David Reardon, MD
Immunotherapy has shown promise for treatment of glioblastoma multiforme (GBM), the most common primary brain tumor in adults with historically poor prognosis, but experts agree that combination regimens have the greatest potential to achieve durable response. This is because GBM exhibits powerful adaptive capabilities, a relative lack of immunogenicity, an immunosuppressive tumor microenvironment, and intratumoral heterogeneity. “We’re not going to hit a home run with any treatment [on its own],” said David A. Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute.
Greater knowledge about the relationship between molecular subtypes and prognosis, the function of the immune system in the tumor microenvironment, and response of the tumor to targeted agents have helped to clarify why chemotherapy, radiation, and targeted therapy have been generally ineffective against GBM, according to Eric C. Holland, MD, PhD, director, Seattle Translational Tumor Research at Fred Hutchinson Cancer Research Center. He stated that although median survival has inched upward, continued research on the biologic behavior of GBM in response to novel treatments will help to refine these therapies and determine the subgroups of patients who will benefit from them.
Because GBM is highly heterogeneous among individuals, careful selection of patients will be important for assessing treatment efficacy in clinical trials, Holland said. “I think things are getting better slowly, but really getting our hands around the biology of this and optimizing everything is about as good as we’re going to get until [there is a breakthrough],” said Holland.
Current Standard of Care
The current standard-of-care therapy is maximal surgical resection, followed by concomitant radiation therapy plus temozolomide for 6 weeks and then adjuvant temozolomide for 6 monthly cycles. This treatment strategy gained traction from a phase III trial, published in 2005, that reported median overall survival (OS) of 14.6 months.1
Results from a clinical trial showed that the addition of a tumor-treating fields device (Optune) to adjuvant temozolomide significantly improved median OS over temozolomide alone (20.5 vs 15.6 months; P
and led to approval of an expanded indication by the FDA for newly diagnosed GBM in 2015.3
However, recurrence is virtually guaranteed with GBM, and none of the currently approved options have demonstrated an OS benefit, although bevacizumab (Avastin) was approved based on improved progression-free survival (PFS) and response rate,4
and the Optune device was approved based on the improved response rate and quality-of-life scores.5
“Our standard of care leaves a lot of room for improvement,” Reardon said. Immunotherapy
Experts agree that therapies targeting the immune system will likely play a central role in improving durability of treatment. “It’s hard to imagine that anything we do that is successful isn’t going to have some sort of immunotherapy component,” said Holland. However, most agree that a combination approach will probably be necessary given early data showing modest survival benefits of single-agent immunotherapies. “What we’re really going to need to do is to bring them together in rationally designed combinations, based on as much preclinical work [as] we can gather, to help guide us toward developing in clinic,” said Reardon.CAR T-Cell Therapies
Chimeric antigen receptor (CAR) T-cell therapy involves modification of a patient’s extracted T cells to express tumor-specific receptors on the surface, followed by reinfusion of the T cells, which can then recognize and kill the tumor cells, into the patient. Some CAR-T cell therapies have demonstrated clinical activity, and a case report demonstrated a 7.5-month continued clinical response after administration of CAR T-cell therapy against interleukin-13 receptor alpha 2, a glioma-associated antigen, in a patient with recurrent multifocal GBM.6
However, Reardon stated that the intratumoral heterogeneity presents a major challenge for obtaining longterm clinical benefit from immunotherapies targeting a single antigen. Results from a study showed movement of peripherally infused epidermal growth factor receptor variant III (EGFRvIII)– directed CAR T cells to GBM sites and decreases in the EGFRvIII antigen in the surgical specimens of patients with recurrent GBM.7
However, further in situ evaluation revealed increased expression of inhibitory molecules and infiltration by regulatory T cells after infusion, suggesting that durable treatment that includes EGFRvIII-directed CAR T cells will likely require additional interventions to overcome these adaptive changes and address antigen heterogeneity.