New Screening Approach Identifies Cancer Mutations in Melanoma That May Lead to More Effective Immunotherapies
Although cancer immunotherapy with adoptive transfer of tumor-infiltrating lymphocytes represents an effective treatment for patients with metastatic melanoma, the antigen targets recognized by these effective tumor-infiltrating lymphocytes remain unclear.
According to a new study, a novel screening approach called tandem minigene library screening may facilitate the antigen repertoire analysis of tumor-reactive T cells, and may lead to the development of new adoptive T-cell therapies. The new approach demonstrated that the recognition of unique cancer mutations appeared to be responsible for complete cancer regressions in two patients with metastatic melanoma who were treated with adoptive T-cell therapy. The study by Lu et al is published in Clinical Cancer Research.
Study Methodology
The researchers took tumor samples from two patients with metastatic melanoma who had benefited from adoptive T-cell therapy and used two screening methods to identify the tumor targets recognized by the clinically effective T cells. First, the researchers used cDNA library screening to identify nonmutated targets. Then they used tandem minigene library screening to identify mutated targets that cannot be found by the conventional method of screening.
For the minigene library screening method, the researchers used next-generation DNA sequencing to sequence the coding regions of the DNA from the two patients’ tumors, and identified mutations. Next, the researchers generated a library of these mutations. Instead of synthesizing the entire mutated gene, they synthesized only a small region surrounding the mutation. They then screened the minigene library to identify those targets in the patients’ tumors that were recognized by their tumor-infiltrating lymphocytes.
Study Findings
Using cDNA library screening, the researchers identified three novel nonmutated tumor targets, and four previously known nonmutated tumor targets. Using the tandem minigene library approach, the researchers identified two novel mutated tumor targets, KIF2C and POLA2, which play important roles in cell proliferation.
“This study suggests that the identification of antigens using the minigene approach can complement the use of conventional cDNA library approach to evaluate the antigen repertoire of tumor-reactive T cells. Mutated gene products, especially gene products that play essential roles in carcinogenesis, may represent particularly potent immunotherapy targets,” concluded the researchers. “The minigene approach demonstrated in this study can facilitate the identification of mutated antigens, and allow more effective cancer immunotherapy by targeting those tumor-specific mutated antigens.”
Yong-Chen Lu, PhD, and Paul F. Robbins, PhD, of the National Cancer Institute, are the corresponding authors for the Clinical Cancer Research article.
Funding for this study was provided by the National Cancer Institute (NCI) Director’s Innovation Award, the NCI Intramural Research Program, the Adelson Medical Research Foundation, the Milstein Family Foundation, and the European Research Council. The researchers reported no conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
