Home » Research Statement

Recent Comments

    Archives

    Categories

    • No categories

    Research Statement

    Checkpoint blockade inhibitors and CAR T cells have demonstrated tremendous breakthroughs in cancer treatment in the past decades. Cancer immunotherapy has already shown significant clinical impact, and vaccines have demonstrated some clinical benefit. In a trial conducted entailing the use of GM-CSF secreting tumor vaccines to treat stage 2-3 pancreatic cancer, vaccinated patients experienced as survival rate of 26 months, whereas unvaccinated patients have a median survival time of 21 months (3). One approach to cancer vaccines entails dendritic cell recruitment, antigen loading, activation and proliferation, due to their ability to promote cytotoxic T lymphocyte responses (1) . Despite the success of such treatments, the results of cancer vaccines have been disappointing in the clinic. Only 5 percent of individuals treated with these vaccines demonstrate a significant response (5).

    Biomaterials have the potential to augment the response elicited by traditional immunotherapies by providing additional control over immunological signaling and the context of antigen presentation. Elastin-like-polypeptides (ELPs), hydrophilic repetitive biopolymers that exhibit temperature-dependent phase behavior, and resilin-like polypeptides (RLPs), a class of hydrophobic repetitive protein polymers, are ideal biomaterials for enhancing immunotherapies. The development amphiphilic RLP-ELP polypeptides diblocks provides a novel and customizable platform for nanoscale micelle formation. The size and morphology of these micelles can be engineered by altering the hydrophilic weight fraction of the diblock polypeptide and the molecular weight of its components (2).

    Recent work has demonstrated that micelle size and morphology impact cellular uptake, accumulation and clearance. The accumulation of antigen and adjuvant in the lymph is particularly important to the development of immunotherapies as the lymph nodes are the site of lymphocyte priming, which initiates cell-mediated immunity. The size of a nanomaterial is crucial to lymph node targeting. For a subcutaneously administered particle molecules smaller than 9 nm in diameter diffuse into the blood, while those with a diameter greater than 100 nm can be entrapped by the extracellular matrix, and can only be transported into the lymph via cell-mediated processes. Additionally, particles with a diameter greater than 60 nm may accumulate in the lungs due to the small size of the vasculature. Other features of nanoparticles that can impact immunotherapies include the morphology of the nanoparticle (i.e. spherical or wormlike) and linked antigen and adjuvant. The simultaneous delivery of antigen and adjuvant to antigen presenting cells can lead to antigen presentation with the proper costimulatory molecules, leading to a robust immune response, with minimal tolerogenic responses (4).

    RLP-ELP diblocks provide a strong platform for the delivery of cancer antigen, adjuvants and cytokines for cancer immunotherapies, allowing for the customization of micelle morphology and size. Here, we describe the incorporation of antigen, Ova, and adjuvant, CpG (bound electrostatically to a polylysine tail) into the RLP-ELP diblock system, with the eventual goal of developing a nanoparticle-based cancer vaccine. An Ova-RLP ELP-K12:CpG library was created with the intention of discovering the ideal formulation that results in optimal micelle size and morphology for accumulation in the lymph. Additionally, the design of the RLP-ELP polypeptide will ensure for the simultaneous delivery of the antigen and adjuvant, allowing for an optimal immune response with minimal tolerogenic effects. We will investigate the optimal route of administration (intraperitoneal, intramuscular, intravenous or subcantaneous injection) to develop micelle-based cancer vaccine with accumulation in the lymph nodes, preferable uptake and thus an enhanced immune response.

    Citations

    1. Ali, Omar, et al. “Inflammatory Cytokines Presented from Polymer Matrices Differentially Generate and Activate DCs In Situ.” Advanced Functional Materials vol. 23, 36 (2013):4621-4628. doi: 10.1002/adfm.201203859.
    2. Dzuricky, M., Xiong, S. Weber, s., & Chilkoti, A. “Avidity and Cell Uptake of Integrin-Targeting Polypeptide Micelles is Strongly Shape-Dependent.” Nano Letters vol. 19, 9 (2019): 6124-6132. doi: 10.1021/acs.nanolett.9b02095
    3. Gupta, Richa, and Leisha A Emens. “GM-CSF-secreting vaccines for solid tumors: moving forward.” Discovery medicinevol. 10,50 (2010): 52-60.
    4. Irvine, Darrell J et al. “Synthetic Nanoparticles for Vaccines and Immunotherapy.” Chemical reviews vol. 115,19 (2015): 11109-46. doi:10.1021/acs.chemrev.5b00109
    5. Klebanoff, C. A., Acquavella, N., Yu, Z. & Restifo, N. P. “Therapeutic cancer vaccines: are we there yet?: Therapeutic cancer vaccines: moving forward.” Immunol. Rev. vol. 239, (2011):27–44.