Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions

Yong Chen Lu, Xin Yao, Jessica S. Crystal, Yong F. Li, Mona El-Gamil, Colin Gross, Lindy Davis, Mark E. Dudley, James C. Yang, Yardena Samuels, Steven A. Rosenberg, Paul F. Robbins

Research output: Contribution to journalArticle

Abstract

Purpose: Cancer immunotherapy with adoptive transfer of tumor-infiltrating lymphocytes (TIL) represents an effective treatment for patients with metastatic melanoma, with the objective regressions in up to 72% of patients in three clinical trials. However, the antigen targets recognized by these effective TILs remain largely unclear. Experimental Design: 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. Results: Screening of an autologous melanoma cDNA library using a conventional approach led to the identification of previously undescribed nonmutated targets recognized by TIL 2359 or TIL 2591. In contrast, screening of tandem minigene libraries encoding tumor-specific mutations resulted in the identification of mutated kinesin family member 2C (KIF2C) antigen as a target of TIL 2359, and mutated DNA polymerase alpha subunit B (POLA2) antigen as a target of TIL 2591. Both KIF2C and POLA2 have been found to play important roles in cell proliferation. Conclusions: These findings suggest that the minigene screening approach can facilitate the antigen repertoire analysis of tumor reactive T cells, and lead to the development of new adoptive cell therapies with purified T cells that recognize candidate-mutated antigens derived from genes essential for the carcino-genesis.

Original languageEnglish (US)
Pages (from-to)3401-3410
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number13
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions'. Together they form a unique fingerprint.

  • Cite this

    Lu, Y. C., Yao, X., Crystal, J. S., Li, Y. F., El-Gamil, M., Gross, C., Davis, L., Dudley, M. E., Yang, J. C., Samuels, Y., Rosenberg, S. A., & Robbins, P. F. (2014). Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clinical Cancer Research, 20(13), 3401-3410. https://doi.org/10.1158/1078-0432.CCR-14-0433