T-cell receptor/CD28-targeted immunotherapeutics selectively drive naive T-cell expansion to generate functional HIV-specific responses

Adoptive transfer of <i>ex vivo</i>-expanded T cells with potent and broad anti-HIV activity may control HIV replication in people with HIV in the absence of antiretroviral therapy. To selectively activate and expand naive CD8+ cells targeting defined viral or cancer epitopes, we developed a unique protein architecture, termed Immuno-STAT, which delivers cognate peptide-specific T cell receptor (TCR) activation alone or in combination with CD28 costimulation. We demonstrated that polyfunctional cytotoxic CD8+ T cells specific for the HIV-associated SL9 or melanoma-associated MART-1 epitopes were expanded by αCD28-Immuno-STAT delivering peptide-specific TCR and CD28 signals, but not peptide-specific TCR signals alone. αCD28-Immuno-STAT-generated SL9-specific CD8+ T cells exhibited diverse TCR clonotypes, polyfunctionality, and potent SL9-specific cytotoxicity. Adoptive transfer of αCD28-Immuno-STAT-generated CD8+ T cells specific for defined HIV epitopes may provide the broad yet targeted responses specific for conserved HIV epitopes and predicted immune escape variants required to control HIV replication and provide a functional HIV cure.