Researchers Outline Ongoing Studies, Challenges of CAR T-Cell Therapy in GBM

With more treatment options needed in glioblastoma multiforme (GBM) to successfully attack disease, attention has been paid to chimeric antigen receptor (CAR) T-cell therapy, which has shown great promise in hematologic malignancies and is being studied in other settings, including central nervous system solid tumors like GBM.

In a recent study, researchers provide a look at clinical trials currently assessing the potential of treatment for the disease.

Although there’s hope CAR T-cell therapy can revolutionize the way GBM is treated, there is stil more research to be done, say the investigators in Cancer Medicine, noting that research on CAR T-cell therapy in this setting is still in early stages.

“Despite the promising results of CAR T technology in hematological malignancies, CAR T cells for GBM are still in their earlier stage,” wrote the researchers. “Several GBM-associated antigens have served as the targets of ongoing clinical trials (EGFRvIII, NKG2D, B7-H3, CD147, IL13Ralpha2, and HER2). Most of the current clinical trials are still in phase 1, testing the safety and efficacy of mostly second-generation CAR T cells constructed with CD28 and 4-1BB costimulatory intracellular domains.”

The researchers write that, to date, evidence suggests combined therapy is more effective than monotherapy in GBM, which not only gives insight into how to enhance the efficacy of CAR T-cell therapy but also to potentially curtail adverse effects. The researchers outlined various ongoing trials of CAR T-cell therapy that combine the therapy with other agents in patients with GBM.

With 70% of patients with GBM expressing B7-H3, which is not expressed on normal tissues, one ongoing trial is currently assessing the safety and tolerability of B7-H3 CAR T-cell therapy with temozolomide, with B7-H3 CAR-T being injected between temozolomide cycles. Data from the study are expected by next year.

EGFRvIII CAR T-cell therapy is being studied in several trials, with one ongoing phase 1 study assessing the therapy in combination with temozolomide and another assessing EGFRvIII CAR T following radiosurgery in patients with recurrent GBM.

CAR T-cell therapy in combination with immune checkpoint inhibitors is also being assessed for both recurrent and resistant disease, say the researchers. A phase 1 trial is currently looking at the safety and efficacy of IL13Ralpha2-CRT T cells used alone or in combination with nivolumab and ipilimumab.

Although still in the preclinical stage, Fcγ-CRs T cells may prove to be a leader in the treatment of GBM and other solid tumors, say the researchers.

As research on CAR T-cell therapy in GBM progresses, the researchers are also calling attention to the challenges facing the therapy in the disease, including the highly unstable tumor microenvironment and the variable genetic nature of the disease.

“The mechanism by which the apparent tumor responses or growth delay in CAR-T cell–treated GBM are multifactorial. This cannot be attributed to the therapy but could instead result from differences in the natural history of disease between patients,” commented the researchers. “Although there are no direct ways to demonstrate the actual killing of tumor cells by CAR T in situ, previous clinical and preclinical data suggest that CAR-T-EGFRvIII cells induce their action by antigen-directed cytolysis after crossing the blood–brain barrier.”

Reference

Marei HE, Althani A, Afifi N, et al. Current progress in chimeric antigen receptor T cell therapy for glioblastoma multiforme. Cancer Med. Published online June 19, 2021. doi:10.1002/cam4.4064