Abstract
e15123 Background: We created “designer T cells” by retroviral gene therapy to express chimeric immunoglobulin-T cell receptors (IgTCR) with specificity for carcinoembryonic antigen (CEA). Our previous Phase I trial with 1st generation (1st gen) designer T cells was well tolerated with proof-of-principle “biologic responses”, but of limited duration. Lab correlates showed modified T cells repeatedly kill tumor targets over 4–7 days but then undergo activation-induced cell death (AICD). We created 2nd gen designer T cells that incorporate CD28 co-stimulation into the IgTCR (IgCD28TCR), suppressing AICD and promoting T cell proliferation on tumor contact with superior tumor responses in vivo (Emtage et al. Clin Cancer Res 2008;14:8112). A Phase I clinical trial was approved under FDA BB-IND 10791. Methods: Patient T cells are modified ex vivo, expanded and then administered in a Phase Ia dose escalation, spanning doses of 10^9 to 10^11 cells. Patients are monitored for safety, pharmacokinetics and response. Results: To date, three subjects enrolled with doses prepared and two were treated. T cells were transduced with equal modification of CD4 helper and CD8 cytotoxic T cells and good ex vivo expansions of 30-fold or more. Cells were infused over 15–30 minutes. Blood clearance was rapid. Dosing was without toxicity but also without responses at this lowest T cell dose level. Results will be updated to include new patients at conference time. Conclusions: The safety of 2nd generation designer T cells is supported in two patients at the lowest T cell dose level. Higher planned doses are 10- to 100-fold more T cells, to be observed for toxicity and where responses may begin to be observed. Funding is from the Office of Orphan Products Development of the FDA. No significant financial relationships to disclose.
Published Version
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