Citations

Abstract Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the direct cytopathic effect is followed, under certain circumstances, by an antitumor immune response responsible for the partial or complete debulking of the tumor mass. OVs alone or combined with other therapeutic modalities have been primarily used in adult neuro-oncology. A surge in encouraging preclinical studies in pediatric brain tumor models recently led to the clinical translation of OVs with encouraging results in these tumors. In this review, we summarize the different virotherapy tested in preclinical and clinical studies in pediatric brain tumors, and we discuss the limitations and future avenues necessary to improve the response of these tumors to this type of therapy.

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (T regs ) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive T reg (darT reg ) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darT reg infusion, 5 received darT regs , and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 10 6 cells. darT reg infusion was not associated with adverse events. Two darT reg -infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darT regs . Mechanistic studies revealed generalized T reg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of T reg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.