- In glioma-bearing mice, dual immunotherapy that combined anti–PD-1 immunotherapy with either whole tumor cell vaccination and agonist anti-OX40 immunotherapy improved survival compared with using any of those approaches alone
- Dual immunotherapy achieved long-term survival for 30% to 50% of the animals
- Triple immunotherapy with vaccination, anti–PD-1 antibody and agonist anti-OX40 led to long-term survival in 100% of glioma-bearing mice
- Triple immunotherapy augmented systemic Th1 immune responses to tumor and shifted the CD4+/CD8+ T cell ratio within the tumor microenvironment toward Th1 immunity
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For the treatment of malignant glioblastoma, initial results from several high-profile trials of vaccination and immune checkpoint inhibition have been negative.
A team led by William T. Curry, MD, co-director of Mass General Neuroscience, believes no single-agent immunotherapy is likely to overcome the multiple types of immunosuppression associated with glioblastoma. In Oncoimmunology, they report that triple combination immunotherapy with whole tumor cell vaccination, a PD-1 inhibitor and an agonist anti-OX40 antibody cured all glioma-bearing mice treated and was associated with long-term survival.
The researchers started by exploring dual combination immunotherapy. They injected glioma cells into the brains of wild-type C57BL/6 mice, then treated them with an anti-PD-1 antibody plus whole tumor cell vaccination (GVAX). Vaccination consisted of subcutaneous implantation of irradiated glioma cells engineered to express granulocyte macrophage colony-stimulating factor.
The combination therapy led to long-term survival (at least 120 days) in 50% of mice, compared with about 20% of mice treated with either component as monotherapy.
Next, the researchers combined the PD-1 inhibitor with an agonist anti-OX40 monoclonal antibody. They explain that OX40 receptor activation can induce proliferation of memory T cells, render effector T cells insensitive to suppression by regulatory T cells and directly inhibit the suppressive capacity of regulatory T cells.
Dual immunotherapy also improved survival when compared with its components used alone, although not always significantly so. It was associated with a 30%-40% cure rate.
In previous studies, researchers had found that a third combination of dual immunotherapy, GVAX plus agonist anti-OX40, was significantly more effective than its single components. This accumulation of positive data prompted them to study triple immunotherapy: simultaneous delivery of GVAX, anti–PD-1 antibody and agonist anti-OX40 on days 3, 6 and 9 after intracranial injection of glioma cells.
Triple immunotherapy led to complete eradication of glioma and long-term survival in all seven mice treated. Splenocytes from those animals expressed significantly higher amounts of interferon gamma and interleukin-2 than those from other treatment groups, indicating a stronger systemic Th1 immune response.
Furthermore, triple immunotherapy increased the CD4+/CD8+ T cell ratio within the tumor microenvironment by a factor of 3.7 compared with baseline, nearly double the increase in any other treatment group. This ratio is a biomarker for the vigor of a Th1 immune response, so the increase suggests intratumoral shifting toward Th1 immunity.
Mice that had been cured with triple immunotherapy or with anti–PD-1 plus agonist anti-OX40 were rechallenged with glioma cells at five-times higher load, 120 days after the initial injection. All of them continued to survive, whereas age-matched tumor-naïve mice died within 25 days. After sacrifice, there was visibly less tumor volume in the brains of triple-treated mice than in those treated with anti–PD-1 plus agonist anti-OX40.
Implications for Further Research
Dr. Curry's group describes "a likely oversimplified, but reasonable" summary of the mechanism of the triple therapy: GVAX expands the number and diversity of activated tumor-specific T cells and increases the number of intratumor CD8+ T cells, while PD-1 inhibition further invigorates the effects of those mobilized cells. Meanwhile, agonist anti-OX40 continues to skew systemic and tumor microenvironments toward Th1 immunity, suppress regulatory T cells and prevent T cell exhaustion.
T cell response is not the only arm of the immune system impaired in glioblastoma. Tumor-associated macrophages, myeloid-derived suppressor cells and innate immunity are also involved and may need to be engaged. Still, tumor-specific activated CD8+ T cells, whose activity is promoted by activated CD4+ Th1 cells, have the ultimate tumoricidal impact.
The glioma cells used (GL261) have responded to a variety of immunotherapeutic approaches in previous research; however, the complete eradication of glioma as seen in this study has been rare. These results underscore the likelihood that glioma immunotherapy should be multipronged.
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