Browsing by Subject "Malignant glioma"

The histologic subtypes of malignant glial neoplasms range from anaplastic astrocytoma to the most deadly World Health Organization (WHO) Grade IV glioblastoma (GBM), the most common primary brain tumor in adults. Over the past 40 years, only modest advancements in the treatment of GBM tumors have been reached. Current therapies are predominantly for palliative endpoints rather than curative, although some treatment modalities have been shown to extend survival in particular cases. Patients undergoing current standard of care therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of 12-15 months, with less than 25% of patients surviving up to two years and fewer than 10% surviving up to five years. A variety of factors contribute to standard treatment failure, including highly invasive tumor grade at the time of diagnosis, the intrinsic resistance of glioma cells to radiation therapy, the frequent impracticality of maximal tumor resection of eloquent cortical structures, and the fragile intolerance of healthy brain for cytotoxic therapies. Treatment with immunotherapy is a potential answer to the aforementioned problems, as the immune system can be harnessed and educated to license rather potent antitumor responses in a highly specific and safe fashion. One of the most promising vehicles for immunotherapy is the use of dendritic cells, which are professional antigen-presenting cells that are highly effective in the processing of foreign antigens and the education of soon-to-be activated T cells against established tumors. The work outlined in this dissertation encompasses the potential of dendritic cell therapy, the current limitations of reaching full efficacy with this platform, and the recent efforts employed to overcome such barriers. This work spans the characterization and preclinical testing of utilizing protein antigens such as tetanus-diphtheria toxoid to pre-condition the injection site prior to dendritic cell vaccination against established tumors expressing tumor-specific antigens.

Chapter 1 comprises an overview of the current standard therapies for malignant brain tumors. Chapters 2 and 3 provide a review of immunotherapy for malignant gliomas in the setting of preclinical animal models and discuss issues relevant to the efficacy of dendritic cell vaccines for targeting of GBM. Chapters 4 provides the rationale, methodology, and results of research to improve the lymph node homing and immunogenicity of tumor antigen-specific dendritic cell vaccines in mouse models and in patients with newly diagnosed GBM. Chapter 5 delineates the interactions discovered through efforts in Chapter 4 that comprise protein antigen-specific CD4+ T cell responses to induced chemokines and how these interactions result in increased dendritic cell migration and antitumor responses. Lastly, Chapter 6 discusses the future utility of migration of DC vaccines as a surrogate for antitumor responses and clinical outcomes.

This dissertation comprises original research as well as figures and illustrations from previously published material used to exemplify distinct concepts in immunotherapy for cancer. These published examples were reproduced with permission in accordance with journal and publisher policies described in the Appendix.

In summary, this work 1) identifies inefficient lymph node homing of peripherally administered dendritic cells as one of the glaring barriers to effective dendritic cell immunotherapy, 2) provides answers to overcome this limitation with the use of readily available pre-conditioning recall antigens, 3) has opened up a new line of investigation for interaction between recall responses and host chemokines to activate immune responses against a separate antigen, and 4) provides future prospects of utilizing chemokines as adjuvants for additional immunotherapies targeting aggressive tumors. Together, these studies hold great promise to improve the responses in patients with GBM.

Malignant glioma formation involves an abundant inflammatory infiltrate dominated by glioma-associated macrophages and microglia (GAMM). GAMM constitutes a large portion of the glioma mass and tumor microenvironment. They are actively involved in tissue repair and immune surveillance, however in the tumor microenvironment (TME), they are subverted to promote tumor progression. The human poliovirus receptor, hCD155h, is constitutively expressed in members of the mononuclear phagocytic system and is upregulated ectopically in the neoplastic compartment of malignant gliomas (and solid cancers in general). Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, has a dual effect of releasing neoantigens by oncolysis and activating the GAMM component via sublethal infection, leading to a substantial but transient immune therapy effect. In a phase I clinical trial, PVSRIPO treatment resulted in 21% long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardins et al. New England Journal of Medicine, 2018). Therefore, studying the mechanisms of PVSRIPO immunotherapy in mouse brain tumor models to decipher contributions of viral infection to GAMM vs. malignant cells is critical to improving the therapeutic efficacy in ongoing clinical trials. We recapitulated the clinical trial scenario in an immunocompetent intracerebral mouse tumor model (CT2A-CD155) and obtained baseline and post treatment brain in a time series. Histopathology studies, combined with detailed multiplex IHC/IF and RNAseq were performed on tumor bearing brains. We found the PVSRIPO therapy induced intense engagement of the GAMM infiltrate accompanied by substantial, but transient tumor regression. There were extensive microglia activation and proliferation in adjacent brain parenchyma and even part of the contralateral cortex. This occurred against a backdrop of sustained innate antiviral inflammation and is associated with an induction of the PD-L1 immune checkpoint on GAMM. In contrast to transient antitumor effects observed after PVSRIPO monotherapy, combining PVSRIPO with PD1/PD-L1 blockade led to durable remission. Our work implicates GAMM as active drivers of inflammation and reveals broad neuroinflammatory activation of the CNS-resident myeloid compartment upon polio virotherapy of malignant glioma.