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Phase II Clinical Development of Galectin-3 Inhibition and Anti-PD-1: Immune Monitoring and Tumor Response

Award Number: R01CA255650
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Phase II Clinical Development of Galectin-3 Inhibition and Anti-PD-1: Immune Monitoring and Tumor Response - Project Summary/Abstract Due to recent advances, immunotherapy is now part of the standard of care for patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). Immune checkpoint blockade with drugs such as pembrolizumab (pembro; anti-PD-1) release the brakes on specialized white blood cells (T cells) to boost anti-tumor immunity. Unfortunately, anti-PD-1 monotherapy infrequently cures patients with advanced malignancy, thus curative regimens are still critically needed for these patients. There are many mechanisms of resistance to immunotherapy, but tumor-induced immune suppression is likely one of the most important. Two ways anti-tumor immunity is suppressed are through PD-1/PD-L1 interactions and the secretion of an inhibitory protein called galectin-3 (Gal-3) by the tumor. Given the ability of PD-1/PD-L1 and Gal-3 to suppress anti-tumor immunity, the central hypothesis of this proposal is that relieving two mechanisms of immune suppression by treatment with a novel Gal-3 inhibitor (GR-MD-02; belapectin) plus PD-1 blockade will enhance tumor regression in patients with MM and HNSCC. This innovative approach targets a unique regulatory pathway capable of changing the tumor microenvironment (TME) and enhancing T cell activity. Importantly, our recent phase 1 trial (NCT02575404) provided evidence of clinical benefit in patients with MM (ORR 50%) and HNSCC (ORR 33%) following GR-MD-02+aPD-1 therapy, which compared favorably with the 15-20% (10% in HNSCC) response rate expected in this population of heavily pre-treated patients. Moreover, combination therapy was associated with significantly fewer immune-mediated adverse events than anticipated with pembro monotherapy. Responding patients experienced significantly increased effector memory T cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) compared to non-responding patients, leading us to hypothesize that combination therapy increases responses by boosting the function of tumor-reactiveT cells and diminishing M-MDSC-mediated immune suppression. These data provide a strong rationale for comparing the clinical and immunological activity of GR-MD-02+pembro vs. pembro monotherapy in patients with MM or HNSCC. This research is significant because improvement to the ORR and reduction of potential side effects associated with pembro monotherapy will considerably enhance clinical care. Our objective is to perform a randomized phase II clinical trial to evaluate the efficacy of GR-MD-02 plus pembro compared to pembro monotherapy in patients with MM or HNSCC. Our goals are to: 1) Determine the objective response of this novel combination for patients with MM or HNSCC; and 2) Elucidate the underlying molecular mechanisms by which combined GR-MD-02+pembro immunotherapy augments anti-tumor immunity and influences galectin-3-induced immune suppression. These studies will help elucidate the mechanisms for the anti-tumor effect of GR-MD- 02+pembro therapy, which will provide critical insight into the underlying mechanisms by which combination therapy, in comparison to anti-PD-1 monotherapy, supports anti-tumor immunity.


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: 2024 ( Subtotal = $571,136 )
2024	2024	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	3	7/10/2024	NON-COMPETING CONTINUATION	$571,136
														Subtotal = $571,136

Issue Date FY: 2023 ( Subtotal = $582,888 )
2023	2023	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	2	9/1/2023	NON-COMPETING CONTINUATION	$582,888
														Subtotal = $582,888

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	1	8/18/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $593,078 )
2021	2021	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	1	8/2/2021	NEW	$593,078
														Subtotal = $593,078

Grand Total All Awards = $1,747,102

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Phase II Clinical Development of Galectin-3 Inhibition and Anti-PD-1: Immune Monitoring and Tumor Response

Award Number: R01CA255650

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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