The standard of care for children with DIPG includes external beam focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with focal irradiation followed by maintenance monthly TMZ was also found to be safe but ineffective. However, in the context of an immunotherapy strategy, it might be beneficial to use TMZ as an adjuvant therapy during and following radiotherapy. Recent pre-clinical and clinical studies in adults with have shown that both myeloablative (MA) and non-myeloablative (NMA) chemotherapy induce a profound but transient lymphopenia and, somewhat counterintuitively, vaccination during recovery from this lymphopenic state and/or the adoptive transfer of tumor-specific lymphocytes into lymphodepleted hosts leads to dramatic in vivo T cell expansion and potent immunologic and clinical responses. Therefore, the study team expects that tumor-specific lymphocytes, expanded ex vivo with the use of TTRNA-pulsed DCs may provide a source of lymphocytes that preferentially expand in this lymphopenic environment following TMZ, and serve as a source of responder cells to subsequent DC vaccination.~TMZ induces profound lymphopenia in children with central nervous system (CNS) tumors. It has not been conclusively shown to help in augmenting vaccine-induced immune responses in this population. Patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups. The immunotherapy regimen will consist of TTRNA-DC vaccines alone followed by adoptive cellular therapy consisting of ex vivo expanded tumor-reactive lymphocytes coupled with TTRNA-DC vaccines and autologous HSCs.~Patients in Group B will not receive DI TMZ, however, they will receive lymphodepletion with cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of ex vivo expanded tumor-reactive lymphocytes. T cell engraftment and persistence has been shown to be augmented by lymphodepletion in numerous studies. TTRNA-pulsed DCs will be given in conjunction with the adjuvants GM-CSF and tetanus-diphtheria toxoid (Td) vaccine which the study team have shown can significantly enhance clinical responses to DC vaccination.
The standard of care for children with DIPG includes focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with RT followed by monthly TMZ was also found to be safe but ineffective. Recent studies in adults have shown that certain types of chemotherapy induce a profound but transient lymphopenia (low blood lymphocytes) and vaccinating and/or the adoptive transfer of tumor-specific lymphocytes into the cancer patient during this lymphopenic state leads to dramatic T cell expansion and potent immunologic and clinical responses. Therefore, patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups.