Development of a lentiviral gene therapy vector to modify effector T and NK cells to control disease activity in perforin deficient hemophagocytic lymphohistiocytosis (HLH) patients
Immunology
Pediatric and Adolescent Medicine
Final Report Abstract
Perforin deficiency is caused by mutations in the PRF1 gene and accounts for up to 58% of familial haemophagocytic lymphohistiocytosis (FHL) syndromes. A deficient cytolytic secretory pathway leads to hypercytokinaemia and hyperactivation of notably CD8 T cells with subsequent inflammation of various organs. The use of autologous gene corrected T cells has the potential to reduce disease activity, alleviate haemophagocytic lymphohistiocytosis (HLH) symptoms and bridge to desired haematopoietic stem cell transplantation (HSCT) or even confer long-term protection. We developed a gammaretroviral vector to transduce murine CD8 T cells and its subsets in the prf-/- mouse model. We saw efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene corrected prf-/- CD8 T cells into prf-/- mice. To verify further the functional correction of prf-/- CD8 T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope transfected murine lung carcinoma cell tumour model that has been evaluated in perforin deficient models. Infusion of prf-/- gene corrected CD8 T cells eliminated the tumour as efficiently as the transplant of wild type CD8 T cells. Similarly, mice reconstituted with gene corrected prf-/- CD8 T cells, displayed complete protection from the HLH phenotype after infection with LCMV. Finally, we show the correction of cytotoxicity in human CD8 T cells of perforin deficient patients after transduction with a PRF1 encoding lentiviral vector. These pre-clinical data demonstrate the potential application of T cell gene therapy for perforin deficient HLH.
Publications
- T-cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents hemophagocytic lymphohistiocytosis manifestations. J Allergy Clin Immunol. 2018 Jan 31
Ghosh S, Carmo M, Calero-Garcia M, Ricciardelli I, Bustamante Ogando JC, Blundell MP, Schambach A, Ashton-Rickardt PG, Booth C, Ehl S, Lehmberg K, Thrasher AJ, Gaspar HB
(See online at https://doi.org/10.1016/j.jaci.2017.11.050)
