| dc.description.abstract |
<p>Glioblastoma (GBM) is a uniformly lethal cancer with an overall survival of less
than 15 months. Aggressive standard of care therapies fail to eradicate these tumors
and are non-specific, resulting in incapacitating toxicities. In contrast to such
therapies, by virtue of exploiting the inherent specificity and vigilance of the immune
system, immunotherapy provides an exquisitely precise approach for safe and effective
tumor treatment. Specifically, peptide vaccines offer a promising strategy for inducing
potent cytotoxic glioma-specific immune responses. However, they are limited by various
mechanisms of glioma-mediated immunosuppression, including low/dysfunctional antigen-presentation,
an increased fraction of regulatory T cells, T cell inhibitory pathways, and cytokine
dysregulation. Such challenges can be overcome by the combined use of immunomodulatory
adjuvants to improve the setting in which T cells recognize and respond to glioma
antigens. To this end, a clinically-relevant high-affinity human anti-human CD27 immunomodulatory
antibody (αhCD27) that induces potent antitumor T cell responses through engagement
of the CD27 T cell costimulatory pathway was recently developed. This antibody is
efficacious as a monotherapy in preclinical tumor models and has given rise to significant
clinical responses in early phase trials. Given the preliminary success of monotherapy
αhCD27 in inducing endogenous antitumor immunity, the overall goal of this dissertation
research was to develop a peptide vaccine platform that employs αhCD27 as a vaccine
adjuvant for its translation as a novel brain tumor immunotherapeutic.</p><p>Chapter
1 provides an overview of brain tumor immunotherapy, including the evolution of the
field to date, various genres of treatment modalities, and ongoing progress and challenges.
Chapter 2 discusses the approach of T cell immunomodulation, an emerging field in
cancer treatment, including the clinical development of various FDA-approved antibodies
and their relevance to brain tumors, synergy with current brain tumor standard of
care, and emerging immunomodulatory targets. Chapter 3 provides the rationale for
targeting the CD27 costimulatory molecule in particular and includes preliminary data
that serves as the basis for the preclinical development of αhCD27 as an immunotherapy
for brain tumors. Chapter 4 shows the systematic approach for optimizing αhCD27 as
a vaccine adjuvant in a murine model of intracranial melanoma alongside a vaccine
targeting a model tumor antigen. Lastly, Chapter 5 explores the use of αhCD27 to combat
tumor-mediated immunosuppression, an important aspect of its adjuvant activity and
the basis for two upcoming phase I clinical trials for malignant glioma. </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 costimulatory T cell immunomodulation as a promising strategy
for brain tumor immunotherapy, 2) explores and optimizes the potential for an agonist
CD27 to enhance the tumor immune response when combined with a vaccine, 3) has opened
up a new line of investigation into the role of CD27 in tumor-mediated immunosuppression,
and 4) provides future prospects of utilizing an agonist CD27 antibody as a vaccine
adjuvant for the treatment of brain tumors. Together, these studies hold great promise
to improve the clinical outlook for brain tumor patients.</p>
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