| dc.description.abstract |
<p>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. </p><p>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.
</p><p>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. </p><p>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.</p>
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