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.