-I clinical trial to determine the dose, safety, and toxicity of DKK1-A2 CAR-T cells in HLA-A2+DKK1+ patients with hematologic cancers.