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Decoding and reprogramming T cells through synthetic biology for cancer immunotherapy

Award Number: R01CA276368
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Decoding and reprogramming T cells through synthetic biology for cancer immunotherapy - ABSTRACT Engineered T cell-based cancer therapies are a major advancement in cancer treatment; however the majority of cancers still do not respond to adoptive cellular therapy. We need to “design” new T cell therapies with increased potency, and we need to overcome cell dysfunction that occurs as T cells face chronic tumor antigen stimulation. We and others have screened for genes that can be “knocked out” in antigen-specific T cells to enhance their functions, but enormous opportunities still remain to “knock-in” new synthetic DNA sequences at targeted genome sites. This proposal is focused on detailed evaluation of genes and inducible gene programs that will enable next-generation cellular therapies for cancer. We have developed several complementary technologies to discover synthetic gene programs that can be “inserted” into T cell genomes to enhance therapeutic functions. We developed a CRISPR technology for high throughput pooled knock-ins to accelerate discovery of synthetic knock-in programs (Roth et al., Cell, 2020), and have now have conducted two screens with ~100-member libraries that include transcription factors and synthetic chimeric receptors (“switch receptors”) to discover programs that make chronically stimulated T cells resistant to dysfunction. In addition, we have optimized a complementary robust platform for genome-wide CRISPR activation (CRISPRa) gain-of-function forward genetic screens in human T cells, and have already completed systematic discovery of factors that regulate stimulation-dependent cytokine production (Schmidt and Steinhart et al., Science, 2022). We propose to translate insights from these high-throughput discovery efforts into preclinical testing of novel knock-in designs with screen hits in vivo using xenotransplanted mouse models. In this proposal, we will test validated candidates from gain-of-function CRISPR PoKI (Aim 1) and CRISPRa (Aim 2) screens to discover new components of knock-in constructs that improve cell-based T cell therapies. We also recognize that these genetic components may be more beneficial if they are not expressed constitutively. In Aim 3, we draw on the power of synthetic biology to engineer synthetic circuits that can induce or repress genetic programs in response to antigen stimulation. This precise and dynamic regulation of genetic elements has great potential to further enhance efficacy and safety of next-generation immune cell therapies. Taken together, we present a proposal that leverages recent discoveries from CRISPR discovery platforms and deep expertise in synthetic biology to engineer powerful “knock-in” circuits that we will validate and study in preclinical cancer models. We leverage functional genomics, CRISPR engineering and synthetic cell program design expertise to address insufficient T cell potency and T cell dysfunction, which remain significant barriers to adoptive cell therapy for cancer.


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: 2025 ( Subtotal = $749,187 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cancer Biology Research	000	3	1/13/2025	NON-COMPETING CONTINUATION	$674,268
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cancer Biology Research	001	3	6/6/2025	NON-COMPETING CONTINUATION	$74,919
														Subtotal = $749,187

Issue Date FY: 2024 ( Subtotal = $711,787 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cancer Biology Research	001	2	4/19/2024	NON-COMPETING CONTINUATION	$37,462
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cancer Biology Research	000	2	12/6/2023	NON-COMPETING CONTINUATION	$674,325
														Subtotal = $711,787

Issue Date FY: 2023 ( Subtotal = $771,499 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cancer Biology Research	000	1	12/16/2022	NEW	$771,499
														Subtotal = $771,499

Grand Total All Awards = $2,232,473

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Decoding and reprogramming T cells through synthetic biology for cancer immunotherapy

Award Number: R01CA276368

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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