Unique cancer mutations may be targets for effective melanoma immunotherapy

Adoptive T-cell therapy, a type of immunotherapy, appears to recognize unique cancer mutations that stimulate immune responses. This treatment led to the complete regression of cancer in two patients with metastatic melanoma.

A new method for the recognition of cancer mutations may lead to development of more effective cancer immunotherapies, according to a study published in Clinical Cancer Research (2014; doi:10.1158/1078-0432.CCR-14-0433).

"Immunotherapy has the potential to successfully treat cancer by targeting tumor mutations. We've moved one step closer because of this study," said Steven A. Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute (NCI) in Bethesda, Maryland.

Adoptive T-cell therapy is a type of immunotherapy in which the immune cells infiltrating a patient's tumor (tumor-infiltrating lymphocytes, or TILs) are harvested, activated, expanded in the laboratory, then transferred back to the patient. These activated cells attack and kill tumor cells.

"In a clinical trial, up to 72% of the patients with metastatic melanoma experienced tumor regression after adoptive T-cell transfer. However, not all patients benefited because the specificity of the TILs remains unclear. The purpose of this study was to establish an efficient method to identify the specificity of these cells," explained Rosenberg.

The researchers took tumor samples from two patients who had benefited from the therapy. Two different screening approaches were used to identify the tumor targets recognized by the activated T cells. A conventional screening method called cDNA library screening was used to identify targets that were not mutated.

A second method called tandem minigene library screening identified mutated targets that were not found by the conventional method of screening. The coding regions of DNA from the two patients' tumors were sequenced, creating a library of mutations. Instead of synthesizing the entire mutated gene, only a small region surrounding the mutation was synthesized (hence the name minigene library). The minigene library was screened to identify the regions in the patients' tumors that the TILs recognized.

The researchers identified three novel tumor targets, and four previously known tumor targets using cDNA library screening. All tumor targets lacked mutations.

Using tandem minigene library screening, the researchers identified two novel mutated tumor targets, KIF2C and POLA2, which play important roles in cell proliferation.

"This study allowed us to identify mutated tumor targets that can stimulate immune responses. The two targets identified in this study play important roles in cancer cell proliferation,” said Rosenberg.

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