PerspectiveIn the Journals

Two mutations linked to success of adoptive T-cell therapy in melanoma

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July 8, 2014

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, MD, PhD 

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.

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Brent Hanks

Brent Hanks

This work represents an exciting step forward in adoptive T-cell therapy and provides a promising strategy to improve its clinical efficacy by identifying those T-cell clones that are more likely to eliminate the target malignancy.
This approach is poised to improve the outcomes of future adoptive T-cell therapy studies at select centers; however, the technical aspects of this personalized protocol and the associated costs likely will continue to be limiting factors for its generalized use in oncology. Although the reported response rates are impressive, the current preparative regimen used by the authors in their adoptive T-cell therapy protocol — including the use of high-dose chemotherapy and total body irradiation — is quite toxic and limits this approach to patients with excellent performance status (ECOG 0 or 1).  
The advances reported in this current study — along with recent and future improvements in the understanding of immune regulation, as exemplified by work accomplished in the field of CTLA-4 and PD-1 immunology — promise to expand the option of adoptive T-cell therapy to a broader population of cancer patients. 

Brent Hanks, MD, PhD
Assistant professor, Melanoma Program
Division of medical oncology
Duke University Medical Center

Disclosure: Hanks reports no relevant financial disclosures.