Abstract
BackgroundGlioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model.MethodsGL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors.ResultsMice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response.ConclusionCombination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.
Highlights
The prognosis for patients with glioblastoma (GBM) remains poor despite treatment with surgical resection followed by adjuvant radiotherapy and the addition of temozolomide [1,2]
We investigated the use of focal radiation therapy in addition to anti-4-1BB and anti-Cytotoxic T lymphocyte antigen -4 (CTLA-4) immunotherapy as a combination strategy in an orthotopic, preclinical model of malignant glioma
Focal radiation therapy combined with CTLA-4 blockade prolonged survival in established intracranial GL261 tumors
Summary
The prognosis for patients with glioblastoma (GBM) remains poor despite treatment with surgical resection followed by adjuvant radiotherapy and the addition of temozolomide [1,2]. Immune checkpoints are a class of cell surface molecules expressed by activated T and B lymphocytes. Studies and clinical trials of immunotherapy for GBM pointed out the immunosuppressive influence of the GBM microenvironment as a significant hurdle, GBM infiltrating immune cells have been found to express immune checkpoint molecules [4,5]. Blocking these immunosuppressive mechanisms while generating a strong antitumor response is an intuitive strategy for cancer immunotherapy. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. We evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model
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