RESUMEN
Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsed/refractory pre-B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Células Precursoras de Linfocitos B/patología , Linfocitos T/patología , Traslado Adoptivo/métodos , Animales , Vacunas contra el Cáncer/uso terapéutico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Ratones Endogámicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos/análisisRESUMEN
INTRODUCTION: Despite Accredited Counsel of Graduate Medical Education (ACGME) guidance and criteria, there remains variability in training both within each specialty and across the specialties involved in the delivery of neuromodulation. NANS advocates for the efficacious and safe the implementation of neuromodulation and therefore an educational mentoring program with a defined educational platform is needed. MATERIALS AND METHODS: This is a structured, patient centered, and evidence-based approach mentorship program performed more than one year. Mentor/Mentee pairs started in 2015 and data collected were more than a five-year period. RESULTS: There was a 70%-86% response rate on each survey administered. All except one respondent reported that the mentorship program met their previously declared expectations. All the respondents self-reported at least a moderate increase in their knowledge in the field of neuromodulation while 54% of the respondents felt their knowledge in the field to have greatly increased. Most respondents reported an increase in the number of spinal cord stimulator trials and permanent implants performed after the mentorship program. The self-reporting of mentees competencies at the conclusion of the program was statistically significant for higher competency scores in all areas assessed. CONCLUSIONS: The NANs mentorship program met expectations and implementation goals by improving neuromodulation education including covering patient care, delivery, and training topics. The mentoring program provides a structured framework for extending formal physician neuromodulation education outside of direct fellowship training.