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Poster Presentation
MyD88/CD40-based inducible co-stimulation to improve CAR T cell therapy
  1. Melinda Mata1,
  2. Claudia Gerken1,
  3. David M Spencer2 and
  4. Stephen Gottschalk3
  1. Aff1 grid.39382.33000000012160926XBaylor College of Medicine Houston TX USA
  2. Aff2 grid.39382.33000000012160926XBellicum Pharmaceuticals and Baylor College of Medicine Houston TX USA
  3. Aff3 grid.39382.33000000012160926XDepartment of Pediatrics, Center for Cell and Gene TherapyBaylor College of Medicine Houston TX USA

http://dx.doi.org/10.1186/2051-1426-3-S2-P118

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    Meeting abstracts

    Background

    Adoptive immunotherapy with genetically modified T cells holds promise in improving outcomes for cancer patients. While a broad array of genetic modification strategies are being explored, few allow for the specific manipulation of adoptively transferred T cells in vivo. One successful example includes the introduction of an inducible ‘suicide gene’ to enable selective T-cell killing in the event of toxicities. Given the limited antitumor activity of adoptively transferred T cells for solid tumors in early clinical studies, we reasoned that introducing an inducible co-stimulatory molecule into T cells would allow for the selective activation of adoptively transferred T cells in vivo resulting in enhanced antitumor activity. Due to the role of MyD88 and CD40 signaling pathways to fine tune T-cell activation, and the recent success of using inducible (i) MyD88 and CD40 molecules to activate antigen-presenting cells, the goal of this project was to explore if T cells can be activated with iMyD88 and/or iCD40 molecules.

    Methods/results

    We constructed a panel of retroviral vectors encoding mOrange as a marker gene and an inducible co-stimulatory molecule (iCO-STIM) consisting of a myristoylation tag, two FKBP dimerizer domains, and i) MyD88, ii) CD40, or iii) MyD88 + CD40. T cells expressing iMyD88, iCD40, or iMyD88.CD40 were generated by retroviral transduction, and transduction was confirmed by FACS analysis and Western blot. T cells expressing iCO-STIMs were activated with the CD3 monoclonal antibody OKT3 in the presence or absence of the chemical inducer of dimerization (CID), AP20187. iMyD88.CD40 T cells secreted the highest amount of IL2 in the presence of OKT3 + CID in comparison to iMyD88 or iCD40 T cells. To evaluate if activating iMyD88.CD40 in CAR T cells also enhances cytokine production, we generated T cells that expressed HER2-CARs and iMyD88.CD40 (HER2-CAR/iCO-STIM T cells). CID enhanced IL2 production of HER2-CAR/iCOSTIM T cells that were either stimulated with recombinant HER2 protein or HER2+ cell lines. Enhanced IL2 production was observed with 1st, 2nd, and 3rd generation HER2-CARs.

    Conclusion

    We have generated CAR T cells with an inducible co-stimulatory molecule based on MyD88 and CD40. Preliminary functional analysis of CAR/iCO-STIM T cells is encouraging, warranting further active exploration of this approach to improve current T-cell therapy approaches for cancer.