A team of researchers from the National Cancer Institute (NCI), in Bethesda, Maryland, has developed a novel approach demonstrating that mutated cancer antigens recognized by T-cells are responsible for complete cancer regression in two metastatic melanoma patients treated with adoptive T-cell therapy.
Cancer immunotherapy using adoptive transfer of tumor-infiltrating lymphocytes (TIL) is an effective treatment for patients with metastatic melanoma, whereby the immune cells infiltrating a patient’s tumor are harvested, activated and expanded in vitro, and transferred back to the patient. These activated T cells are capable of efficiently attacking tumor cells, as demonstrated in three different clinical trials that resulted in tumor regression in up to 72% of patients treated. However, despite the efficacy of this type of immunotherapy, the antigen targets recognized by these TILs is still unclear.
“This study provides the technical solution to identify mutated tumor targets that can stimulate immune responses, which is one of the major bottlenecks in developing a new generation of adoptive T-cell therapy,” said Steven A. Rosenberg, MD, PhD, chief of surgery at the NCI.
The research team aimed to establish an efficient method of identifying the specificity of these TILs. As such, they analyzed tumor samples from two patients who had benefited from the therapy and had durable complete regressions of metastases ongoing beyond five years following adoptive TIL transfer.
Two different screening approaches were carried out to identify the antigens recognized by the TILs, either conventional cDNA library screening or tandem minigene library screening, containing nonsynonymous mutation sequences identified by whole-exome sequencing of autologous tumors, to identify mutated targets that could not be found by the conventional method of screening.
Using the cDNA screening approach, the team identified previously undescribed nonmutated targets recognized by the TILs from the two patients. In contrast, screening of tandem mini gene libraries resulted in the identification of mutated kinesin family member 2C (KIF2C) antigen and mutated DNA polymerase alpha subunit B (POLA2) antigen as targets of either patient’s TILs.
“The two targets identified in this study play important roles in cancer cell proliferation. Immunotherapy has the potential to successfully treat cancer by targeting tumor mutations. We’ve moved one step closer because of this study,” said Dr. Rosenberg.
These findings, published in the Clinical Cancer Research journal, suggest that the minigene screening approach can improve the antigen repertoire analysis of tumor reactive T cells, leading to the development of new adoptive cell therapies for cancer therapy. Furthermore, using this approach, Rosenberg and colleagues recently reported another novel tumor target recognized by the activated T cells of a patient with bile duct cancer, who responded to adoptive T-cell transfer.