CAR T-Cell Therapy to Target CD94 in T/NK Cell Malignancies
Abstract
Genetically engineered T-cell therapy called chimeric antigen receptor (CAR) T-cell therapy has been shown to be potentially curative for patients with B-cell leukemias and lymphomas with four CAR T-cell therapy products approved in the last 5 years for the treatment of patients with various B-cell malignancies. However, the development of CAR T-cell therapy products for T/NK-cell leukemias and lymphomas has been challenging due to difficulty in identifying appropriate targets. We identified CD94 as a potential target for CAR T-cell therapy for certain T/NK-cell leukemias and lymphomas, which include extranodal NK/T-cell lymphoma, hepatosplenic T-cell lymphoma, aggressive NK-cell leukemia, T-large granular lymphocytic leukemia (T-LGL), and chronic lymphoproliferative disorder of NK cells (also known as NK-LGL). While these are rare malignancies, collectively, they represent a group with significant unmet clinical need and they fall into the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of blood cancers, lymphoma, and young adult cancers. Indeed, the median age of patients with aggressive NK-cell leukemia and hepatosplenic T-cell lymphoma is 30-40 years and their median survival is only 6-24 months. Similarly, in extranodal NK/T-cell lymphoma, which affects patients in their 40’s, outcomes are poor in those who have extensive disease or chemoresistant disease. T-LGL and NK-LGL have a median age of onset in the 60’s and have an indolent course, although a subset, exhibit aggressive disease and need novel therapies. We developed a CAR molecule to target the above malignancies from a proprietary antibody we generated against CD94. CAR T cells targeting CD94 were very effective at killing CD94-expressing NK-cell leukemia cell lines but not B-cell lymphoma cell lines that did not express CD94. In this proposal, we will investigate strategies to optimize the CAR design and then test them in preclinical studies including in mouse models of T/NK-cell leukemias and lymphomas to determine the optimal CAR T-cell therapy product for eventual evaluation in patients. In addition, we will develop a novel safety switch, which could be activated to eliminate these CAR T cells in case of unexpected toxicity in patients. In the long term, this novel therapeutic product could significantly improve survival in these patients who have a major unmet clinical need. Furthermore, the novel safety switch could potentially be applied to other CAR T-cell products and cell therapies in the future. Development of a novel and highly effective CAR T-cell therapy for such T/NK-cell leukemias and lymphomas that predominantly affect young adults would improve health and mission readiness of military personnel, Veterans, and their dependents, an FY22 PRCRP Military Health Focus Area, while also addressing the FY22 PRCRP Overarching Challenge through the identification of new target (CD94) and by advancing a novel immunotherapy strategy for treatment of five different cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310606
Entities
People
- Sattva Neelapu
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army