UH Seidman Cancer Center to Launch First-Ever Trial of NK Therapy and Vactosertib in Treating Colorectal Cancer and Hematological Malignancies

Trial employs new method of expanding and activating universal donor NK cells developed in Cleveland

Innovations in Cancer | Winter 2022

Researchers at University Hospitals Seidman Cancer Center and the Case Comprehensive Cancer Center at Case Western Reserve University are launching a first-ever, investigator-initiated clinical trial to study universal donor NK cells in combination with IL-2 and vactosertib as a potential treatment for colorectal cancer and hematological malignancies. Vactosertib is a clinical drug candidate that inhibits TGF-β signaling, a pathway that is known to inhibit the therapeutic effect of immunotherapy. By modulating the tumor microenvironment, vactosertib is thought to play a synergistic role in improving the response of various drugs and suppressing the proliferation and metastasis of cancer cells.

Eva Selfridge, MD, PhD

“We have developed a novel NK cell therapy product of ex vivo-expanded non-HLA-matched universal donor NK cells, which we recently showed was safe in patients with metastatic colorectal cancer and refractory hematological malignancies,” says UH Seidman oncologist J. Eva Selfridge, MD, PhD, and Assistant Professor at Case Western Reserve University School of Medicine, who is leading the upcoming trial. “This new study seeks to safely improve the responses to our NK cell product by co-administering with subcutaneous IL-2, which is known to activate NK cells, and by co-administering with the oral TGF-β receptor inhibitor, vactosertib. Vactosertib has shown enough safety in a number of different combination clinical trials that we think combining it with the NK cells is going to be safe and has our best chance at having efficacy.”

The immunological properties of colorectal tumors, in particular, make them a good target for an NK cell approach, Dr. Selfridge says.

“All the standard therapies we have in immunotherapy are using a T cell pathway looking for abnormal MHC class 1 on the surface of the cell,” she says. “But in colorectal cancer, the problem isn’t that the colorectal cancer cells are expressing abnormal MHC class 1. It’s that they’re not expressing MHC class 1 at all. They’re trying to be invisible. No matter what you do to a T cell to make it more active, if it’s looking for a MHC class 1 and it’s not there, you are not going to be effective in treating the cancer. The difference with NK cells is that they aren’t looking for an abnormal MHC class 1 – they’re looking for cells that don’t have an MHC class 1 at all. It very well may be that using NK cells is going to be a better cell to use to target the colorectal cancer.”

Vactosertib, in turn, can potentially disrupt the TGF-β signaling pathway, which has been shown to limit the effectiveness of immune therapies like NK cells, Dr. Selfridge says.

“Vactosertib has never been used in combination with NK cells in the clinic, but it has been used in humans in other clinical trials,” she says. “The goal of using it in this trial is to disrupt the TGF-β signaling pathway that is so strong in colorectal cancer and cells. We want to shut down that TGF-β signaling pathway so that the NK cells can actually make it into the tumors. Once they’re there, they have a chance or being active instead of just being silenced right away.”

An Investigational New Drug (IND) application with the U.S. Food and Drug Administration for the new trial has been approved. Once launched, the Phase Ib trial will enroll 12 patients at UH Seidman Cancer Center with either locally advanced/metastatic colorectal cancer or relapsed/refractory hematologic malignancies.

The main objective is to establish the safety of donor NK cells in combination with IL-2 and vactosertib and to test if IL-2 and vactosertib improves persistence of donor NK cells seven days after infusion, which is a surrogate marker predicting response to NK cells.

Dr. Selfridge says she is hopeful this new clinical trial at UH Seidman Cancer Center will present patients with more and better options for treatment and care.

“T cell-directed immunotherapy is only available for 5 percent or less of cancer patients, but immunotherapy is really the only way we have to cure people with metastatic disease,” she says. “There’s only so many chemotherapies that we have for these cancers before we run out of effective options.  Ultimately, we’re trying to find ways of getting the immune system to effectively treat these cancers, to give people better options. We’re just beginning our study, but ultimately the goal is to find immune therapies that work long-term.”

For more information about this trial, please email Jennifer.Selfridge@UHhospitals.org.

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