Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer

Daniel Abate-Daga, Daniel E. Speiser, Nachimuthu Chinnasamy, Zhili Zheng, Hui Xu, Steven A. Feldman, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticle

Abstract

The clinical success of adoptive immunotherapy of cancer relies on the selection of target antigens that are highly expressed in tumor cells but absent in essential normal tissues. A group of genes that encode the cancer/testis or cancer germline antigens have been proposed as ideal targets for immunotherapy due to their high expression in multiple cancer types and their restricted expression in immunoprivileged normal tissues. In the present work we report the isolation and characterization of human T cell receptors (TCRs) with specificity for synovial sarcoma X breakpoint 2 (SSX2), a cancer/testis antigen expressed in melanoma, prostate cancer, lymphoma, multiple myeloma and pancreatic cancer, among other tumors. We isolated seven HLA-A2 restricted T cell receptors from natural T cell clones derived from tumor-infiltrated lymph nodes of two SSX2-seropositive melanoma patients, and selected four TCRs for cloning into retroviral vectors. Peripheral blood lymphocytes (PBL) transduced with three of four SSX2 TCRs showed SSX241-49 (KASEKIFYV) peptide specific reactivity, tumor cell recognition and tetramer binding. One of these, TCR-5, exhibited tetramer binding in both CD4 and CD8 cells and was selected for further studies. Antigen-specific and HLA-A*0201-restricted interferon-γ release, cell lysis and lymphocyte proliferation was observed following culture of TCR engineered human PBL with relevant tumor cell lines. Codon optimization was found to increase TCR-5 expression in transduced T cells, and this construct has been selected for development of clinical grade viral vector producing cells. The tumor-specific pattern of expression of SSX2, along with the potent and selective activity of TCR-5, makes this TCR an attractive candidate for potential TCR gene therapy to treat multiple cancer histologies.

Original languageEnglish (US)
Article numbere93321
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 28 2014
Externally publishedYes

Fingerprint

Synovial Sarcoma
Adoptive Immunotherapy
immunotherapy
Testicular Neoplasms
sarcoma
T-Cell Antigen Receptor
epitopes
Epitopes
testes
T-lymphocytes
antigens
Antigens
receptors
neoplasms
Tumors
Neoplasms
Lymphocytes
T-cells
Cells
Melanoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer. / Abate-Daga, Daniel; Speiser, Daniel E.; Chinnasamy, Nachimuthu; Zheng, Zhili; Xu, Hui; Feldman, Steven A.; Rosenberg, Steven A.; Morgan, Richard A.

In: PLoS One, Vol. 9, No. 3, e93321, 28.03.2014.

Research output: Contribution to journalArticle

Abate-Daga, D, Speiser, DE, Chinnasamy, N, Zheng, Z, Xu, H, Feldman, SA, Rosenberg, SA & Morgan, RA 2014, 'Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer', PLoS One, vol. 9, no. 3, e93321. https://doi.org/10.1371/journal.pone.0093321
Abate-Daga, Daniel ; Speiser, Daniel E. ; Chinnasamy, Nachimuthu ; Zheng, Zhili ; Xu, Hui ; Feldman, Steven A. ; Rosenberg, Steven A. ; Morgan, Richard A. / Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer. In: PLoS One. 2014 ; Vol. 9, No. 3.
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