A research team at the Abramson Cancer Center of the University of Pennsylvania has been awarded a $500,000 grant from the Alliance for Cancer Gene Therapy (ACGT) to develop a CAR T-cell therapy to treat prostate cancer.
The ACGT grant was awarded to Joseph Fraietta, PhD, an assistant professor of microbiology with expertise in tumor immunology, and Naomi Haas, MD, an associate professor of medicine and director of the prostate and kidney cancer program. Haas is currently conducting a Phase 1 clinical trial (NCT03089203) investigating the safety and proper dosage of a form of CAR T-cell therapy for prostate cancer patients.
In previous studies and clinical trials, prostate cancer has been resistant to the CAR T-cell therapeutic approach. However, as many prostate cancer patients are resistant to traditional approaches — such as chemotherapy, hormonal treatment, and surgery — developing a new strategy is of the utmost importance.
CAR T-cell therapy is a technique in which T-cells, a type of immune cell, are collected from a patient and then treated in the laboratory to elevate their anti-tumor activity. This is accomplished by genetically engineering the T-cells to produce what is called a chimeric antigen receptor, or CAR, which is a protein that is specifically designed to recognize some component of the patient’s tumor. The engineered CAR T-cells are expanded in the lab, and then infused back into the patient’s bloodstream, where they can then help eliminate cancer cells.
The new award will fund research into improving the effectiveness of T-cells in battling the cancer cells of solid tumors. The team’s study will investigate how the availability of nutrients may play a role in the regulation of what genes are active in T-cells — a process called epigenetic coding. The variation in gene expression may affect a T-cell’s ability to fight tumors.
“The grant from ACGT will help us advance our clinical work in a very novel way,” Fraietta said in a press release. “If we can unlock the epigenetic code that controls the fate and function of T-cells, it could be a game changer.”
Part of the ACGT’s motivation for funding this research is that it will build upon results from the clinical trial currently being conducted by Haas, a renowned expert in the field of prostate and kidney cancer.
In that open-label, non-randomized study at the University of Pennsylvania, 18 patients with metastatic prostate cancer are being given a single dose of CAR T-cell therapy, with or without a dose of the chemotherapy drug cyclophosphamide. Chemotherapy is often used in CAR T-cell treatments to suppress the immune system and avoid any potential immune response to the re-introduced engineered cells.
The clinical trial will follow a standard “3+3 dose escalation” format, in which patients are placed into groups of three and given doses of ascending concentrations. By monitoring for any adverse reactions over a two-year period, this format allows researchers to determine the safety and maximum tolerated dosage of the treatment — one of the study’s primary goals.
A secondary goal of the trial is to determine whether the treatment shows signs of anti-tumor activity. The researchers will measure tumor burden before the participants begin receiving the CAR T-cell treatment, and then again at four weeks, three months, and six months afterward.
The CAR T-cells used in this trial carry a receptor for a prostate cancer surface protein called prostate-specific membrane antigen, which is being explored as a target for many prostate cancer therapies.
The researchers note that these cells also carry another receptor that renders them insensitive to the immunosuppressive effects of transforming growth factor β (TGF-β), which is produced by prostate cancer tumors to block local immune system activity.
In preclinical studies, these cells proliferated more, had increased activity and persistence in circulation, and were able to eradicate aggressive human cancers in mice more efficiently than PSMA CAR T-cells lacking the TGF-β receptor.
“The ACGT Scientific Advisory Council is impressed with the potential of this research team and their successful innovations in the use of T-cell therapy,” said Kevin Honeycutt, the CEO and president of ACGT. “Because Drs. Fraietta and Haas are building on direct results already achieved with patients, there may be less transition time required to get a promising new treatment into the clinic for prostate cancer patients.”
“Plus, we believe this research could provide a tumor-attack roadmap to help fight other cancers, including lung, pancreatic, ovarian and brain,” Honeycutt said.
The U.S. nonprofit has supported the development of CAR T-cell therapy for many years, awarding grants in 2004 and 2008 to another university researcher, Carl June, MD. June pioneered the CAR T-cell technique to treat leukemia.
“ACGT has been dedicated to funding innovative science that harnesses the power of cell and gene therapy and transforms how cancer is treated,” Honeycutt said. “The work of Drs. Fraietta and Haas is a great example of this promise.”
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