A new technique allows the creation of more personalized therapies for people with advanced cancer
CONCLUSIONS
Being able to identify targets for adoptive cell therapies is one of the first steps in developing personalized treatments for people with difficult-to-treat cancers. However, predicting whether a patient will have an immune response to a particular abnormal protein caused by mutations that serve as a new antigen (neoantigen), can be difficult. Using ultra-sensitive, high throughput isolation technology (called imPACT Isolation Technology®) designed to isolate specific T cells from neoepitopes, UCLA researchers were able to characterize and identify the neoantigens responsible for antitumor responses in a patient treated with anti-PD-1 blocking and isolate receptors from the T cells responsible for this effect.
BACKGROUND
The use of inhibitors at immune control points to treat people with metastatic melanoma has helped to transform the way people with the most deadly skin cancer are treated. Despite its success, there are still many people who do not receive treatment. To date, adoptive cell therapy, which involves extracting and harvesting T cells from a patient and designing them in a laboratory, has targeted common antigens. This limits the number of people who can potentially be treated with therapy because not all cancers have the same antigen that needs to be targeted. Researchers are working to improve methods for identifying new targets for these therapies in the hope of developing more effective and personalized therapies.
METHOD
The researchers analyzed T cell responses in two patients with advanced melanoma, one who responded to anti-PD1 therapy and the other who did not respond to treatment. From samples taken before and during treatment, the team isolated T lymphocytes by specifically recognizing mutations on the tumor using imPACT Isolation Technology® developed by PACT Pharma. This technology allows researchers to identify T lymphocytes and their receptors, which have the ability to detect mutations. After identifying T cell receptors, they were reintroduced into T cells from peripheral blood using a non-viral genome engineering method to generate new neoantigen-specific T cells that were used to kill melanoma cells in the same patient.
"In the treatment of patients with anti-PD-1, we have identified for the first time, in a high throughput manner, which neoantigenic mutations in the tumor are targeted by T cells. More importantly, we were able to identify their T cell receptors and demonstrate that they can actually specifically kill tumor cells," said Cristina Puig-Saus, PhD, Associate Researcher in Hematology/Oncology at the David Geffen School of Medicine, UCLA. "We hope that a better understanding of T cell responses that occur after the immune control point blockade will guide the design of customized adoptive T cell therapies."
IMPACT
The discovery of new ways to identify targets for immunotherapies significantly increases the number of patients who will benefit from immunotherapy. The imPACT® isolation technology allows researchers to identify mutation-specific T cells and understand which mutations induce responses against tumours.
AUTHORS
The lead author is Cristina Puig-Saus, PhD, Associate Researcher in Hematology/Oncology at UCLA's David Geffen School of Medicine. The main author is Antoni Ribas, MD, PhD, Director of the Tumor Immunology Program at UCLA Jonsson's Comprehensive Cancer Center and Professor of Medicine at UCLA's David Geffen School of Medicine. Thirty-three other authors are listed in the abstract.
JOURNAL
The research was presented at the American Associate of Cancer Research's special conference on immune cell therapies against cancer.
