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In Search of an Immunotherapy Innovation for Ovarian Cancer

Perron, Michelle

doi: 10.1097/01.COT.0000577048.80342.e7
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Ovarian Cancer, Immunotherapy

Ovarian Cancer, Immunotherapy

Researchers at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., are delivering perhaps the most personalized medicine yet to women with ovarian cancer. In a phase I clinical trial, they are assessing the safety and potential effectiveness of a new immunotherapy approach to refractory ovarian cancer that essentially reprograms a patient's own cells to fight recurrence.

Ovarian cancer is a refractory disease that is diagnosed in 22,000 women in the U.S. annually. Each year, 14,000 women in this country die from the disease. Approximately 70 percent of women with ovarian cancer experience a recurrence, the Ovarian Cancer Research Alliance reports.

“Our goal is to prolong the effects of immunotherapeutic cells against ovarian cancer by genetically engineering them to provide a supply of T cells that will prevent cancer recurrence,” said Richard Koya, MD, PhD, Associate Professor of Oncology, Associate Director of the Center for Immunotherapy, and Director of the Vector Development and Production Facility at Roswell Park Comprehensive Cancer Center.

“This is a phase I trial, which means the actual goal is to determine feasibility and potential toxicity,” Koya said. “The secondary goal is to look at markers for efficacy, and at tumor burden. We expect to have positive outcomes and responses.”

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Study Background

The clinical trial (NCT03691376), primarily funded by a grant from New York Stem Cell Science, opened in January and enrolled one of a planned 15 patients. The primary objective is to assess the safety and feasibility of intravenous infusion of autologous peripheral blood mononuclear cells and CD34+ peripheral stem cells that have been genetically modified ex vivo to express NY-ESO-1 T-cell receptor (TCR). These will be administered after a myeloablative conditioning regimen delivered in an inpatient setting. The researchers hope to demonstrate an ability to manufacture the cell therapies for more than 80 percent of patients enrolled. Secondary objectives include progression-free survival, the demonstration of a durable tumor response, and long-term persistence of TCR transgenic cells.

The study is noteworthy because it implements a novel approach: genetically engineering a patient's own hematopoietic stem cells and mature T cells with tumor-recognizing T-cell receptors. After they are infused into patients, these “designer” cells generate two types of immune cells: CD8+ T cells, which kill tumor cells, and CD4+ “helper” T cells, which boost the functioning of the CD8+ T cells.

“This is a unique type of therapy, providing a combination of two T-cell receptors,” Koya said. “Other trials have examined only one type of T-cell receptor. Preliminary data already show a synergistic effect of CD4 and CD8 T-cell receptors in T lymphocytes. ... Due to tumor cytolysis mediated by CD8+ T cells, CD4+ cells would provide cytokines and support for the CD8+ T cells to do their job.

“We have already shown in pre-clinical models that synergy exists,” he continued. “We now hope to see this synergy in patients.”

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Expected Findings

The researchers expect the incorporation of the hematopoietic component to allow T-cell activity to persist. “The hematopoietic progenitor cells have the potential to show persistence—to stay in the bone marrow and differentiate into the T cells later,” Koya said. “This could potentially provide a lifelong supply of T cells that can specifically destroy cancer cells—almost like a surveillance mechanism to prevent the cancer coming back again.”

The researchers believe this study is the first to attempt to reprogram hematopoietic stem cells for adoptive T-cell immunotherapy to generate a long-lasting supply of antitumor CD4-TCR T cells. The study duration is expected to be 2 years.

Michelle Perron is a contributing writer.

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