Reprogramming T lymphocytes for melanoma adoptive immunotherapy by T-cell receptor gene transfer with lentiviral vectors

Sara Bobisse, Maria Rondina, Anna Merlo, Veronica Tisato, Susanna Mandruzzato, Mario Amendola, Luigi Naldini, Ralph A. Willemsen, Reno Debets, Paola Zanovello, Antonio Rosato

Research output: Contribution to journalArticlepeer-review

Abstract

T-cell receptor (TCR) gene transfer for cancer immunotherapy is limited by the availability of large numbers of tumorspecific T cells. TCR α and β chains were isolated from a highly lytic HLA-A2-restricted cytotoxic T lymphocyte (CTL) clone recognizing the melanoma-associated Melan-A/MART-1 antigen and inserted into a lentiviral vector carrying a bidirectional promoter capable of robust and coordinated expression of the two transgenes. Lentiviral vector-based gene delivery systems have shown increased transfer efficiency and transgene expression compared with the widely used γ-retroviral vectors. This vector performed more efficiently than a γ-retrovirus-based vector containing the same expression cassette, resulting in a T-cell population with 60% to 80% of transgenic TCR expression with mainly CD8+ intermediate effector phenotype. Transgenic T cells specifically produced cytokine in response to and killed antigen-expressing melanoma cells, retained an overlapping functional avidity in comparison with the TCR donor CTL clone, and exerted significant therapeutic effects in vivo upon adoptive transfer in melanoma-bearing severe combined immunodeficient mice. Optical imaging showed their accumulation in the tumor site. Overall, our results indicate that lentiviral vectors represent a valid tool for stable and high-intensity expression of transgenic TCR and support clinical exploitation of this approach for therapeutic application.

Original languageEnglish
Pages (from-to)9385-9394
Number of pages10
JournalCancer Research
Volume69
Issue number24
DOIs
Publication statusPublished - Dec 15 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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