Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions
Yong-Chen Lu1, Xin Yao2, Jessica S Crystal2
1Authors' Affiliations: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland; and Yong-Chen.Lu@nih.gov Paul_Robbins@nih.gov.
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 carcinogenesis.
Insights
Tumor-infiltrating lymphocytes (TIL) therapy shows promise for melanoma. A novel minigene screening approach identified mutated KIF2C and POLA2 antigens, paving the way for new adoptive cell therapies.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is an effective cancer immunotherapy for metastatic melanoma.
- High objective regression rates (up to 72%) have been observed in clinical trials.
- However, the specific antigen targets of these effective TILs are largely unknown.
Purpose of the Study:
- To identify the antigen targets recognized by TILs from patients with durable complete regressions.
- To evaluate a novel minigene screening approach for identifying mutated T-cell antigens.
Main Methods:
- Two melanoma patients (2359 and 2591) with long-term complete regressions post-TIL transfer were studied.
- Conventional screening methods and a novel tandem minigene library approach were employed.
- The minigene library comprised nonsynonymous mutations identified by whole-exome sequencing of autologous tumors.
Main Results:
- Conventional screening identified nonmutated targets for TIL 2359 and TIL 2591.
- The minigene approach identified mutated KIF2C as a target for TIL 2359.
- Mutated POLA2 was identified as a target for TIL 2591; both KIF2C and POLA2 are involved in cell proliferation.
Conclusions:
- The minigene screening approach effectively analyzes the antigen repertoire of tumor-reactive T cells.
- This method can aid in developing novel adoptive cell therapies targeting mutated antigens.
- Targeting mutated antigens from genes crucial for carcinogenesis offers a promising therapeutic strategy.
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