Phase II clinical development of galectin-3 inhibition and anti-PD-1: immune monitoring and tumor response

Ended Project Grant Awarded Last action

Award ID
R01CA255650
Recipient
Awarding agency
Obligated
$4,741,528

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date
Place of performance
Oregon, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $0
Amendment $1,205,769
Amendment $1,205,769
Amendment $0
Amendment $0
Amendment $571,136
Amendment $582,888
Amendment $582,888
Amendment $0
Amendment $0
Amendment $0
Original award $593,078
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Quick answers

Who received award R01CA255650?

R01CA255650 was awarded to Providence Health & Services - Oregon by National Cancer Institute (National Institutes of Health) on August 2, 2021.

How much is award R01CA255650 worth?

$4,741,528 has been obligated on R01CA255650.

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