Since he was in college, Thomas Shum wanted to pursue a career in cancer research. As he advanced in his studies, he was able to pinpoint immunotherapy as the focus of his research interests. Unfortunately, his alma mater did not offer advanced training in this field so he looked into other institutions for programs offering opportunities to work in tumor immunotherapy.
“When I was looking for M.D./Ph.D. programs, Baylor’s was one of the top places to do immunotherapy research. I came to Baylor, and Dr. Cliona Rooney accepted me in her lab. I was very lucky to come here because Dr. Rooney and other researchers in her group are leaders in the field of tumor immunotherapy,” said Shum, who is in the Medical Scientist Training Program, the combined M.D./Ph.D. program at Baylor and conducted his Ph.D. training in Baylor’s Translational Biology and Molecular Medicine graduate program.
Shum became particularly interested in studying T cells with chimeric antigen receptors (CARs) for treating human solid tumors. T cells are essential components of the immune system; they orchestrate the immune response and the killing of cancer cells, as well as cells infected by pathogens. CAR T cells are patient T cells that have been genetically engineered to express CARs, an artificial construct consisting of a synthetic T-cell receptor – a molecule on the surface of T cells that recognizes and binds to a preselected antigen molecule expressed on a tumor. CARs not only allow T cells to recognize tumor cells specifically, ignoring bystander healthy cells, but also trigger a signal that activates T cells’ proliferation and their killing abilities. Physician-scientists have been able to manufacture CAR T cells from the blood of cancer patients and inject the modified cells back into the patients to treat their cancer.
“CAR T cell therapy has achieved remarkable results against leukemia and lymphoma, but this approach has not reached the same success with solid tumors,” Shum said. “I wanted to tackle some of the deficiencies we see in CAR T cell therapy for solid tumors.”
“For this type of immunotherapy to be effective against solid tumors, CAR T cells need to proliferate substantially and persist in the patient for quite some time, but our studies showed that standard CAR T cells failed to do so in the presence of solid tumors,” said Rooney, who is professor in the pediatrics division of hematology and oncology and the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital.
Results from the Rooney lab and others have shown that CAR T cells directed toward solid tumors remained in peripheral blood for only a short time after infusion. This is a major limitation to the effectiveness of CAR T cell therapy for solid tumors.
“Dr. Rooney convinced me that improving the endurance of CAR T cells battling solid tumors would be a very important problem to work on,” Shum said.
Our goal was to have T cells that can proliferate at the tumor site after they are introduced into the body and remain until the tumor is eliminated,” said Shum.
Special delivery of IL7 signaling confers increased survival and endurance to CAR T cells
Like all T cells, CAR T cells require three signals to sustain cell proliferation. The first signal is provided by the binding of the T cell receptor to specific antigen molecules on the surface of tumor cells, which unlocks the cells’ killing ability. Second, the T cells require a co-stimulatory signal to unleash cell proliferation and also to enable T-cells to secrete a wide number of inflammatory factors called cytokines. These cytokines can enlist other immune cells to join the battle and raise the overall effectiveness of an immune response. The third signal is required to sustain the cells’ long-term survival and is provided by a specific subset of cytokines that T-cells cannot produce themselves.
“CAR molecules have been engineered to simultaneously activate signals one and two in a T cell once the CAR binds to its target antigen. Unfortunately, the cells are generally deficient in providing cytokine-derived signal three,” Shum said. “Previous work had shown that cytokines such as IL7 are key to T cell proliferation; IL7 binds to the IL7 receptor on the T cell surface, triggering the third signal. The challenge has been how to effectively deliver cytokine signals to T cells. In this study, we designed a strategy to overcome this challenge.”
Previous studies tried to enhance T cell activity by delivering cytokines via direct injection into patients, but this approach resulted in toxic effects that appeared quickly, before the treatment showed benefits. Other studies attempted to deliver the third signal by inducing tumor-specific T cells to secrete their own cytokines, but this also had negative side effects.
“Our approach to deliver the third signal was to focus on the cytokine receptor itself. We genetically engineered an IL7 receptor that would deliver an autonomous third signal without needing to bind IL7,” Shum said. “When these CAR T cells are activated with signals one and two through the CAR molecule bound to a tumor cell, each cell is also selectively reinforced by its own third signal from the engineered IL7 receptor. Once the CAR T cells receive all three signals, they are able to undergo multiple rounds of proliferation and retain anti-tumor activity.”
The researchers compared the activity of their CAR T cells with and without modified IL7 receptors in two different tumor models in laboratory animals. They found that the CAR T cells enhanced with the engineered IL7 receptor sustained the ability to eradicate established tumors at doses at which CAR T cells without the modified IL7 receptor were ineffective.
“An additional advantage of this particular IL7 signal is that it also makes CAR T cells more resistant to the immunosuppressive tumor environment,” Rooney said. “Fighting tumors is a stressful process. When CAR T cells enter solid tumors, they are surrounded by a microenvironment that triggers stress factors and activates cell death pathways to counteract the T cells’ attempts to eliminate the tumor. CAR T cells with the modified IL7 receptor show less activation of cell death pathways and increased activation of survival factors. We think that those are some of the reasons our cells have better endurance to keep fighting the tumor longer.”
“In summary, the IL7 signaling special delivery method we designed confers all the benefits of survival and endurance packaged in a way that prevents non-specific activation that may cause toxicity,” Shum said.
The researchers’ next step is to move to phase I clinical trials designed to evaluate both safety and efficacy of this procedure in patients. If the phase I clinical trial is successful, then they can conduct other CAR T cell studies for other types of tumors and other branches of adoptive cell therapy.
Read all the details of this study, as well as a list of all the contributors and their affiliations in the journal Cancer Discovery.