2nd generation anti-HIV designer T cells cure HIV-infected cultures and preferentially survive versus 1st generation designer T cells (52.19)

Abstract Immunotherapies that have the potential to eradicate reservoirs of HIV infected cells may be useful to suppress or cure HIV/AIDS. T cells expressing chimeric immune receptors (CIR) through gene modification (designer T cells) can be redirected to kill HIV-infected cells. Previously, an anti-HIV CIR, CD4ζ (1st generation), was created to kill HIV+ cells. However, the adoptive transfer of autologous CD4ζ T cells failed to control the viral infection in clinical trials. We created a 2nd generation CIR for enhanced potency by providing co-stimulatory signal (CD4CD28ζ). Our data show that both 1st and 2nd generation CIRs expressed well on retrovirally transduced human T cells and kill HIV+ targets with high efficiency, whereas CD28 in the CIR confers a distinct advantage in the expansion potential and cytokine IL2 secretion. Interestingly, our preliminary data show that all 1st generation designer T cells died in 7 days when co-cultured with HIV+ cells, whereas 2nd generation designer T cells survived with cure of the infected cultures. This stunning result shows dramatic benefit in the new 2nd generation CIR versus the 1st generation that was used in human clinical trials. We are presently exploring whether this cell death in the 1st generation designer T cells is due to heightened sensitivity to AICD and/or due to HIV infection. Either way, these data show a striking benefit to our new 2nd generation designer T cells as a promising therapy for HIV/AIDS.