Inhibiting an inhibitor: NIH-funded study targets galectin-3 protein

Authors: Brendan Curti, M.D., medical director, Melanoma Program, Cytokine and Adoptive Immunotherapy, Providence Cancer Institute, and William L. Redmond, Ph.D., director, Immune Monitoring Laboratory, Earle A. Chiles Research Institute, a division of Providence Cancer Institute

The goal of cancer immunotherapy is to enhance immune recognition and destruction of cancer cells. There are many possible ways to achieve these goals including therapeutic vaccines that train the immune system to recognize specific cancer antigens, cytokines that enhance immune cell function, or adoptive cell therapies, such as T cell receptor therapy (TCR-T) that uses engineered immune cells to better target and destroy cancer cells.

Another strategy focuses on the use of inhibitory antibodies that block immune checkpoints, including PD-1, CTLA-4 and LAG-3. Inhibiting these suppressive pathways “removes the brakes” from the immune system and helps unleash the body’s natural anti-tumor response. 

Checkpoint antibodies have improved the prognosis for patients with melanoma, lung, kidney, bladder, head and neck squamous cell carcinoma (HNSCC) and other cancers. These agents have been the catalyst for the last decade of innovation in cancer immunotherapy, yet few patients are cured.

Galectin-3: Another immune checkpoint

Galectin-3 is a protein associated with cancer progression and immune checkpoint antibody resistance. Although galectin-3 plays important roles in various normal biological processes, such as cell growth and cell death, galectin-3 can adversely affect cancer outcomes when it’s overexpressed.

Since the 1990s, research has explored the involvement of galectin-3 in cancer initiation, progression, metastasis and resistance. Although a body of research has accumulated, there remain gaps in our understanding of how galectin-3 contributes to cancer and its progression.

Phase I study showed promise

Between 2016 and 2021, we led a phase I investigator-initiated study at Providence Cancer Institute of Oregon evaluating a combination of a galectin-3 inhibitor known as GR-MD-02 (belapectin) plus pembrolizumab (anti-PD-1) in patients with metastatic melanoma and HNSCC.

The results showed an encouraging objective response rate of seven out of 14 patients (50%) and a disease control rate of nine out of 14 patients (64%) with advanced melanoma.

In comparison, the published objective response rates in randomized studies using pembrolizumab in patients with advanced melanoma ranged from 21% in patients who have had prior therapy to 39% in patients who had not received prior systemic therapy.

Perhaps more importantly, the combination of pembrolizumab and GR-MD-02 was well tolerated, and treatment appears to be associated with fewer adverse events than pembrolizumab alone. In 2021, the study was published in the Journal for ImmunoTherapy of Cancer.

Next steps: Why the study is important

Based on the translational research and findings of the phase I study, we were awarded a R01 Research Project Grant from the National Cancer Institute, National Institutes of Health. This award has allowed us to launch a phase II investigator-initiated trial enrolling patients at the Earle A. Chiles Research Institute, a division of Providence Cancer Institute, to evaluate an oral galectin-3 inhibitor for treating patients with metastatic melanoma and HNSCC. Cancers like melanoma and HNSCC have been associated with higher levels of galectin-3.

The study will determine if the addition of GB1211, a galectin-3 inhibitor candidate developed by Galecto, increases the response rate of pembrolizumab, a checkpoint inhibitor, in metastatic melanoma and HNSCC patients.

The current study will employ a fixed dose of GB1211 in conjunction with the standard therapeutic dose of pembrolizumab in patients with unresectable or metastatic melanoma or recurrent or metastatic HNSCC progressing during or after platinum-containing chemotherapy.

Our study also has a placebo control group, which is important to verify our hypothesis about the impact of galectin-3 on immune responses and help us understand how pembrolizumab works at a deeper level.

In addition to monitoring for toxicity and clinical response, biospecimens will be collected to assess immunologic measures relevant to galectin biology and T cell checkpoint inhibition. Tumor volume will be assessed by immune response RECIST criteria.

Studies exemplify translational research

Early scientific studies, such as the ones we pursued on galectin-3 in the Immune Monitoring Laboratory at Earle A. Chiles Research Institute, are critical to paving the way for advancements in cancer care, particularly in understanding and addressing checkpoint inhibitor resistance. By focusing on the complex mechanisms underlying resistance, such as the way galectin-3 impedes the body’s natural immune defenses, we move the needle closer to developing effective therapies for patients.

Providence Cancer Institute is investigating other immune checkpoints and ways to change the tumor microenvironment to promote better antitumor effects. Current research includes a study led by Matthew Taylor, M.D., that is evaluating a treatment targeting FAS ligand, and transforming growth factor beta (TGFβ) research led by Kristina Young, M.D., Ph.D.

Learn more about the phase II study or refer a patient:

GB1211 and Pembrolizumab Versus Pembrolizumab and Placebo in Patients with Metastatic Melanoma and Head and Neck Squamous Cell Carcinoma

Brendan Curti, M.D., medical oncologist, medical director, Melanoma Program, Cytokine and Adoptive Immunotherapy, Providence Cancer Institute, Robert W. Franz Endowed Chair for Clinical Research, Earle A. Chiles Research Institute

William L. Redmond, Ph.D., member, Cancer Immunotherapy Laboratory, director, Immune Monitoring Laboratory, Earle A. Chiles Research Institute, a division of Providence Cancer Institute
 

Providence Center of Excellence for precision immuno-oncology and cellular therapy  
Since 1993, cancer research has been the primary focus of the Earle A. Chiles Research Institute, the research arm of Providence Cancer Institute of Oregon. Under the leadership of Walter J. Urba, M.D., Ph.D., our team of physicians and scientists work together to improve cancer treatment methods – seamlessly joining lab research and clinical trials with medical practice.   

Our main area of research is cancer immunotherapy, and with the advancements in genomic sequencing, we are bringing together the power of immunotherapy and personalized medicine to accelerate leading-edge research and groundbreaking discoveries for patients with cancer.  

Learn more about the latest research and clinical trials at Earle A. Chiles Research Institute.  

About the Author

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