A First-in-human Clinical Trial of CD5 knocked-out Chimeric Antigen T Cells for T-cell Lymphomas

Marco Ruella

MD

Perelman School of Medicine at the University of Pennsylvania

Project Term: July 1, 2022 - June 30, 2025

Project Summary

For the 2021 Leukemia Lymphoma Society Translational Research Program, we assembled a group of investigators from different but complementary disciplines, including the Principal Investigator (Dr. Ruella – CART translational research) and clinical lead (Dr. Barta, lymphoma clinical trials) and collaborators (Drs. Lim, Hwang, Siegel, and June) to tackle the issue of the treatment of relapsed or refractory T cell lymphoma. CAR-T cell immunotherapy is a novel type of cancer therapy that includes the engineering of patient's own immune cells (CAR-T cells) to recognize and fight cancer. CART immunotherapy has been very successful in certain cancers, such as B-cell leukemia and lymphoma. Nevertheless, the needle has not moved for most other malignancies, in particular T cell lymphomas that have a very poor prognosis with current therapies. This proposal seeks to develop a novel approach for patients with relapsed or refractory T cell lymphoma by developing a novel CAR-T cell immunotherapy to recognize the tumor-associated target CD5. However, one challenge of targeting T cell lymphomas using CAR-T cell immunotherapy is that most targets expressed in tumor cells, like CD5, are also expressed by the CAR-T cells themselves, leading to the potential reduction of the CAR-T anti-tumor effect. Therefore, we developed a strategy to remove CD5 from CAR-T cells using the genetic engineering technology called CRISPR-Cas9. Indeed, this novel CAR-T cell product (CD5-deleted CART5) showed increased anti-tumor effect against T cell lymphoma in the laboratory. The present project seeks to translate this discovery into a first-in-human clinical trial to evaluate the feasibility, toxicity, and efficacy of CD5-deleted anti-CD5 chimeric antigen receptor CART for T-cell lymphoma. We will first translate our preliminary results - that were obtained in the research laboratory - into a clinical-grade immunotherapy CART product. Then, we will test this novel CD5-deleted CART5 immunotherapy product in a first-in-human clinical trial. We will treat patients with relapsed and refractory T cell lymphoma to define the safety and feasibility of this therapy. This proposal's feasibility is underpinned by our preliminary results and our Institution's extensive expertise in translating CART therapies. The proposed research is highly relevant to public health because patients with r/r T-NHL have no available cures and addresses those parts of the LLS's mission that pertain to the development of personalized and novel therapies for cancer treatment. This study will significantly impact the field of cancer immunotherapies by developing a novel potent anti-T-cell lymphoma immunotherapy.