An Agonist CD27 Antibody for Brain Tumor Immunotherapy

Abstract

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.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. 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 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.