Multimodal immunotherapy for DIPG: status today

Diffuse Intrinsic Pontine Glioma (DIPG) is a brain stem glioma typically found in children aged between 3 and 9. The standard of care is radiotherapy. Clinicians are searching to add (eventually biology-driven) chemotherapy in order to improve the uniformly dismal prognosis. Nevertheless, almost all children die within 2 years after diagnosis. DIPG tumor cells have been shown to be sensitive to Newcastle disease virus (NDV). Culturing DIPG cell lines in the presence of NDV showed reduced viability. A shift in survival curve has been demonstrated in nude mice orthotopically injected with E98 cells and subsequently treated with intratumoral NDV.

This knowledge together brought us to a novel strategy. Children are infused with NDV for 5 consecutive days. Each time, some extra moderate local-regional radiofrequency hyperthermia (LHT) is administered to stress the cells for release of heat shock proteins. At day 5, exosomal tumor antigens are harvested out of the serum to load patient-specific monocyte-derived DCs that are cultured in the lab. Besides, DCs are also loaded with NDV and are further matured with a cytokine cocktail. This active specific vaccine is then injected intradermally at day 8 of the vaccination cycle, in combination with LHT and NDV. A second vaccination cycle is repeated after 3 weeks. Then finally, a blood test is performed to measure the enrichment of cytotoxic immune cells that respond against tumor antigens and/or against viral antigens.

We administered this treatment, which is a licensed medicinal drug in Nordrhein-Westfalen, to 14 children with DIPG on a compassionate use basis. The patient group was heterogeneous with immunotherapy as neo-adjuvant treatment before (n = 4) or adjuvant treatment after (n = 5) radiotherapy, or rescue treatment at time of disease progression (n = 5). The treatment was feasible. No toxicities were noted except some minor flu-like symptoms the first days of NDV administration. We were able to quantify the induced immune response in all 4 children tested. One child postponed radiotherapy by 4 months, while the other child who was treated with two cycles of oral TMZ + IV CDDP postponed radiotherapy for at least 10 months. One child with adjuvant immunotherapy in combination with Panobinostat during and Gallium Maltonate after radiotherapy showed a tumor response. Two childen under corticosteroid treatment at time of progressive disease died 2 resp. 4 months after start of immunotherapy.

We conclude that with the development of advanced multimodal immunotherapy (LHT + NDV + DC), we are ready to treat children with DIPG. Experiences in pilot patients show feasibility without toxicity, and with efficacy at least at the level of immune monitoring. Whether that will translate into longer survival with good quality of life is still pending and should be confirmed in a proper clinical trial.