Chimeric Antigen Receptor T cell therapy (CAR T cell therapy) re-engineers patient’s immune cells to target and fight cancer
By BRANDON NGUYEN — science@theaggie.org
UC Davis Health is one of the few institutions in California and the only University of California campus that is producing Chimeric Antigen Receptor (CAR) T cells as an immunotherapeutic weapon to help patients fight lymphomas and blood cancers. CAR T cell therapy, an immunotherapy that extracts a patient’s T cells and genetically re-engineers them to target cancer cells, is currently under clinical trial at the UC Davis Medical Center.
Dr. Joseph Tuscano, a professor of medicine at the UC Davis Comprehensive Cancer Center and co-investigator of the clinical trial for developing this therapy, described the science behind this immunotherapy rising in popularity.
“CAR T cell therapy is an immunotherapy where we try to fix the patient’s immune system by removing the T-killer cells in the body and then genetically modifying those using a virus called lentivirus that will go in and change the DNA,” Tuscano said. “So what is done is that the T cells are harvested from the patient there, and are modified to carry these new genes that code for a new receptor that is on the surface of the T cell. This receptor is able to target a protein or ligand that’s on the surface of the cancer cell.”
This receptor on the genetically modified T cell is called the Chimeric Antigen Receptor, from which the therapy derives its name. With newly built-in receptors on the patient’s T cells, its binding to the targeted cancer cells leads to the T cells’ activation and proliferation into an army of immune cells that can now fight the tumor.
“The immune system plays a very important role in the eradication of cancer and, in fact, most of us are probably developing cancer when we’re very young,” Tuscano said. “And our immune system, using a method that we term ‘immune surveillance,’ identifies cancers and eradicates them all through our lives. So why do we develop cancer? It’s because our immune system fails as we age from exhaustion or from factors like environmental factors, genetic factors, medications, viruses and all kinds of reasons for our immune system to no longer be effective.”
The retraining of a patient’s T cells is not cheap, costing up to $500,000 for a patient to receive CAR T cell therapy if the cells were transported to and modified at a third-party commercial lab. This contributes to inequitable health care which is a concern addressed by the goals of this clinical trial.
Dr. Jan Nolta, the director of the UC Davis Stem Cell Program and Gene Therapy Center, explains the importance of making this therapy attainable by genetically modifying the patient’s T cells on the UC Davis campus itself.
“Giving more patients equal access to CAR T cell therapy is important because we’re in the business of saving lives,” Nolta said. “I hope this could become a frontline therapy soon, as I am a cancer survivor myself, having gone through chemotherapy and everything. So I think making this form of immunotherapy accessible by retraining and growing these T cells in our labs would drastically bring the costs of cancer treatment down for these patients.”
Nolta coordinates the transfer of patients’ T cells from the UC Davis Medical Center to the Good Manufacturing Practice (GMP) Facility for the ongoing clinical trial. Being one of the few institutions that can re-engineer the T cells on campus can reduce the transportation costs incorporated in otherwise commercial products, reducing the overall cost from $500,000 down to even $50,000 for each patient treated.
Once the CAR T cells are grown to become a large population of cancer-fighting cells, they are ready to be infused back into the patient. However, prior to this infusion, the patient must undergo “lymphodepleting condition,” which is a type of chemotherapy that makes more room for the CAR T cells to expand as they conquer and destroy the targeted cancer cells.
Dr. Mehrad Abedi, a UC Davis oncologist and primary investigator of the clinical trial, discusses the importance of phase I of the clinical trial.
“Our Phase I trial at UC Davis allows us to get more innovative about how we do CAR T cell therapy,” Abedi said. “For example, because we can transform the T cells on site, we have better control over the quality of the product. We feel this is the best way to ensure the CAR T cells continue to grow over the lifetime of the patient, providing a constant army of re-engineered T cells ready to attack any cancer cells that show up.”
However, with every treatment, there are some drawbacks, which Tuscano discusses the clinical trial is trying to minimize to become an optimal form of therapy.
“There are side effects from the initial chemotherapy, and then, T cells become activated following infusion so you have a very active or overactive immune system, and that overactive immune system can be harmful sometimes,” Tuscano said. “In the process, it releases these hormones called cytokines that cause a lot of what we call morbidity or sickness in the patient. This is called cytokines release syndrome or CRS, which then can result in drops in blood pressure, neurologic complications called cell-associated neurologic syndrome, where you can have seizures as well.”
Aside from the high release of cytokines and potential neurological complications, a weakened immune system from CAR T cells attacking not only the cancer cells but also normal B lymphocytes in a patient, can predispose them to infections.
“Fortunately, we’ve become very good at identifying and treating these side effects early, so that they’re relatively mild,” Tuscano said. “We monitor the patients very closely and carefully to prevent them from resulting in further health complications for the patient.”
With the rise of CAR T cell therapy as an option to potentially become a frontline therapy for cancer patients one day, UC Davis is also expanding the therapy in other clinical trials to potentially cure solid tumors and cancers.
“We are already expanding into solid tumors. There’s clinical trials actually right here at UC Davis looking at solid tumors like liver cancer, ovarian cancer and other cancers,” Tuscano said. “We’re hopeful that if we find the right targets that it will be effective for solid tumors as well, but it’s also being used for other diseases like other autoimmune diseases, skin diseases and infectious diseases as well. It’s a very exciting time and just the idea of being able to take the cells out of the body, genetically modifying them and putting them back is also a big step toward the implementation of gene therapy for many, many diseases.”
Written by: Brandon Nguyen — science@theaggie.org
