The goal of this study was to increase the number of these cells via an ex vivo cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell HXTC process. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses.
While HIV-specific T cells are necessary for viral control, they are unable to suppress virus to undetectable levels in most individuals and are insufficient to clear infection 1 , 2. HIV-specific T cells often target the variable, non-conserved regions of the virus, allowing viral mutation and immune escape without substantial fitness cost 3. We 4 β 9 and other investigators 10 have employed different vaccine strategies to redirect the T-cell response towards conserved viral regions.
Our Conserved Elements CE approach is distinct in that it employs immunogens determined by both sequence conservation analyses and associations with viral control. Furthermore, following SIV challenge, we found that higher levels of CE-specific T-cell responses were associated with improved viral control during acute infection 13 , The goal in this study was to increase the frequency of CE-specific T-cell responses in vivo by first expanding CE-specific T cells ex vivo.
We have shown that ex vivo antigen presentation by peptide-pulsed dendritic cells and PHA-stimulated peripheral blood mononuclear cells PBMCs efficiently expands antigen-specific T cells, generating both de novo T-cell responses and amplifying existing antigen-specific T-cell subsets For individuals with CMV infection, this process was previously shown to efficiently expand virus-specific T cells and was associated with prolonged periods of disease-free survival and complete remission 15 β An analogous therapy prevented relapse after hematopoietic stem cell transplantation in patients with B cell- or T cell-derived, EBV-associated lymphoma or lymphoproliferative disorders Here, we applied this knowledge to build an NHP model of adoptively transferred antigen-specific T-cell therapy.
We redirected HIV-specific immune responses in both uninfected and SHIV-infected macaques to target conserved epitopes via CE vaccination, expanded these potent antigen-specific T cells ex vivo , and then reinfused each product into the autologous host. We achieved the goal of increasing the frequency of T cells targeting conserved viral sequences, observing large median: fold increases in the frequency of CE-specific T cells during ex vivo expansion. Our novel NHP model furthermore establishes the safety of CE-XTC and recapitulates limitations that have been observed in early-stage clinical trials, providing proof-of-principle for further optimization in the preclinical setting to achieve greater persistence.
