RESUMEN
Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8+ T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.
Asunto(s)
Anticuerpos/inmunología , Linfocitos T CD8-positivos/trasplante , Citomegalovirus/inmunología , Epítopos de Linfocito T/inmunología , Inmunoconjugados/uso terapéutico , Neoplasias/terapia , Animales , Anticuerpos/química , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Epítopos de Linfocito T/química , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunoconjugados/química , Inmunoconjugados/inmunología , Inmunoconjugados/metabolismo , Inmunomodulación , Inmunoterapia Adoptiva , Activación de Linfocitos , Metaloproteinasas de la Matriz/metabolismo , Ratones , Neoplasias/inmunologíaRESUMEN
OBJECTIVE: Examine outcomes for the National Parkinson Foundation (NPF) Allied Team Training for Parkinson (ATTP), an interprofessional education (IPE) program in Parkinson's disease (PD) and team-based care for medicine, nursing, occupational, physical and music therapies, physician assistant, social work and speech-language pathology disciplines. BACKGROUND: Healthcare professionals need education in evidence-based PD practices and working effectively in teams. Few evidence-based models of IPE in PD exist. METHODS: Knowledge about PD, team-based care, the role of other disciplines and attitudes towards healthcare teams were measured before and after a protocol-driven training program. Knowledge, attitudes and practice changes were again measured at 6-month post-training. Trainee results were compared to results of controls. RESULTS: Twenty-six NPF-ATTP trainings were held across the U.S. (2003-2013). Compared to control participants (n = 100), trainees (n = 1468) showed statistically significant posttest improvement in all major outcomes, including self-perceived (p < 0.001) and objective knowledge (p < 0.001), Understanding Role of Other Disciplines (p < 0.001), Attitudes Toward Health Care Teams Scale (p < 0.001), and the Attitudes Toward Value of Teams (p < 0.001) subscale. Despite some decline, significant improvements were largely sustained at six-month post-training. Qualitative analyses confirmed post-training practice changes. CONCLUSIONS: The NPF-ATTP model IPE program showed sustained positive gains in knowledge of PD, team strategies and role of other disciplines, team attitudes, and important practice improvements. Further research should examine longer-term outcomes, objectively measure practice changes and mediators, and determine impact on patient outcomes.