Game Changer Grant Awarded to Catherine Flores

Malignant brain tumors currently represent the most frequent cause of cancer-related deaths in children. Diffuse intrinsic pontine glioma (DIPG) is an inoperable childhood brain tumor that is almost universally fatal. Devastating survival has remained static over decades and DIPG is now the main cause of brain tumor-related deaths in children. Frequently practiced radiation directed at the tumor site, subsequently causes severe damage to healthy brain tissue. The development of more effective and specific therapies that can increase the efficacy of current treatment without additional toxicity is an extraordinarily high priority for DIPG. The immune system, with its capacity for systemic surveillance and its ability to leverage potent cytotoxic mechanisms against specific target cells, holds the potential to meet this clear and urgent need.

Immunotherapy has emerged as a treatment modality with high curative potential in patients with refractory malignancies. Adoptive cell therapy using ex vivo expanded tumor specific lymphocytes has led to notable overall response rates in patients with metastatic melanoma, including up to 40% durable complete responses of tumors within the brain, demonstrating that the brain is not refractory to effective treatment with cell based immunotherapy. A major limitation thus far in the extension of this success against DIPG is that these approaches require large amounts of patient tumor tissue or previously identified tumor-specific targets, neither of which is available for this patient population. Our group uses the host’s own cells to generate what is
called adoptive cell therapy that uses bone marrow derived dendritic cells pulsed with total RNA isolated from small numbers of tumor cells to generate large amounts of polyclonal tumor-specific T cells. A needle biopsy of human tumor is all that is required for this approach. In the laboratory setting, this approach has been demonstrably efficacious including in a novel murine model of DIPG.

Our previous findings show that the efficacy of adoptive cell therapy against brain tumors is enhanced by co-administration of hematopoietic stem and progenitor cells (HSC). In addition, tumor-specific T cell infiltration and activation within intracranial tumors is also significantly enhanced by co-transfer of HSCs during adoptive cell therapy. In a novel murine model of DIPG, we demonstrate that HSC co-transfer also leads to a significant increase in the accumulation of tumor-specific TTRNA-T cell infiltration into brain stem glioma. Although tumor infiltrating lymphocytes in the brain stem has not been previously described, we observe adoptively transferred TTRNA-T cells within brain stem glioma in our platform. Here we seek to determine the mechanisms this phenomenon occurs in order to increase the efficacy of our platform for patient use. We will also explore human HSCs to determine if they recapitulate the effects we observe in our murine models.