Preclinical development of breakthrough immunotherapy for brain tumors - Abstract The ultimate success of immunotherapy for brain malignancies, such as malignant glioma, will require integration of in-depth understanding of immunology with solutions for the following long-standing challenges: 1) paucity and heterogeneous expression of glioma-specific antigens; 2) on-target off-tumor toxicity and exhaustion of therapeutic T lymphocytes, such as chimeric antigen receptor (CAR) T-cells; 3) immunological privilege of the CNS and 4) immunosuppression involving tumor, neuronal, and immune cells. My laboratory has contributed to critical discoveries in these areas and integrated our findings into novel immunotherapy clinical trials for glioma patients. In the current proposal, I will enhance my research by mobilizing multiple immune mechanisms. To this end, I will collaborate with an outstanding group of investigators whose diverse expertise in multi-disciplinary areas complements my own in brain tumor immunology as the central component and apply a wide variety of resources available at UCSF and collaborators to one overarching program. I will evaluate the overarching hypothesis that the integration of novel cell-engineering and antigen-targeting approaches will allow us to develop safer and more effective immunotherapy strategies by overcoming heterogeneous expression of antigens and unique challenges in brain immunology. I will evaluate the following strategies: 1. Develop neo- junction-targeting T-cell receptor (TCR)-T cell-based immunotherapy. We will leverage our highly reliable and valuable pipeline for T-cell epitope prediction, which we established during the current funding cycle, to discover novel neoepitopes derived from tumor-specific alternative splicing events (neojunctions). 2. Develop novel cell therapies using allogeneic induced pluripotent stem cells (iPSCs) and in vivo transduction approaches. While my current NINDS R35 award allowed me to implement the first-in-human phase I study of Synthetic Notch (synNotch)-CAR T-cell therapy in patients with glioblastoma, inherent and logistical challenges associated with the use of autologous T-cells motivate us to develop these novel and alternative approaches. 3. Enhance “epitope spreading” to overcome the antigen heterogeneity. While the novel synNotch-CAR approaches are promising, one major inherent challenge is that targeting a few or several antigens by CARs or TCRs may not adequately cover the marked antigenic heterogeneity of tumors. We will enhance the effects of low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce adaptive immune responses against heterogeneous tumor antigens. 4. Investigate the glioma-neuronal circuit-induced immune regulation. We will delineate essential mechanisms on our recent discovery of neuronal activity-driven immunosuppression as a previously unrecognized resistance mechanism of cancer immunotherapy for gliomas. These 4 strategies will be logically integrated into combination approaches. As expected per the purpose of the NINDS R35 mechanism, these strategies may involve high risks. However, based on our preliminary proof-of-principle data, we will persistently pursue our goals with long-term support from the R35 mechanism and adopt new technologies flexibly and swiftly.
