Engineering the Brain Immune System for Tumor Therapy Abstract Brain glioblastoma multiforme (GBM) kills through glioma cells that infiltrate normal surrounding brain, with consequent displacement and destruction of healthy brain tissue. Therefore, even aggressive surgical resection fails to excise completely all infiltrating cells and provide long term survival. Alternatively, the immune system could specifically target infiltrating tumor cells using specific immune mediated homing mechanisms. However, the immune system has reduced activity in the brain, due to the brain's immune privilege, i.e. the blood-brain barrier, a lack of proper antigen presenting cells (i.e., dendritic cells, DCs) in the healthy brain, absence of classical lymphatic outflow channels, and local expression of the endogenous immune inhibitors, i.e., transforming growth factor beta. Nevertheless, experimental and clinical studies have shown that immune-therapy can effectively eradicate experimental GBM, and can be harnessed to develop novel therapies for human brain tumors. Recently, we have shown that gene transfer mediated modification of the brain immune microenvironment induces systemic anti-tumor immune responses. Specifically, expression of fms-like tyrosine kinase 3 ligand (Flt3L) recruits antigen presenting cells (e.g., dendritic cells, DCs) to the brain parenchyma and into the tumor mass. To increase the availability of tumor antigens to the DCs, tumor cells are killed using conditional cytotoxicity [herpes simplex virus type 1 thymidine kinase (TK) plus ganciclovir (GCV)]. This combined approach induces tumor regression, long-lasting systemic immunological memory, and long-term survival in animals with large syngeneic tumors. The overall goals of the experiments outlined in this proposal are to define the immune cells involved in this anti-GBM immune response, determine the origin and functional activities of brain DCs, and elucidate the specific mechanism(s) underlying their ability to induce systemic long-term anti-tumor immunity. Our hypothesis is that Flt3L and conditional cytotoxicity recruit a specific subtype of dendritic cells to the brain, i.e. plasmacytoid dendritic cells (pDCs), which leads to a systemic anti-tumor immune response. Understanding the mechanisms that stimulate this immune response from within the brain in situ will lead to novel treatments for one of the deadliest human cancers. The novelty of our approach is our capacity to specifically recruit pDCs to the brain parenchyma and the tumor microenvironment in response to expression of Flt3L, an approach that achieves the priming of a systemic immune response against GBM from within the tumor mass in situ. We hypothesize that this will maximize the generation of an effective anti-GBM immune response to GBM antigens.
Gliobastoma multiforme (GBM) is a devastating brain tumor, for which there is no cure, and no significant improvements in patients'survival has occurred over the last 30 years. Using an intracranial brain tumor model we have shown that a novel combined conditional cytotoxic/immune-stimulatory gene therapy eliminates the growing tumor, and induces immunological memory which protects animals from tumor recurrence. Further, we have shown that any adverse side effects are limited, and reversible, with no long term permanent negative sequalae.
We aim to elucidate the cellular mechanisms which mediate these effects, the migration of immune cells into the tumor microenvironment and devise novel therapeutic approaches for this devastating cancer which will be implemented in phase I clinical trials.
|Kamran, Neha; Chandran, Mayuri; Lowenstein, Pedro R et al. (2018) Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy. Clin Immunol 189:34-42|
|Koschmann, Carl; Nunez, Felipe J; Mendez, Flor et al. (2017) Mutated Chromatin Regulatory Factors as Tumor Drivers in Cancer. Cancer Res 77:227-233|
|Calinescu, Anda-Alexandra; Yadav, Viveka Nand; Carballo, Erica et al. (2017) Survival and Proliferation of Neural Progenitor-Derived Glioblastomas Under Hypoxic Stress is Controlled by a CXCL12/CXCR4 Autocrine-Positive Feedback Mechanism. Clin Cancer Res 23:1250-1262|
|Chandran, Mayuri; Candolfi, Marianela; Shah, Diana et al. (2017) Single vs. combination immunotherapeutic strategies for glioma. Expert Opin Biol Ther 17:543-554|
|Kamran, Neha; Kadiyala, Padma; Saxena, Meghna et al. (2017) Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy. Mol Ther 25:232-248|
|Ashley, Shanna L; Pretto, Carla D; Stier, Matthew T et al. (2017) Matrix Metalloproteinase Activity in Infections by an Encephalitic Virus, Mouse Adenovirus Type 1. J Virol 91:|
|Baker, Gregory J; Chockley, Peter; Zamler, Daniel et al. (2016) Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells. Oncoimmunology 5:e1163461|
|Koschmann, Carl; Calinescu, Anda-Alexandra; Nunez, Felipe J et al. (2016) ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med 8:328ra28|
|Kamran, Neha; Candolfi, Marianela; Baker, Gregory J et al. (2016) Gene Therapy for the Treatment of Neurological Disorders: Central Nervous System Neoplasms. Methods Mol Biol 1382:467-82|
|VanderVeen, Nathan; Raja, Nicholas; Yi, Elizabeth et al. (2016) Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn ""On"" Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model. Hum Gene Ther Methods 27:98-111|
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