Researchers at Roswell Park Cancer Institute in upstate New York have started a Phase 1/2a clinical trial to evaluate the use of “super T-cells” for the treatment of solid-tumor cancers.
The trial (NCT02650986) will enroll 24 participants to determine the safety and best dose regimen of the super T-cells, which are thought to outperform common T-cell-based immunotherapies in solid tumors.
T-cells are the killers of a body’s immune system and play a major role in destroying cancer cells. Using T-cells as a living treatment to attack cancer cells has been evaluated in many clinical trials.
The U.S. Food and Drug Administration recently approved two T-cell-related immunotherapies, Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel). However, the only cancers that have shown significant benefit from this treatment are blood cancers, such as leukemia and lymphoma.
“What we see over and over in trying to treat some of the most aggressive and intractable cancers, including many lung, brain, ovarian, breast, melanoma and sarcoma tumors, is that the tumor fights back. The area around the tumor is a hostile environment that disarms immune cells and deprives them of the ability to kill tumor cells,” Kunle Odunsi, MD, PhD, deputy director and chair of gynecology at Roswell Park and the study’s principal investigator, said in a press release. “We have identified a major pathway by which these kinds of cells try to disable immune cells, and formulated a strategy for exploiting that weakness.”
Usually, these T-cell-based immunotherapies use a patient’s own T-cells, which are genetically engineered to recognize a specific cancer protein. But researchers have now devised a two-pronged strategy to engineer the T-cells to better attack cancer cells.
After extracting the T-cells, researchers insert two genes in their genome. Like any other “living” T-cell therapy, one gene codes for a receptor designed to target a cancer protein, in this case, the NY-ESO-1 protein. This allows the T-cells to bind and destroy the cancer cells.
The second gene is designed to block the effect of transforming growth factor beta (TGF-beta), which is highly expressed in cancers and works by increasing cancer cell growth and suppressing the immune system.
“It’s an approach that allows the immune system to be on the offense and on the defense at the same time,” said the study’s scientific lead, Richard Koya, MD, PhD, associate director of the Roswell Park Center for Immunotherapy. “First we arm the T cells with a receptor to help them hunt down the cancer cells, and then we add a TGF-beta blocker to suppress the suppressor. The result of this two-step gene modification — forcing expression of the receptor for NY-ESO-1, and adding a blocker gene to nullify the effect of TGF-beta — is a super T cell engineered to both more effectively kill target cancer cells and to resist the tumor’s attack.”
Preclinical studies using this method have shown that it may be an effective and long-lasting strategy to destroy cancer cells in humans.