Mounting an Immune Response Against Melanoma

September 1, 2015

Activated T cells cultured in shorter, patented process focus of new Phase I clinical trial at UH Seidman Cancer Center

Innovations in Cancer  - Fall 2015 - View Full PDF

JULIAN KIM, MD

Chief Medical Officer, UH Seidman Cancer Center, Charles A. Hubay Chair in Surgery, UH Case Medical Center; Professor of Surgery, Case Western Reserve University School of Medicine

Adoptive immunotherapy with ex vivo-activated T cells has shown promise among patients with malignant melanoma, including select patients with bulky, metastatic disease. However, the clinical reach of this therapy has been limited by logistical constraints on generating sufficient numbers of antigen-specific cells in a short time period. “The process to generate activated T cells is extremely cumbersome,” says Julian Kim, MD, MS, Chief Medical Officer at University Hospitals Seidman Cancer Center. “The current process takes eight weeks and relies on highly skilled people to test the cells while they’re being grown in the lab. It’s just not practical.”

At UH Seidman Cancer Center, Dr. Kim and colleagues from the Case Comprehensive Cancer Center and National Center for Regenerative Medicine at Case Western Reserve University have discovered a way around this problem. They’ve developed an alternative, simplified method of generating and processing a large number of T cells for infusion. The unique, patented process shortens the time required to culture activated T cells from eight weeks to 14 to 16 days. “There is no one else in the world who is using the process that we’re using,” Dr. Kim says. “It’s a big collaborative effort here.”

In preclinical research with T cells derived from human lymph nodes draining a melanoma tumor (melanoma-draining lymph nodes, or MDLN), Dr. Kim and his team have developed a process of T cell expansion and activation that results in melanoma-specific anti-tumor responses, both in laboratory tests and in a mouse xenograft model.

“We have evidence for the first time that the MDLN T cells contain melanoma antigen- specific CD4 and CD8 T cell populations capable of mediating in vitro and in vivo immune responses against human melanoma,” Dr. Kim says.

The activated MDLN cells demonstrated reactivity in response to overlapping peptides spanning the sequence of four different known melanoma antigens.” Dr. Kim and colleagues published their findings recently in the Journal of Immunotherapy.

Buoyed by this early success, Dr. Kim and his team have launched a Phase I clinical trial, administering infusions of the activated T cells to patients with advanced melanoma. The team is monitoring patients for any significant side effects, as well as comparing different dosing regimens and using DNA sequencing to measure how long the activated T cells persist in the body.

“No one really knows how many T cells patients should receive,” Dr. Kim says. “All the trials in the past, they’ve just grown as many cells as possible and given them all to the patient. But there’s some indication that when you do that, your body’s immune system will actually ‘push back’ and develop a regulatory mechanism to suppress them.”

To hone in on the optimal dose and schedule, the team is comparing immune responses among four groups of advanced melanoma patients. The first group is receiving a single dose of activated T cells, another is receiving the same dose in two infusions four weeks apart, another is receiving a double dose in two infusions four weeks apart, and the last is receiving the same double dose but administered over four infusions, four weeks apart.

“We’re going to look at persistence of the infused cells and the regulatory response by the patient’s immune system to determine the best dose and schedule moving forward,” Dr. Kim says. “But the whole endeavor is very exciting. It’s a home-grown, living therapy.”

For more information on this clinical trial, contact Julian.Kim@UHhospitals.org.

 

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