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  • Genetic engineering of T cells with receptors from NY-ESO-1-specific tumor-recognizing CD4+ T cell as a novel approach for adoptive T cell therapy

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Poster Presentation
Genetic engineering of T cells with receptors from NY-ESO-1-specific tumor-recognizing CD4+ T cell as a novel approach for adoptive T cell therapy
  1. Junko Matsuzaki1,
  2. Takemasa Tsuji1,
  3. Immanuel Luescher2,
  4. Hiroshi Shiku3,
  5. Junichi Mineno4,
  6. Sachiko Okamoto4,
  7. Lloyd Old5,
  8. Protul Shrikant6,
  9. Sacha Gnjatic7 and
  10. Kunle Odunsi1
  1. Aff1 grid.240614.50000000121818635Roswell Park Cancer Institute Buffalo NY USA
  2. Aff2 Ludwig Center for Cancer Research Epalinges Switzerland
  3. Aff3 grid.260026.0000000040372555XMie University Graduate School of Medicine Tsu Japan
  4. Aff4 grid.410820.fTAKARA BIO INC Otsu Japan
  5. Aff5 grid.1052.60000000097371625Ludwig Institute for Cancer Research New York NY USA
  6. Aff6 grid.417468.80000000088756339Mayo Clinic Scottsdale AZ USA
  7. Aff7 grid.59734.3c0000000106702351MSSM New York NY USA

https://doi.org/10.1186/2051-1426-3-S2-P34

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    Meeting abstracts

    Background

    Tumor antigen-specific CD4+ T cells generally orchestrate and regulate innate and adaptive immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4+ T cells is restricted at local tumor sites where antigen-presenting cells are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4+ helper T cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II (MHC-II) on cancer cells. In addition, we clone the TCR gene from tumor-recognizing CD4+ T cells (TR-CD4) and test the function of TCR gene-engineered cells.

    Methods

    NY-ESO-1-specfic CD4+ or CD8+ T cells were obtained from ovarian cancer patients who received NY-ESO-1 vaccine. Full-length TCR α and β chain genes of TR-CD4 were cloned by 5' RACE PCR. TCR gene was transduced into activated T cells by MSCV-based retroviral vector. The effector function was evaluated against cognate peptide-pulsed target cells or NY-ESO-1+MHC-II+ cancer cell lines by ELISA, intracellular cytokine staining or CTL assay.

    Results

    TR-CD4, but not conventional NY-ESO-1-specific CD4+ T cells, directly recognized cancer cells in MHC-II-dependent and NY-ESO-1-specific manners. Presentation of intracellular NY-ESO-1 on MHC-II by cancer cells required non-classical MHC-II antigen presentation mechanisms. Upon direct recognition of cancer cells, TR-CD4 potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8+ T cells by enhancing cytotoxic activity, and improving viability and proliferation. Notably, the TR-CD4 either alone or in combination with NY-ESO-1-specific CD8+ T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering of polyclonally activated T cells with TCR derived from TR-CD4 successfully produced large numbers of functional TR-CD4.

    Conclusions

    These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients. Large numbers of TR-CD4 that directly recognize cancer cells and enhance CD8+ T cell functions can be generated by gene-engineering with TCR from TR-CD4. Antigen-presenting cell-independent provision of CD4-help by TR-CD4 is especially important to enhance durable CD8+ T cell anti-tumor functions at the tumor local site. Adoptive T cell therapy using TR-CD4 in combination with CD8+ T cells could be a promising strategy for effective eradication of tumors.