Outcomes are typically grim for patients with recurrent glioblastoma multiforme. At the 2019 Annual Scientific Meeting of the American Association of Neurological Surgeons (AANS), three early-stage studies hinted at ways that standard treatments might be made more effective.
Metronomic Dosing of Temozolomide May Enhance Efficacy of Checkpoint Inhibition
The efficacy of temozolomide, when combined with checkpoint inhibition, may be enhanced by metronomic dosing, according to a study from University of Florida researchers and reported by Maryam Rahman, MD, MS, of the Brain Tumor Immunotherapy Program.1
Maryam Rahman, MD, MS
“We found standard-dosing strategies with temozolomide have the potential to diminish any benefit of checkpoint inhibition due to exhaustion of cytotoxic T cells and an increase in immunosuppressive cells. These changes are not seen when the dose is decreased and given over a longer period,” explained Dr. Rahman.
Immune dysfunction is a hallmark of glioblastoma, where T cells have signs of exhaustion at diagnosis, and counts can be as low as those seen in patients with AIDS. Patients with glioblastoma have had a poor response to immunotherapy due to poor baseline function and worsening of immune function with standard therapy, she said.
Dr. Rahman and colleagues aimed to determine whether there are immunomodulatory effects of temozolomide that would impact response to checkpoint inhibition in the treatment of experimental glioblastoma. They hypothesized that variations in dosing would impact efficacy. In two murine glioma models, the researchers evaluated immune function and the antitumor efficacy of checkpoint inhibition after treatment with a metronomic dose of temozolomide (25 mg/kg × 10 days) or standard-dose temozolomide (50 mg/kg × 5 days).
“When metronomic-dose temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by the PD-1 antibody therapy alone.”— Maryam Rahman, MD, MS
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Standard-dose temozolomide did, indeed, result in upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes; this was not seen with metronomic dosing. When temozolomide was combined with an antibody against the programmed cell death protein 1 (PD-1), the researchers saw a decrease in exhaustion markers in tumor-infiltrating lymphocytes in the metronomic-dose group but not in the standard-dose group. RNA sequencing demonstrated an immune exhaustion phenotype in the intratumoral microenvironment in animals treated with the PD-1 antibody plus standard-dose temozolomide but not with metronomic-dose temozolomide.
“The survival advantage of PD-1 antibody therapy in a murine glioma model was abrogated by adding standard-dose temozolomide to treatment. However, when metronomic-dose temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by the PD-1 antibody therapy alone,” said Dr. Rahman. “These results demonstrate the importance of thoughtfully modulating host immunity with chemotherapy when combining with immunotherapy.”
Radiation Plus Immunotherapy and the Abscopal Effect
Radiation plus treatment with an antibody directed against the programmed cell death ligand 1 (PD-L1) induced an immunologic response to glioblastoma lesions outside of the radiation field, resulting in improved survival in a study of 47 patients with recurrence.2 A companion in vivo experiment helped better understand these effects.
“Immunotherapy for glioblastoma has been largely unsuccessful, in part, because molecular heterogeneity drives selective elimination of only a subset of tumor cells. Therapeutic success in patients, therefore, will require achieving an ‘abscopal effect,’ where nontargeted tumor cells are attacked by the immune system after focused radiation therapy. Inducing an abscopal response in glioblastoma may slow tumor recurrence and improve survival, without significant morbidity,” said Chibawanye Ene, MD, PhD, of the University of Washington, who presented the findings of the companion experiment at AANS.
Chibawanye Ene, MD, PhD
The investigators developed a genetically engineered mouse model of bilateral glioblastoma. In the model, one side of the mouse brain has a tumor treated by focal radiation, whereas the contralateral untreated tumor is used as a readout of abscopal therapeutic efficacy after treatment with an anti–PD-L1 agent.
In mice, the researchers found that focal radiation of one tumor combined with anti–PD-L1 immunotherapy induced an immunologic response against tumor cells outside the radiation field and also enhanced survival (P < .05).
