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Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments

Award Number: R01CA251514
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/17/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments - PROJECT SUMMARY The immune system remarkably distinguishes between self and non-self/self-aberrant antigens, affording exquisite anti-tumor specificity and inhibition of tumorigenesis. However, tumor immunosurveillance is unfortunately opposed by tumor cell evasion of the immune response. Immune checkpoint blockade (ICB) targeting PD-1, PD-L1, CD40 and others, as well as adoptive cell transfer (CAR-T, bulk TILs) favorably modulate this equilibrium for therapeutic benefit. However, response rates are often incomplete, progressive disease is common, and predictive biomarkers are suboptimal. The development of next-generation immunotherapies has been hindered by a lack of in vitro models that functionally recapitulate syngeneic interactions between tumor and infiltrating immune cells. In response, we have developed organoid methods that culture primary human tumor biopsies together with their infiltrating immune components as a cohesive unit without reconstitution. These “patient-derived tumor organoids” (PDO) preserve tumor cells alongside endogenous T, B, NK cells and macrophages, robustly recapitulate the T cell receptor clonotype repertoire of the original tumor, and crucially, manifest tumor-infiltrating lymphocyte (TIL) expansion, activation and tumor cell killing in response to anti-PD-1/PD-L1 therapeutic antibodies (Cell, 2018). The PDO system thus represents a holistic organoid model of human tumor-immune interactions. Here, we leverage the PDO technique to investigate immunotherapeutic mechanisms and treatments in PD-1-responsive cutaneous squamous cell carcinoma (cSCC) and melanoma, exploiting pre- and post-treatment human biopsies and mouse models. Aim 1 hypothesizes that checkpoint inhibition induces a complex and sequential network response involving immune-tumor and immune-immune crosstalk. Thus, Aim 1 employs the ability to perform serial time-course sampling of PDOs to define a single cell RNA-seq network cellular crosstalk model of the early anti-PD-1-stimulated anti-tumor immune response over multiple acute time points typically inaccessible to clinical biopsies performed after months. Importantly, comparison of this immune propagation in responding versus non-responding mouse and human organoids will define nodal points conferring resistance. Aim 2 improves bulk TIL adoptive transfer immunotherapy by using PDOs as living bioreactors to enrich tumor-reactive mouse and human melanoma TILs by anti-PD-1 checkpoint inhibition, followed by testing of enhanced anti-tumor activity in vitro and in vivo. Lastly, Aim 3 performs a co-treatment trial comparing anti-PD-1 responses of pre-treatment biopsy cSCC PDOs to clinical outcomes. Further, post- treatment biopsy PDOs are re-challenged with anti-PD-1 and a novel agent inactivating PD-1 by dephosphorylation. We thus utilize the holistic PDO model preserving endogenous tumor epithelial and immune components en bloc to investigate and improve cancer immunotherapy via our team of Calvin Kuo (organoids), Mark Davis and Chris Garcia (tumor immunology) and Anne Chang and Dimitri Colevas (cSCC clinicians).


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 = $655,548 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	001	5	5/26/2025	NON-COMPETING CONTINUATION	$65,555
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	5	2/13/2025	NON-COMPETING CONTINUATION	$589,993
														Subtotal = $655,548

Issue Date FY: 2024 ( Subtotal = $623,480 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$32,817
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	4	2/13/2024	NON-COMPETING CONTINUATION	$590,663
														Subtotal = $623,480

Issue Date FY: 2023 ( Subtotal = $643,856 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	3	2/24/2023	NON-COMPETING CONTINUATION	$643,856
														Subtotal = $643,856

Issue Date FY: 2022 ( Subtotal = $643,552 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	001	2	4/22/2022	NON-COMPETING CONTINUATION	$52,537
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	2	3/7/2022	NON-COMPETING CONTINUATION	$591,015
														Subtotal = $643,552

Issue Date FY: 2021 ( Subtotal = $657,944 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Treatment Research	000	1	3/17/2021	NEW	$657,944
														Subtotal = $657,944

Grand Total All Awards = $3,224,380

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Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments

Award Number: R01CA251514

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/17/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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