Wednesday, February 5, 2025 2/5/2025

Targeting T cell dysfunction in glioblastoma: A proof-of-concept Phase 0/I trial of anti-TIGIT antibody AB154 in combination with anti-PD1 antibody AB122

Award Number: R01CA266757
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Glioblastoma (GBM), the most common primary brain tumor in adults, is associated with a poor prognosis and short survival in spite of aggressive management. T cell dysfunction is a crucial component in the immunosuppressed state observed in the GBM tumor microenvironment and remains a significant barrier for the development of successful immunotherapies. Recent work suggests modulation with the immune-checkpoint inhibitors α-PD-1 or α-CTLA-4 do not provide significant clinical benefit in GBM, as opposed to other cancers. These data suggest that multiple co-inhibitory receptors are involved in the GBM tumor microenvironment driving T cell dysfunction. While investigating T cell dysfunction in human inflammatory disease, we first identified a key role for engagement of TIGIT on T cells by CD155 as a major co-inhibitory pathway; we then demonstrated a role for TIGIT in maintaining functional stability of Tregs, in that TIGIT signaling prevents conversion of Tregs into proinflammatory cells. Moreover, we and others have found that TIGIT and its ligand CD155 are highly expressed in GBM. Our new preliminary data using single-cell RNAseq shows that, among GBM tumor-infiltrating T cells, Tregs express the highest levels of TIGIT. Anti-TIGIT therapies are now entering clinical trials in cancer and recently, α-TIGIT mAb tiragolumab was given FDA breakthrough designation. In this proposal, we will elucidated mechanisms of T cell dysfuction in GBM by conducting a phase 0/1 clinical trial of α-TIGIT and α-PD- 1 mAbs as checkpoint inhibitors for treatment of recurrent GBM. The trial design allows for establishing the safety of this combination, while providing tumor samples and blood specimens for a robust evaluation of in human effects of α-TIGIT & α-PD-1 either alone or in combination, with transcriptomic single-cell resolution. Our mechanistic hypothesis is that while anti-PD-1 enhances both effector and regulatory T cell proliferation, the addition of α-TIGIT to α-PD-1 will destabilize Treg function and optimize the immune response. To investigate this hypothesis, our trial utilizes a “window-of-opportunity” design, within a bench-to-bedside-to-bench approach. Prior to surgery for resection of recurrent tumor, patients will be randomized to receive placebo, or α-PD-1, or α- TIGIT either alone or in combination. Single-cell RNAseq (10x) will be performed on baseline blood, post- treatment blood and tumor specimens from the trial patients. We will compare clonality and functional traits of tumor-infiltrating Tregs and effector T cells, and frequency of proinflammatory and suppressive tumor-derived myeloid cells. Multiplexed immunofluorescence (4i) will be used for spatial validation. We will analyze circulating T cells clonally related to tumor-infiltrating T cells to identify peripheral correlates and develop a non-invasive biomarker of emerging immune response. We will then model effects of PD-1 and TIGIT blockade on T regs in vitro using healthy donors T regs and compare to effects observed in the trial. Through this comprehensive approach, our study will determine whether PD-1 and TIGIT receptor engagement on T cells in the GBM tumor microenvironment induces immune dysfunction not allowing for immune survelliance in this CNS tumor.


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 = $614,421 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	4	1/1/2025	NON-COMPETING CONTINUATION	$614,421
														Subtotal = $614,421

Issue Date FY: 2024 ( Subtotal = $648,555 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	001	3	2/1/2024	NON-COMPETING CONTINUATION	$0
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	002	3	5/22/2024	NON-COMPETING CONTINUATION	$34,135
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	3	1/3/2024	NON-COMPETING CONTINUATION	$614,420
														Subtotal = $648,555

Issue Date FY: 2023 ( Subtotal = $673,408 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	2	2/15/2023	NON-COMPETING CONTINUATION	$673,408
														Subtotal = $673,408

Issue Date FY: 2022 ( Subtotal = $695,125 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	1	2/15/2022	NEW	$695,125
														Subtotal = $695,125

Grand Total All Awards = $2,631,509

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Targeting T cell dysfunction in glioblastoma: A proof-of-concept Phase 0/I trial of anti-TIGIT antibody AB154 in combination with anti-PD1 antibody AB122

Award Number: R01CA266757

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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