Abstract 3144: Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes

Abstract

Abstract Anaplastic large cell lymphoma (ALCL), a type of T/null-cell lymphoma, represents about 20-30% of paediatric lymphomas and has an aggressive clinical course with frequent relapse. Recently, high-level expression of CSF1R on malignant cells in ALCL has been linked to shorter progression free survival, providing a rationale to test adoptive C28ζ-mediated T-cell therapy. This approach encompasses the genetic modification of T-cells to express a chimeric antigen receptor (CAR) named C28ζ, a fusion receptor coupling the recognition of CSF1R on the tumour cell surface to the delivery of tailored T-cell activation signal provided by a fused CD28+CD3ζ endodomain. To optimize this approach for human translation, the C28ζ CAR was co-expressed with the chimeric cytokine receptor 4αβ (combination termed “C4”), which allows for selective expansion and enrichment of CAR-transduced T-cells using IL-4. PBMCs of healthy donors were isolated and activated using anti-CD3/CD28 beads. Following retroviral T-cell transduction and 14 days expansion of C4+ T-cells in the presence of IL-4, co-cultures with a panel of ALCL cell lines (2 ALK positive and 2 ALK negative ALCL cell lines) were set up to test C4 efficacy in vitro. Successful re-targeting of C4+ T-cells was confirmed by monitoring target cell destruction. Conditioned media was collected and analysed for IFN-γ and IL-2 production. Cytotoxicity, cytokine release and T-cell proliferation data demonstrated Ag-specific activation of the C4+ cells, which contrasted with T-cells expressing a control CAR with truncated endodomain. This data provides for the first time the basis for successful application of CAR-based immunotherapy against CSF1R-expressing malignancies. Citation Format: Daniela Achkova, James Spicer, John Maher. Development of immunotherapy for anaplastic large cell lymphoma (ALCL) using CSF1R retargeted human T lymphocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3144. doi:10.1158/1538-7445.AM2015-3144