Fighting Glioblastoma: Could CAR-T Cell Therapy Be The Next Frontier?

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor, making up over 50% of all gliomas. The incidence of GBM is approximately 3 out of 100,000 people every year and mainly affect people between 45 and 70 years old. GBM is driven by several different mutations and genomic aberrations such as epidermal growth factor (EGFR) amplification, TP53 variants and chromosome 10 loss. Prognosis for GBM patients remains extremely poor, with a median survival time of 12-16 months post-diagnosis and, despite advancements in treatment, only the 5% of affected people can survive more than five years. Standard therapies include surgical resection, followed by radiotherapy and chemotherapy with temozolomide but recurrence of GBM is almost inevitable, posing a significant challenge in GBM treatment and representing a major unmet medical need. However, emerging treatments, such as immunotherapy, mRNA vaccines, targeted therapy and novel drug delivery methods, are being explored to improve outcomes. In this context, two newly published studies in The New England Journal of Medicine and Nature Medicine illustrate the potential application of CAR-T cells in the fight against recurrent GBM.

CAR-T cells are engineered T lymphocytes carrying recombinant proteins on their surface called chimeric antigen receptors (CARs). These CARs recognize and bind specific protein, or antigens, on the surface of tumor cells, thus redirecting the function and specificity of T lymphocytes against malignant cells. While CAR-T cells now represent an effective therapy for against refractory lymphoid malignant neoplasms, their employment in solid tumor, such as GBM, has been hampered by the high heterogeneity of cancer cells, the presence of tumor-associated immunosuppressive mechanisms and the difficulty to penetrate within the tumor mass.

In these two recent studies, CAR-T cells were designed to recognize EGFR variant III (EGFvIII), which is highly expressed by malignant cells, but were also improved with further modifications to address the issue of tumor heterogeneity. In the first study, researchers employed 2nd generation CAR-T cells (called CARv3-TEAM-E), which also secrete antibodies against wild type EGFR, expressed by recurrent malignant cells. As results, all tumor cells, expressing either mutated or wild type EGFR, are targeted by CAR-T cells and a single intraventricular treatment with CARv3-TEAM-E cells leads to a dramatic and rapid, even though transient, tumor regression (INCIPIENT study; ClinicalTrials.gov identifier, NCT05660369). In the other research, bivalent CAR-T cells were designed to target both EGFR and interleukin-13 receptor alpha 2 (IL13Rα2), which is expressed in more than 50% of GBM patients, and were delivered intrathecally to 6 patients with recurrent GBM (ClinicalTrials.gov identifier: NCT05168423). All patients exhibited a reduction of tumor mass and partial regression up to 28 days, with only mild and manageable adverse effects; nevertheless, none of treated patients achieved an objective response, as defined by the RANO (Response Assessment in Neuro-Oncology) criteria.

It is worth noting that these data are the results, in both cases, of interim analyses which researchers will reassess in a global context at the end of the study, and they represent Phase I trials focused on safety issues and the search for the maximum tolerable dose. However, the researchers are satisfied with the results, which seem to open a window of hope for a tumor that, to date, has limited treatment options. The new CAR-T cells have demonstrated the versatility and efficacy needed to successfully fight recurrent GBM but these features will need to be confirmed along with ongoing studies to truly reach the patients’ bedside.

By Roberto Oleari, Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan

Source:

Link: https://www.nature.com/articles/s41591-024-02893-z and https://www.nejm.org/doi/full/10.1056/NEJMoa2314390

Doi: 10.1038/s41591-024-02893-z and 10.1056/NEJMoa2314390