Cancer Researchers Identify Mutations as Targets of Effective Melanoma Immunotherapy

Cancer Researchers Identify Mutations as Targets of Effective Melanoma Immunotherapy

A new study published in the American Association for Cancer Research journal Clinical Cancer Research demonstrates that recognition of unique cancer mutations appeared to be responsible for complete cancer regressions in two metastatic melanoma patients treated with a type of immunotherapy called adoptive T-cell therapy. The researchers suggest this innovative approach may help develop more effective cancer immunotherapies.

The Clinical Cancer Research paper, entitled “Efficient Identification of Mutated Cancer Antigens Recognized by T Cells Associated with Durable Tumor Regressions” (Clinical Cancer Research, June 2014 DOI: 10.1158/1078-0432.CCR-14-0433 ) is coauthored by Yong-Chen Lu, Xin Yao, Jessica S. Crystal, Yong F. Li, Mona El-Gamil, Colin Gross, Lindy Davis, Mark E. Dudley, James C. Yang,, Steven A. Rosenberg, and Paul F. Robbins of the Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland; and Yardena Samuels of the Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

The researchers say cancer immunotherapy with adoptive transfer of tumor-infiltrating lymphocytes (TIL) represents an effective treatment for patients with metastatic melanoma, with objective regressions in up to 72% of patients in three clinical trials. However, they caution that antigen targets recognized by these effective TILs remain largely unclear.

In the study, melanoma patients 2359 and 2591 both experienced durable complete regressions of metastases ongoing beyond five years following adoptive TIL transfer. Two conventional screening approaches were carried out to identify the antigens recognized by these clinically effective TILs. In addition, a novel approach was developed in this study to identify mutated T-cell antigens by screening a tandem minigene library, which comprised nonsynonymous mutation sequences identified by whole-exome sequencing of autologous tumors.

The coauthors conclude that their findings suggest that the minigene screening approach can facilitate the antigen repertoire analysis of tumor reactive T cells, and lead to development of new adoptive cell therapies with purified T cells that recognize candidate-mutated antigens derived from genes essential for the carcinogenesis.

More research data are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

N0088590_Image04.tif“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,” says coauthor Steven A. Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute (NCI) in Bethesda, Maryland. “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.”

An American Association for Cancer Research release notes that Adoptive T-cell therapy is a type of immunotherapy in which the immune cells infiltrating a patient’s tumor, so called tumor-infiltrating lymphocytes (TILs, which are T cells), are harvested, activated and expanded in the laboratory, and transferred back to the patient. Such activated cells are capable of efficiently attacking 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. 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,” explains Dr. Rosenberg.

The researchers took tumor samples from two patients who had benefited from the therapy and pursued two screening approaches to identify the tumor targets recognized by the clinically effective T cells. First, they used a conventional screening method called cDNA library screening to identify nonmutated targets. Second, they used a novel method called tandem minigene library screening to identify mutated targets that cannot be found by the conventional method of screening.

For the second approach, the researchers used next-generation DNA sequencing to sequence the coding regions of the DNA from the two patients tumors, and identified mutations. Next, they generated a library of these mutations. Instead of synthesizing the entire mutated gene, they synthesized only a small region surrounding the mutation (hence the name minigene library). They then screened the minigene library to identify those targets in the patients tumors that were recognized by their TILs.

Using cDNA library screening, the researchers identified three novel nonmutated tumor targets, and four previously known non-mutated tumor targets.

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

With the minigene library approach, Dr. 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.

This study was funded by the NCI Directors Innovation Award, the NCI Intramural Research Program, the Adelson Medical Research Foundation, the Milstein Family Foundation, and the European Research Council. Rosenberg declares no conflicts of interest.

Sources:
American Association for Cancer Research
Clinical Cancer Research
National Cancer Institute

Image Credit:
National Cancer Institute

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