UH Cleveland Medical Center Exploring New Way to Treat Metastatic Colorectal Cancer

Innovations in Digestive Health | Winter 2022

Oncologists use immunotherapy to treat certain types of cancers, such as melanoma, with good success. However, to date, these therapies have not been as effective for the majority of patients with colorectal cancer (CRC).

Hoping to change that is J. Eva Selfridge, MD, PhD, a hematologist and oncologist at University Hospitals Cleveland Medical Center. Dr. Selfridge is continuing the work of UH’s David Wald, MD, PhD, Associate Director for Basic Research at the Wesley Center for Immunotherapy at UH Seidman Cancer Center, who found that natural killer (NK) cells in the immune system might offer an option for treating metastatic CRC.

Eva Selfridge, MD, PhD

Enhancing the effectiveness of the immune system

“We know that immune therapies, which either activate or suppress the immune system, have a huge benefit in some types of solid tumors,” Dr. Selfridge says. “In some cases, by stimulating the immune system, patients who may have died from stage IV metastatic cancer can actually be cured. That’s our ultimate goal, but we realize we have to take baby steps.”

To that end, Dr. Selfridge is enrolling patients in a phase 1b clinical trial to study the efficacy of NK cells in combination with other medications. The hope is that NK cells will make the body’s immune system more reactive to CRC by changing the signaling pathway in the tumor itself and making it more sensitive to immune therapies.

“One way to do this is by targeting the Transforming Growth Factor Beta [TGF-β] pathway,” she says. “We know that in solid tumors, especially CRC, the TGF-β pathway naturally promotes cancer cell growth, proliferation and metastases.”

Early attempts to use NK cells were challenging due to a lack of clinical-grade NK manufacturing platforms and the need to find suitable matching NK cell donors. However, Dr. Wald found that precise matching was not biologically necessary, and mismatched NK cells might even offer a better response against tumors. He developed a novel way to quickly grow large numbers of clinical grade NK cell therapy products from healthy universal donors.

“We already have data we’re ready to publish that shows universal donor NK cells are safe for patients with malignant CRC tumors, and some patients even had a positive clinical response,” Dr. Selfridge says. “However, because this was the first time we were using Dr. Wald’s platform in humans, we couldn’t use NK cells with cytokines, which help NK cells survive and enhance their cytotoxicity.”

Because the NK cells are proven safe in humans, Dr. Selfridge says the next step is to improve efficacy by infusing them with cytokines so the NK cells don’t die immediately and can actively target the tumor’s unique microenvironment using the TGF-β signaling pathway.

Clinical trial now enrolling patients

Dr. Selfridge is enrolling patients for this clinical trial, which she’ll launch in late March.

“The ideal candidate is a patient who has stage IV CRC and has received at least one or two standard of care chemotherapies,” she says. “The patients need to be healthy enough to participate in the required infusion schedule. We are also enrolling patients with hematologic malignancies, which are probably also driven by this pathway.”

The treatment takes place over one month, Dr. Selfridge says. Patients first receive a small dose of chemotherapy to ensure their immune system doesn’t immediately reject and destroy the NK cells. Then they receive a dose of the NK cell product, along with a subcutaneous injection of endogenous IL-2 cytokines.

Patients also begin taking an oral TGFB receptor I inhibitor called vactosertib. Two weeks later, patients receive a second dose of the NK cells. At the end of the month, patients undergo a tumor biopsy and CT scan to see if the treatment is working.

Dr. Selfridge encourages physicians to refer potential candidates and welcomes patients who learn about the trial to self-refer.

“Of course, we hope the study is effective,” she says, “but if not, we will collect good data on how to make it better.”

For more information about the clinical trial or to enroll patients, call Dr. Selfridge at 216-844-6031.

Contributing Expert:
J. Eva Selfridge, MD, PhD
Oncologist
University Hospitals Seidman Cancer Center
Assistant Professor of Medicine
Case Western Reserve University School of Medicine