Two mutations linked to success of adoptive T-cell therapy in melanoma
Two novel mutations, KIF2C and POLA2, appeared to be linked to complete cancer regression in two patients with metastatic melanoma who underwent adoptive T-cell immunotherapy, according to study results.
“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,” Steven A. Rosenberg, MD, PhD, chief of surgery at the NCI, said in a press release. “The two targets identified in this study play important roles in cancer cell proliferation.”
Steven A. Rosenberg
Rosenberg and colleagues evaluated tumor samples from two patients who had experienced durable complete regressions of metastases with responses ongoing for 5 years since they received adoptive tumor-infiltrating lymphocyte (TIL) transfer. Researchers analyzed the samples with tandem minigene library screening — a novel method comprised of non-synonymous mutation sequences identified by whole-exome sequencing of autologous tumors — and two conventional screening approaches including cDNA library screening.
“In a clinical trial, up to 72% of the patients with metastatic melanoma experienced tumor regression after adoptive T-cell transfer,” Rosenberg said. “However, not all patients benefited. This is because the specificity of the TILs remains largely unclear. Our goal was to establish an efficient method to identify the specificity of these cells.”
cDNA library screening identified seven targets, three of which were novel and unmutated, and four of which were previously known and also unmutated.
However, the tandem minigene library screening identified two novel mutated targets. Researchers found the mutated kinesin family member 2C (KIF2C) was a target of TIL 2359, and the mutated DNA polymerase alpha subunit B (POLA2) was a target of TIL 2591.
“Immunotherapy has the potential to successfully treat cancer by targeting tumor mutations,” Rosenberg said. “We’ve moved one step closer because of this study.”
Disclosure: See the study for a full list of the researchers’ relevant financial disclosures.