Interleukin-12 (IL-12) is a potent cytokine that may be harnessed to treat cancer. To date, nearly 100 IL-12-based clinical trials have been initiated worldwide. Yet systemic administration of IL-12 is toxic. Different strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Our previous studies employed lentivector-mediated expression of murine IL-12 in tumor cells and demonstrated effective protection in both mouse leukemia and solid tumor challenge models. In this study, we carried out preclinical validation studies using a novel lentivector to engineer expression of human IL-12 in acute myeloid leukemia blast cells isolated from 21 patients. Acute myeloid leukemia cells were transduced with a bicistronic lentivector that encodes the human IL-12 cDNA as a fusion, as well as a LNGFR (ΔLNGFR)/mutant thymidylate kinase cassette as a marking and cell-fate control element. A range of 20–70% functional transduction efficiencies was achieved. Transduced acute myeloid leukemia cells produced bioactive IL-12 protein and displayed dose-dependent sensitivity to the prodrug 3′-azido-3′-deoxythymidine. In vitro immortalization assays using transduced mouse hematopoietic stem cells demonstrated minimal genotoxic risk from our IL-12 vector. Scale-up transduction and cell processing was subsequently validated in a GMP facility to support our (now approved) Clinical Trial Application (CTA).
CanCer -Immunotherapy, CanCer VaCCInes II against CD5-negative cell lines. Upon longer-term coculture, CD5 CAR T cells eliminated >95% of leukemia cells from 3 T-ALL lines within 48h and 100% by day 7. We also observed the ability of CD5 CAR T cells to eliminate leukemia cells in sequential killing assays where we recurrently replenished fresh target cells for at least 4 iterations. Lack of functional exhaustion in sequential killing assays supports the fitness of CD5 CAR T cells for eradicating large numbers of tumor cells in vivo. CD5 CAR T cells dramatically suppressed systemic in vivo disease progression in 3 different xenograft mouse models, doubling median survival. Importantly, CD5 CAR T cells demonstrated significant cytokine production and cytotoxicity against primary T-ALL blasts (n=6), highlighting the therapeutic potential of CD5 CAR for patients with T cell malignancies. Overall, we demonstrated for the first time that CD5 CAR redirects T cells to eliminate CD5-positive malignant T cells in vitro and in vivo while producing only limited fratricide of the normal T cell population. 412.Development of GD2-Specific Immunoliposomes for Immunotherapy of Neuroblastoma
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