The Case for Optimism: Progress in Glioblastoma Immunotherapy at Penn

Xenograft H&E demonstrating an invasive high-grade glioma.

Following the dramatic results of CAR T trials in lymphoma and leukemia, it was hoped that CAR T therapy could be readily applied to the solid tumor cancers, and particularly to glioblastoma (or GBM), the grade IV glioma that is both the most prevalent, most aggressive and most lethal primary brain malignancy in adults. GBMs are particularly resistant to therapy; surgery, chemotherapy, and radiation can abate, but not eliminate the tumors.

Thus, a profound incentive for new therapies in glioblastoma exists. The current standards of care for newly diagnosed GBMs have not made a substantial impact on survival time in decades. There is no standard of care for recurrent disease.

Immunotherapy is an area of great interest, but the prospects for immunotherapy in glioblastoma have met setbacks and challenges. Glioblastomas reside in a hostile microenvironment defined by poor T-cell infiltration and the presence of immunosuppressive macrophages, among other physiological impediments. Recent attempts to overcome these obstacles at Penn (i.e., the Perelman School of Medicine and the Abramson Cancer Center) have focused, respectively, on CAR T cells directed at epidermal growth factor receptor variant III (EGFRvIII), and early-stage efforts to enhance immune checkpoint inhibition (ICI) by addressing tumor-associated macrophage (TAM) activity in glioblastoma.

CAR T Therapy for Glioblastoma

At Penn, the effort to achieve an effective CAR T therapy for gliomas has focused largely on a mutant of the epidermal growth factor receptor gene (EGFRvIII). EGFRvIII is present in many human cancers including gliomas, but is absent from normal tissues, making it an ideal target for immunotherapy. Dr. Donald O'Rourke and colleagues conducted the first-in-human investigation (NCT02209376) of autologous T cells modified to target EGFRvIII in recurrent glioblastoma.

Since this time, studies at Penn and elsewhere have demonstrated that the key challenges in targeted EGFRvIII immunotherapy include heterogeneity of EGFRvIII expression and an increase in PD-1 and other immunoregulators consequent to CAR T cell introduction.

In the face of these difficulties, there is reason for optimism, however. In a recent report, Dr. O'Rourke, et al, describe the case of a 59-year-old patient who survived 36 months after a recurrence of glioma following a single peripheral infusion of CAR T EGFRvIII-directed cells. In addition to exceeding the expected survival time by more than two years, CAR T EGFRvIII cells persisted in the patient's peripheral circulation for 29 months of follow-up, the longest period of CAR T persistence reported in GBM trials to date. According to the authors, these findings demonstrate that peripherally administered CAR T-EGFRvIII cells can persist for years in the circulation, and suggest that the approach could be optimized to achieve broader efficacy in recurrent GBM patients.

Current efforts to enhance CAR T cell therapy in glioma include strategies to overcome the dual challenges of heterogenous antigen expression and selective deletion, as well as methods to address the increase in PD-1 by combining CAR T EGFRvIII with PD-1 inhibitors. The combination of CAR T-EGFRvIII and PD-1 blockade is currently the focus of a clinical trial at Penn for newly diagnosed glioblastoma (NCT03726515). Optimization of CAR T therapy may also be achieved in the future by gene engineering to equip the cells with new capacities.

Synergistic Immunotherapy for Glioblastoma

In preclinical studies, researchers at the Perelman School of Medicine have been making progress in another area of GBM immunotherapy by targeting tumor-associated macrophage (TAM) activity.

TAMs comprise up to half of the non-neoplastic cells in GBMS, where they are assumed to be a principal source of immunosuppression. Known to blunt T cell recruitment, TAMs secrete growth factors and immunosuppressive cytokines that promote tumor progression and metastases, as well as resistance to all of the standard therapies in oncology, including checkpoint inhibitor resistance.

Efforts to counter TAM activity and improve the efficacy of the ICIs in GBMs have lately centered upon synergistic approaches by which the ICIs are combined or used as complements to other established anti-cancer treatments or immunotherapeutic modalities.

Outside of ICI therapy, synergistic approaches to GBM therapy at Penn now include agents that modulate CD40 and IL-6. An immunomodulatory cytokine, IL-6 has been found by Penn researchers to induce TAM activation in GBM via its interaction with CD40, a costimulatory protein, and STAT3, a transcription factor.

In a preclinical trial reported in Nature, the researchers developed a dual-targeting anti-IL-6 and pro-CD40 strategy that tempered TAM-mediated tumor immunosuppression to moderately improve T cell infiltration into GBM and reverse TAM-mediated tumor immunosuppression. Moreover, while the researchers found no beneficial synergy with ICI therapy for IL-6 neutralization alone, adding a CD40 agonist to ICI therapy (anti-PD-1 and the CTLA-4 inhibitor ipilimumab) resulted in sensitization of GBMs to ICI therapy.

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