Manel Juan
Head of the Immunology Service
This is a very important study in a disease that has a terrible prognosis (Diffuse Intrinsic Pontine Pontine Glioma, known in the field as DIPG). With only 11 patients in a phase 1 trial to demonstrate safety, it provides enough response data (9 of 11 patients) to be able to say that we are in a preliminary but crucial year for the treatment of nervous system tumours with CAR-T therapy to be approved for systematic use, because unlike other solid tumours where the results are usually clearly insufficient for the CAR-Ts studied, in brain tumours several very clear and more than promising proposals have been published since February 2024.
In addition, this case of the 9 patients with responses includes a young adolescent-adult who has been without detectable disease for 4 years. The study is technically flawless for this safety study, and very promising in suggesting efficacy.
The study reinforces the idea that brain tumours are likely to be treatable by CAR-T. The main (and initial) implication is in the case of DIPGs, where there is really no chance of 2-year survival in children. With this study, there is clear hope for effective treatment for those who do not have it. Other work in the field (mainly in glioblastoma multiforme) published in 2024 (and some earlier) shows that CAR-T can and will be effective for solid tumours (non-hematological, as in the case of haematological tumours, almost 40,000 patients worldwide have already received this last-line treatment, with data that at all levels are considered spectacular).
Other implications beyond brain tumours such as DIPG are that other solid tumours are approachable, although possibly needing to incorporate improvements in the basic conventional procedure. In this regard, data related to local reinfusion in brain compartments indicate that enhancing CAR-T lymphocyte localisation is relevant. Finally, it is also confirmed that GD2 [antigen] may be a good target in these tumours, a controversial concept as many adverse effects have been found in the use of this target with monoclonal antibodies. It is clear from the work that we should not infer results from products with the same target if the effector media are different.
The results also imply that the route of administration (directly into the central nervous system) is more convenient, less toxic and potentially more effective. Finally, there is the fact that it opens up the possibility of ‘chronifying’ a currently incurable disease (an important concept in immunotherapy and one that in some ways distinguishes it from radiotherapy or chemotherapy, as immunotherapy treatment can endure and integrate into the body itself as a ‘living drug’, whereas radiotherapy and chemotherapy only act as long as they are applied).
Of course, as most of the positive results with CAR-T open the door to explore new CAR-T and immunotherapy combinations to try to anticipate the mechanisms of tumour immunoediting and escape (also very relevant in neurological tumours).
It is worth remembering that treatment with anti-GD2 CAR-T was shown in another Italian study published in NEJM to be effective in neuroblastoma, another neurological tumour. Both reinforce the relevance of the safety and potential efficacy of these CAR-Ts with this target, although other targets (in combination) will surely be essential to ensure that these tumours have real therapeutic options.
The main limitation of the study has to do with the low number of cases treated and the fact that only one patient seems to achieve a complete response (with ‘only’ 4 years of follow-up, but in this disease this is much more than any other treatment has achieved so far). This is an intrinsic limitation that in no way detracts from the quality of the work, which does not claim to be definitive or conclusive.