Surviving Gliomas Through Antibodies and Vaccination
Key findings
- The combination of GVAX (a well-established type of tumor cell vaccination) and anti-OX40 antibody had a synergistic effect on survival
- GVAX and anti-OX40 immunotherapy were complementary in driving enhanced Th1 antitumor immunity and reversing T-cell exhaustion
- In mice with glioma, both GVAX and systemic delivery of a monoclonal antibody against OX40 prolonged survival
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To date, immunotherapy has not been effective against glioma, which is protected by a network of immunosuppressive pathways. Published in Neuro-Oncology, researchers at Massachusetts General Hospital found that a combination therapy slows the growth of glioma in mice and discovered the mechanisms by which the therapies overcome tumor suppressive networks.
In a previous study published in Clinical Cancer Research, Mass General researchers determined that GVAX is safe and feasible for patients with advanced-stage glioma. GVAX involves injecting patients with irradiated autologous tumor cells that have been engineered to express granulocyte macrophage colony-stimulating factor, which can stimulate systemic antitumor immunity.
To build on that work, William T. Curry, MD, co-director of the Mass General Neuroscience Institute, and research fellows Nusrat Jahan, PhD, and Dipongkor Saha, PhD, decided to combine GVAX with a monoclonal antibody inhibitor of OX40, which is expressed on T cells after antigenic stimulation. Like GVAX, inhibition of OX40 stimulates T-cell activity, and the anti-OX40 antibody has shown antitumor activity in several preclinical studies.
As part of this study, the team implanted glioma cells into the right frontal lobes of mice. The animals were divided into four groups that received subcutaneous injections of anti-OX40, GVAX, both anti-OX40 and GVAX, or two placebos. As single agents, both vaccination and anti-OX40 significantly improved survival compared with the control group, and combination therapy yielded significantly improved survival compared with either type of monotherapy.
Analysis of spleen cells showed that combination immunotherapy significantly enhanced systemic tumor-specific T helper cell type 1 (Th1) immune responses, compared with either type of monotherapy. Brain analysis demonstrated that GVAX and OX40 stimulation overcame tumor suppressive networks in a complementary fashion. It showed synergistic effects on increased effector lymphocyte infiltration in gliomas, orientation of intratumoral CD4+ cells toward Th1 antitumor responses and improvement of the ratio of cytotoxic CD8+ T cells to regulatory T cells.
Most notably, the Mass General researchers provide new insights into T-cell exhaustion. This phenomenon, which was unknown until recently, prevents optimal control of tumors. It is characterized by high cellular expression of three immune checkpoint molecules: programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3). In the study, combination immunotherapy reversed intracranial T-cell exhaustion, as signaled by reduced coexpression of PD-1 and TIM-3 in T cells as well as reduced coexpression of PD-1 and LAG-3.
The authors urge more study of various combination therapies for glioma, particularly glioblastoma, which drives immune tolerance via multiple mechanisms.
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