Author of

• 12736

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  P3.14 - Poster Session 3 - Mesothelioma (ID 197)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Mesothelioma
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12743

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    P3.14-007 - Chimeric Antibody Receptor (CAR) Augmented Adoptive T Cell Therapy (ACT) for Patients with Progressive Malignant Pleural Mesothelioma (MPM) (ID 1870)

    09:30 - 09:30  |  Author(s): M. Kalos
    • Abstract

    Background
    ACT using genetically modified T cells has shown great promise in different malignancies (eg melanoma, chronic lymphoid leukemia.) Our group has recently applied this technology by creating T cells that express a chimeric antibody receptor (CAR) that targets the highly expressed tumor antigen, mesothelin to treat malignant mesothelioma (MM), ovarian, and pancreatic cancer and has initiated a Phase I trial in MM patients using mRNA transfected CAR T cells against mesothelin (CART-meso cells) to test its feasibility and safety.

    Methods
    Three patients with progressive MPM with epithelial or biphasic MPM underwent apheresis for T cell isolation/electroporation/expansion. To mitigate concerns about potential off-target toxicity due to low levels of mesothelin expression in normal tissues we developed “biodegradable” mesothelin-specific CAR engineered T cells that transiently express CAR transcripts following mRNA electroporation. T cells were electroporated with the CAR mRNA and then frozen aliquots were thawed and administered to the patients. Serum/peripheral blood/marrow mononuclear cells were acquired from patients during the trial to detect/quantify abundance of transgene and CD3e transcripts, soluble cytokine factors, human anti-mouse antibody (HAMA), CAR T cell-induced humoral responses against tumor antigens.

    Results
    Adoptive transfer of mRNA engineered to express “biodegradable” CAR that target mesothelin was feasible. CARTmeso cells were detected in the blood and demonstrated the predicted transience of persistence in peripheral blood. Infusions were safe from the perspective of off target toxicity due to low level mesothelin expression in normal tissues. However, in one patient who received two courses of T cells, with the second course after a 6 week delay developed an anaphylactic reaction after T cell infusion, presumably due to IgE antibodies generated against the murine single chain antibody that is part of the CAR. We observed clinical activity in one patient who showed a 50% reduction in mediastinal tumor volume (Figure 1). This patient also developed antibodies against other proteins present in mesothelioma cell lines. Figure 1 Fig 1. Greater than 50% reduction in volume of mediastinal MPM tumor in one patient after infusion.

    Conclusion
    ACT of mRNA engineered CART-meso cells is feasible and safe from the perspective of off target toxicity due to low level mesothelin expression in normal tissues. mRNA engineered T cells can be used to evaluate potential issues of off-target CAR-mediated toxicity and support the development of CAR-based strategies to target mesothelin.