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Enhancing Melanoma TIL Efficacy with Multifactor mRNA-Mediated T Cell Reprogramming

Award Number: R21CA282629
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 08/22/2024

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Enhancing Melanoma TIL Efficacy with Multifactor mRNA-Mediated T Cell Reprogramming - PROJECT SUMMARY Although T cell mediated immune responses are critical for the success of immunotherapy, those T cells associated with malignant lesions are typically dysfunctional and fail to control tumor growth. Treatment with tumor infiltrating lymphocytes (TIL) that are isolated, activated, and expanded ex vivo has proven very effective in some patient populations of melanoma. However, a substantial number of patients do not respond, presumably due to one of a number of host immune factors. Current understanding of TIL mechanism of action suggests that both an early robust expansion of tumor-specific effector T cells and transfer of less differentiated cells with long-term survival capacity are key to a successful therapy. Evidence for the former includes the need for high dose exogenous IL-2 at the time of TIL infusion, the correlation of response with a high frequency of effector T cells, and the majority of tumor killing occurring very early after the initiation of therapy. Evidence for the latter is found in many pre-clinical experiments as well as clinical observations where the presence of TILs from the central memory subset in the infusion product correlates with tumor regression. Our overall goal is to improve TIL therapeutic efficacy through the generation of TIL products with both the transient ability to effectively immediately kill tumor cells as well as the long-term ability to persist and maintain durable anti-tumor responses. To address these challenges we have developed robust methods to reprogram TILs with mRNA-mediated gene therapy. The use of our mRNA approach has the advantages of increased safety, high efficiency, rapid production, tightly controlled expression levels and simultaneous multi-factor reprogramming. In preliminary work we have developed a system that increases mRNA lifespan by an order of magnitude. Our single cell analysis of patient TILs pre- and post-expansion has identified two specific pathways deficient in the expanded TIL product that likely contribute to their poor immediate efficacy and absence of memory fate. Both of these will be augmented by TIL mRNA reprogramming. In Aim 1 we will develop a method to enhance post-expansion TIL survival, while in Aim 2 we will improve the production of central memory TILs. We will evaluate the effect of these improvements in TIL production using paired tumor/TIL sets derived from the melanomas from multiple patients by studying tumor-mediated TIL activation and tumor lysis in vitro and in pre-clinical humanized mouse models using single cell analysis and advanced spatial transcriptomics. This application addresses the need to improve response rates to adoptive cell immunotherapies for melanoma and is designed to be translatable to clinical trials in the near future.


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 = -$65,598 )
2026	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	2	11/24/2025	NON-COMPETING CONTINUATION	-$65,598
														Subtotal = -$65,598

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	2	5/7/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $303,663 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	003	2	8/9/2024	SUPPLEMENT FOR EXPANSION	$84,638
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	002	2	7/1/2024	NON-COMPETING CONTINUATION	$185,977
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	1	6/3/2024	SUPPLEMENT FOR EXPANSION	$33,048
2024	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	001	1	6/5/2024	NEW	$0
														Subtotal = $303,663

Issue Date FY: 2023 ( Subtotal = $234,919 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	1	5/30/2023	NEW	$234,919
														Subtotal = $234,919

Grand Total All Awards = $472,984

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Enhancing Melanoma TIL Efficacy with Multifactor mRNA-Mediated T Cell Reprogramming

Award Number: R21CA282629

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 08/22/2024

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