RESUMEN
Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.
Asunto(s)
Células Presentadoras de Antígenos/trasplante , Ingeniería Celular/métodos , Eritrocitos/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Ligando 4-1BB/genética , Ligando 4-1BB/inmunología , Ligando 4-1BB/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Eritrocitos/metabolismo , Femenino , Antígeno HLA-A2/genética , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Interleucina-12/genética , Interleucina-12/inmunología , Interleucina-12/metabolismo , Activación de Linfocitos , Neoplasias/inmunología , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/inmunología , Proteínas E7 de Papillomavirus/metabolismo , Cultivo Primario de Células , Linfocitos T/inmunología , Linfocitos T/trasplante , Trasplante Homólogo/métodosRESUMEN
Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native ß cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple ß cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+ and CD8+ diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+ T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+ and CD8+ T cells.
