T-cells modified to express dominant-negative TGF-Î² receptor type 2 overcame cancer cell defenses.
Cancer cells are frequently able to outsmart and evade the body’s immune system and numerous cancer drugs. Targeting these defense mechanisms has become a top priority for researchers.
Recently, investigators have validated a method to overcome this resistance by engineering T-cells to rid cancer cells of their defense mechanisms. This approach was able to induce a 4-year remission among patients with Hodgkin lymphoma, according to a study published by the Journal of Clinical Oncology.
This treatment was also seen as beneficial because patients received infusions of the tumor-directed T-cells without undergoing chemotherapy.
"These results come 18 years after this revolutionary approach was first conceptualized,” said lead study author Catherine M. Bollard, MD, MBChB. “While the study is small, its findings are incredibly encouraging for our families and for the cancer field.”
The authors said that the use of T-cells for cancer treatment has been explored for nearly 2 decades.
“Even then, when T-cell therapy was in its relative infancy, some research institutions began to see more than 90% complete responses and cure rates in some settings,” Dr Bollard said. “This most recent study points to the potential of specialized T-cells to fight even more types of immune-evading tumors."
In the new dose-escalation study, 8 patients with Epstein Barr virus-positive Hodgkin lymphoma received 2 to 12 doses of specially engineered T cells. The production of transforming growth factor-β (TGF-β) in the tumor microenvironment was found to inhibit targeted therapies by having detrimental effects on T-cell function in vivo, according to the study.
To combat this mechanism, the researchers forced the expression of dominant-negative TGF-β receptor type 2 (DNRII) onto LMP-specific T cells (DNRII-LSTs). These LMP-specific T cells were engineered to target and destroy proteins derived from the Epstein Barr virus. DNRII expression allowed the T-cells to overcome the hostile tumor environment and kill cancer cells, according to the authors.
Seven of the 8 patients had active lymphoma at baseline.
"DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their ability to kill the cancer cells. After infusion, the signal from the genetically modified T-cells in the peripheral blood increased up to 100-fold," the authors wrote.
These findings suggest that the engineered T cells may be able to induce long-term remission among patients with relapsed disease, according to the study.
"DNRII-LSTs persisted for up to 4 years,” the authors wrote. “Four of the 7 patients with active disease achieved clinical responses that were complete and ongoing in 2 patients for more than 4 years, including in 1 patient who achieved only a partial response to unmodified tumor-directed T-cells."
The authors concluded that these results highlight the potential of expressing DNRII when combatting resistant tumors.