Browsing by Author "Kelly, Garrett"

Therapeutic cancer vaccines have the potential to revolutionize cancer treatment by providing systemic control of both local and metastatic malignancies. However, stimulating antitumor immune responses in patients with cancer has proven difficult and the success rate associated with cancer vaccines is low. Therefore, there is an urgent need to develop novel cancer vaccine strategies to overcome immunosuppression and produce robust anticancer immunity. Addressing this problem will require the development of new tools to achieve improved localized control of the microenvironment in which cancer antigens are present. Motivated by this rationale, we developed a toolbox of sustained-release immunostimulatory fusions to create cancer vaccines that provide tunable spatiotemporal control of immunostimulatory signals. The backbone of these immunostimulatory fusions is a set of protein biopolymers, elastin-like polypeptides (ELPs), that can undergo a thermally triggered phase transition to form a depot upon injection in vivo for localized and sustained delivery of their payload. To create the toolbox, a set of ELPs were covalently fused to the cytokines, granulocyte-macrophage colony-stimulatory factor (GM-CSF), and interleukin-12 (IL-12), the antigenic peptides SVYFFDWL and SIINFEKL, and the immune adjuvant fibronectin III extra domain A (Fn3EDA). The CpG oligodeoxynucleotide (ODN) adjuvant was bound to an ELP with an oligolysine tail by electrostatic complexation. This toolbox of immunostimulatory, depot-forming ELP fusions was used to develop two new cancer vaccines to improve anticancer immunity: 1) an intratumoral (i.t.) in situ vaccine, consisting of a previously developed ELP-Iodine-131 (131I-ELP) radioisotope conjugate for localized radiotherapy combined with the ELP fusion to locally deliver CpG ODN and 2) a subcutaneous (s.c.) subunit vaccine, consisting of ELP fusions to provide sustained release of an antigenic peptide, GM-CSF, and CpG. Characterization studies demonstrated the depot-forming phase behavior and immunostimulatory activity for each fusion in the toolbox, the ability of the ELP-GM-CSF fusion to recruit antigen-presenting cells (APCs) in vivo, and the ability of an ELP-oligolysine fusion to prolong retention and enhance the activity of electrostatically complexed CpG. Furthermore, we demonstrated that an in situ i.t. depot vaccine improves the local and systemic control of 4T1 mammary carcinoma, leading to a synergistic improvement in survival. Finally, we demonstrated that an optimized s.c. depot vaccine augments CD8 T cell response to both a model antigen and a cancer neoantigen and provides protection from melanoma in a tumor challenge experiment. Altogether, these studies establish a versatile delivery platform to spatiotemporally control immune signaling that advances the development of cancer vaccines.