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TCR Targeting Antibodies for the Treatment of T cell Cancers

Award Number: K08CA270403
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/08/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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TCR Targeting Antibodies for the Treatment of T cell Cancers - Project Summary Antibody-mediated targeted immunotherapies are highly effective in killing cancer cells. T cell leukemias and lymphomas, collectively known as T cell cancers, affect ~100,000 patients worldwide each year. Relapsed T cell cancers respond poorly to aggressive chemotherapy with a 5-year survival between 7% to 38%. Thus, T cell cancers particularly warrant antibody-mediated targeted immunotherapy to improve patient outcomes. However, developing a T cell cancer targeting immunotherapy is challenging as the immunotherapy will have to preserve enough healthy T cells to maintain a functioning immune system. T cells express the T cell receptor (TCR) on the cell-surface. Although all T cells express TCR, they can be distinguished based on the TCR beta chain constant region (TRBC) which is derived from one of two gene segments, TRBC1 or TRBC2. I led a team that demonstrated that in healthy T cell populations, about 45% of cells express TRBC1 while the other 55% express TRBC2. However, clonal T cell cancers express either TRBC1 or TRBC2 (Paul et al., Sci. Transl. Med. 2021). Thus, I hypothesize that antibody-mediated specific TRBC1 or TRBC2 targeting will eradicate the clonal T cell cancers while preserving half of the healthy polyclonal T cell population. I also developed a TRBC1- targeting bispecific antibody (αTRBC1) that selectively kills TRBC1+ T cell cancers (and TRBC1+ healthy T cells) while preserving the healthy TRBC2+ T cells in vitro. These in vitro observations will require confirmation in animal models before initiation of future human clinical trials. For Aim 1, I will determine the in vivo activity of the αTRBC1 bispecific antibody. I will test the ability of αTRBC1 antibodies to induce tumor regression in multiple mouse models of T cell cancers. I will then examine if the remaining healthy TRBC2+ T cells retain all of the immune cell subsets required for a functioning immune system. I will also test if therapeutic pressure from the αTRBC1 bispecific antibody will give rise to a low TCR expressing T cell population that will be resistant to therapy. For Aim 2, I will test feasibility of TRBC2-targeting on T cell cancers. As a TRBC2-targeting antibody is currently unavailable, I will use phage display to develop TRBC2-specific antibodies. I will then test the cytotoxicity of TRBC2 targeting antibodies in vitro and in multiple mouse models of T cell cancers. Our TRBC- directed antibodies will fill an unmet need for the treatment of T cell cancer patients. The proposed in vivo and mechanistic studies will provide the pre-clinical validation required for the initiation of an early-phase human clinical trials that will test the safety and efficacy of TRBC1- and TRBC2-targeting antibodies. My long-term goal is to become an independent laboratory-based physician-scientist focusing on developing novel therapeutic approaches for T cell cancers. Through this proposal, I will also acquire the research skills and career experience needed to reach this goal. These skills will be critical to the development of a relevant, impactful translational research program in human T cell leukemias and lymphomas.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $195,129 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	5	1/19/2026	NON-COMPETING CONTINUATION	$195,129
														Subtotal = $195,129

Issue Date FY: 2025 ( Subtotal = $216,810 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	4	1/22/2025	NON-COMPETING CONTINUATION	$216,810
														Subtotal = $216,810

Issue Date FY: 2024 ( Subtotal = $216,810 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	3	1/12/2024	NON-COMPETING CONTINUATION	$216,810
														Subtotal = $216,810

Issue Date FY: 2023 ( Subtotal = $216,810 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	2	1/12/2023	NON-COMPETING CONTINUATION	$216,810
														Subtotal = $216,810

Issue Date FY: 2022 ( Subtotal = $216,810 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	1	4/7/2022	NEW	$216,810
														Subtotal = $216,810

Grand Total All Awards = $1,062,369

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TCR Targeting Antibodies for the Treatment of T cell Cancers

Award Number: K08CA270403

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/08/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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