Promising target for CAR T cell therapy leads to powerful anti-tumor responses against cutaneous and rare melanomas

Scientists at UCLA Health Jonsson Comprehensive Cancer Center constructed and demonstrated the potential effectiveness of a novel chimeric antigen receptor (CAR) T-cell immunotherapy specifically designed to treat patients with cutaneous and rare subtypes of melanoma.

CAR T cell therapy uses genetically modified versions of a patient’s immune cells to target and destroy cancer cells. This type of treatment has transformed the field of cancer, especially for people with difficult-to-treat cancers.

The new approach, described in Natural communications, uses a CAR T cell designed to recognize and attack cells with high levels of TYRP1, a protein found on the surface of melanoma cells. The team found that these modified CAR-T cells can effectively eliminate cancer cells in preclinical testing without causing serious side effects.

“One of the biggest challenges for CAR T cell therapies is the scarcity of suitable tumor targets,” said Cristina Puig-Saus, Ph.D., assistant professor of medicine at the David Geffen School of Medicine. at UCLA and lead author of the study. study. “While TYRP1 has previously been targeted in clinical trials using monoclonal antibodies, this new approach harnesses the power of CAR-T cell therapy and has led to very good anti-tumor responses, improving overall treatment efficacy.

Despite the success of immune checkpoint blockade, a considerable number of melanoma patients do not respond well or experience relapse after initial success. Scientists are exploring new ways to create more precise and effective treatments. Additionally, rare melanoma subtypes present additional challenges due to their resistance to standard therapies, including immunotherapies such as immune checkpoint blockade.

To find better ways to use CAR T cell immunotherapy to treat melanoma, the team first looked for an antigen that could be used to target a protein that is expressed on the surface of cancer cells but exhibits lower in normal cells.

By analyzing three different melanoma datasets, they identified TYRP1, which plays a key role in melanin synthesis, and its surface expression is greater in melanoma cells than in normal tissues.

They found that approximately 30% of patients with cutaneous melanoma had elevated TYRP1 overexpression. Importantly, the percentage of overexpression was even higher in patients with rare melanomas. The authors showed that 60% of patients with acral and mucosal melanoma and approximately 90% of patients with uveal melanoma overexpress TYRP1.

“This protein is intracellular, but a small part reaches the plasma membrane as part of the cell’s vesicular transport and is endocytosed again after a short period of time. When it is on the cell surface, it becomes a target for CAR T-cells,” said Puig-Saus, a member of the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

To study the potential new target, the team designed a CAR construct that specifically targeted cells with high TYRP1 expression and then tested the newly designed CAR T cell in different types of melanoma models.

Through this design, they found that CAR T cells completely eradicated cancer cells in cell lines and animal models, showing promising results without inducing toxicity or causing treatment-related adverse effects.

“These preclinical results pave the way for clinical trials, in which CAR T cell therapy targeting TYRP1 can be tested in patients with all types of melanomas,” Puig-Saus said. “If proven safe and effective in human trials, this treatment presents an exciting prospect for future advances in the fight against cancer.”

The research team plans to launch a clinical trial to evaluate the safety and effectiveness of the therapy in treating patients with melanoma.