The researchers showed that molecular subtype may influence immune infiltration into the unirradiated lesions. Significant macrophage and T-cell infiltration occurred in mesenchymal subtype–like tumors (P < .01); in proneural subtype–like tumors, macrophage infiltration alone was associated with “out-of-field” tumor regression (P < .05). In vitro, treatment of mouse macrophages with anti–PD-L1 antibodies induced significant gene-expression changes and enhanced phagocytosis in an ERK-dependent fashion. All three commercially available human anti–PD-L1 antibodies induced ERK signaling in the model, with varying benefit, they reported.
“Inducing an abscopal response in glioblastoma may slow tumor recurrence and improve survival, without significant morbidity.”— Chibawanye Ene, MD, PhD
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The researchers are currently optimizing other treatment combinations that could be readily assessed in phase I human clinical trials.
Targeted Brachytherapy May Improve Outcomes in Recurrent Brain Tumors
The U.S. Food and Drug Administration has approved a novel brachytherapy technology, known as GammaTile Therapy, for the treatment of recurrent brain tumors. The device incorporates proprietary cesium (Cs)-131 seeds within customizable collagen-based carriers and delivers radiation into the tumor bed.
Peter Nakaji, MD
In a study of 74 recurrent brain tumors, the median time until local recurrence was 12 months for high-grade gliomas and 48.5 months for meningiomas.3 The time to failure was as good as, or somewhat better than, that achieved with the patients’ previous line of therapy, reported Peter Nakaji, MD, of Barrow Neurological Institute in Phoenix. A more detailed report of this study can be found in the May 25, 2019, issue of The ASCO Post. ■
DISCLOSURE: Drs. Rahman and Ene reported no conflicts of interest. Dr. Nakaji holds stock in GT Medical, which is commercializing the treatment discussed in this presentation.
REFERENCES
1. Rahman M, Karachi A, Yang C, et al: Modulation of temozolomide dose differentially affects T cell response immune checkpoint inhibition. 2019 American Association of Neurological Surgeons Annual Scientific Meeting. Abstract 208. Presented April 15, 2019.
2. Ene C, Kreuser S, Jung M, et al: Anti-PD-L1 antibody enhances radiation-induced abscopal response in glioblastoma. 2019 American Association of Neurological Surgeons Annual Scientific Meeting. Abstract 206. Presented April 15, 2019.
3. Nakaji P, Youssef E, Dardis C, et al: Surgically targeted radiation therapy: A prospective trial in 79 recurrent, previously irradiated intracranial neoplasms. 2019 American Association of Neurological Surgeons Annual Scientific Meeting. Abstract 207. Presented April 16, 2019.
TREATMENTS UNDER STUDY IN GLIOBLASTOMA
- The efficacy of temozolomide, when combined with checkpoint inhibition, may be enhanced by metronomic dosing, experiments in a mouse model showed.
- The survival advantage of the programmed cell death protein 1 (PD-1) antibody therapy was abrogated by adding standard-dose temozolomide to treatment; however, when metronomic-dose temozolomide was added, it preserved the survival benefit offered by the PD-1 antibody therapy alone.
- Radiation plus treatment with an anti– programmed cell death ligand 1 (anti– PD-L1) agent induced an immunologic response to glioblastoma lesions outside of the radiation field, resulting in improved survival in a study of 47 patients with recurrence.
- In a companion experiment in two murine models, focal radiation of one tumor combined with anti–PD-L1 immunotherapy induced an immunologic response against tumor cells outside the radiation field and also enhanced survival.
- A novel brachytherapy technology, GammaTile Therapy, incorporates proprietary cesium-131 seeds within customizable collagen-based carriers and delivers radiation into the tumor bed.
- In a study of 74 recurrent brain tumors, the median time until local recurrence was 12 months for high-grade gliomas and 48.5 months for meningiomas. The time to treatment failure was as long as, or longer than, in patients who received previous lines of treatment.
