Glioblastoma (GBM) is a uniformly lethal cancer with an overall survival of less than 15 months, despite aggressive standard of care therapies. In contrast to such therapies, which are limited by their lack of specificity and resultant toxicities, immunotherapy provides an exquisitely precise approach for safe and effective tumor treatment. A peptide vaccine derived from the glioma-associated antigen cytomegalovirus (CMV) phosphoprotein 65 (pp65) is a promising strategy for inducing potent cytotoxic glioma-specific immune responses. The broad success of this approach, however, is limited by the ability to overcome glioma-mediated immune deficiencies and T cell inhibitory pathways to promote robust T cell activation. Such limitations can be addressed through the combined use of immunomodulatory adjuvants to improve the setting in which T cells recognize and respond to glioma antigens. Celldex Therapeutics has developed a clinically-relevant high-affinity human anti-human CD27 immunomodulatory antibody (CDX1127) that induces potent antitumor T cell responses through engagement of the CD27 T cell costimulatory pathway. 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 CDX1127 in inducing endogenous antitumor immunity, the overall goal of this proposal is to develop a CMV-pp65 peptide vaccine platform that employs CDX1127 as a vaccine adjuvant. Our preliminary data in human CD27 transgenic mice show that CDX1127 enhances the vaccine-induced immune response to a model tumor antigen and is efficacious against intracranial tumors. Interestingly, this adjuvant effect occurs to a greater degree in the setting of a whole protein vaccine compared to a minimal peptide epitope vaccine, suggesting that the vaccine composition considerably influences the immunomodulatory activity of CDX1127. To progress the clinical translation of CDX1127 as a vaccine adjuvant, our proposed studies will elucidate the mechanism by which CDX1127 most effectively enhances the vaccine-induced immune response, further informing design of our CMV-pp65 peptide immunotherapy. Our overall goal is to further my training as a biomedical scientist pursuing a career in translational immunotherapy while advancing the CMV-pp65 peptide vaccine platform for patients with GBM. The completion of these aims will cultivate a strong foundation in tumor immunology and T cell biology, as well as exposure to the complex process of translating an experimental therapy to the clinic.
Glioblastoma (GBM) is the most common malignant primary brain tumor and is also the most fatal. Vaccine-based immunotherapy to enhance tumor-specific killing while sparing normal brain is a promising treatment modality, but the ability to mount robust immune responses to tumor antigens proves challenging. With a focus on training in translational biomedical research, this proposal aims to develop a novel clinically- relevant immunomodulatory antibody as an adjuvant to improve vaccine-based immunotherapy for GBM and has significant potential to advance a general therapeutic approach useful in treating many forms of cancer.
