Targeted Antibody and Immunotoxin Combination Improves T-Cell Lymphoma Therapy
Abstract
This proposal aligns with the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Lymphoma. We propose developing a novel antibody and immunotoxin combination therapy for T-cell lymphomas. T cells are a type of blood cells that play a critical role in the body’s immune system. T-cell lymphomas are a diverse group of T-cell cancers that are usually fast-growing and difficult to treat with conventional cancer therapies. To date, there is no curative therapy for the vast majority of patients. CD3-immunotoxin (CD3-IT), a promising T-cell specific precision medicine agent, has been developed to treat T-cell lymphomas. CD3-IT showed great potential to cure T-cell lymphoma patients in a recent clinical test, but its effects were limited to certain T-cell lymphoma patients for unknown reasons. We have recently found that a special type of T cells that reside in a unique anatomic site (B-cell follicle) are difficult to kill with CD3-IT. It is likely that the local tissue environment surrounding these cells protects them from being killed by CD3-IT. Here, we propose to investigate the mechanisms underlying the resistance of these local difficult-to-kill T cells and to test whether a specific antibody agent (called costimulatory blockade) used in combination with CD3-IT will reduce such treatment resistance and in turn improve the overall effectiveness of CD3-IT treatment. We will also test whether newly engineered CD3-ITs with an improved safety profile would further enhance T-cell depletion in mice. To that end, we will use cutting-edge cell-tracking technologies and an advanced mouse T-cell lymphoma model to extensively evaluate the effects of our new treatment approaches on both circulating and local organ-resident T cells. If successfully completed, this study will identify an unexplored cancer treatment resistance mechanism and generate an innovative treatment approach that can significantly improve T-cell lymphoma therapy in clinic. Furthermore, the new resistance mechanisms and new treatment strategies we propose here will be applicable to other T-cell targeting biologics, including other anti-T-cell immunotoxins, antibodies, and antibody-drug conjugates. This proposal aligns with the FY22 PRCRP Topic Area of Lymphoma. We propose to address the FY22 PRCRP Military Health Focus Area Gaps in cancer research that may affect mission readiness by identifying an unexplored treatment resistance and developing innovative therapeutic strategies for patients with T-cell lymphomas. Our novel treatment strategies can minimize the likelihood of cancer relapse and time spent in the hospital, thereby enabling a more expeditious return to duty for Service Members. This proposal addresses the FY22 PRCRP Overarching Challenge Therapeutics. It identifies previously unknown treatment resistance mechanisms of T-cell lymphomas, especially in advanced stages, and proposes a therapeutic innovation to overcome a major barrier to successful T-cell lymphoma therapy. In addition, the knowledge gained through the proposed studies will also advance immunotherapy generally across the various PRCRP Topic Areas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310582
Entities
People
- Sanggu Kim
Organizations
- Ohio State University
- United States Army