Cytokine-based immunotherapies have the potential to treat a wide range of diseases including cancer. Unfortunately, pro-inflammatory cytokines with potent antitumor activity are frequently toxic upon systemic exposure. The lack of effective local delivery strategies capable of controlling the distribution cytokines has prevented cytokine therapeutics from impacting cancer immunotherapy. This project proposes a novel delivery technology in which a potent recombinant cytokine, interleukin-12 (IL-12), is chemically-linked to a biodegradable polysaccharide called chitosan prior to intratumoral (i.t.) injection. This novel strategy is expected to provide sustained, high concentrations of IL-12 in the tumor microenvironment, while minimizing potentially harmful systemic dissemination. The proposed project is comprised of three aims focusing on the development and evaluation of IL-12-chitosan bioconjugates in preclinical tumor models. In the first aim, novel IL-12-chitosan bioconjugates will be synthesized and evaluated in vitro for bioactivity. The mutation of solvent accessible amino acids will allow for site-specific conjugation of IL-12 to chitosan.
Aim 2 will assess safety by documenting the spatiotemporal distribution of IL-12-chitosan bioconjugates and any potential toxicities associated with IL-12-chitosan administration.
Aim 3 will evaluate antitumor efficacy of IL-12-chitosan bioconjugates as well as the elaboration of tumor-specific immunity in relevant preclinical models. The overall goal of this project is to determine if conjugation to chitosan can maintain the potent antitumor activity of IL-12 while alleviating toxicity concerns. I the long-term, validation of this cytokine-chitosan delivery platform may pave the way for additional cytokine therapeutics in cancer immunotherapy.
The administration of pro-inflammatory cytokines has demonstrated remarkable antitumor activity in numerous preclinical studies. Unfortunately, these cytokines have not been widely effective in humans due to the lack of effective delivery strategies which maximize appropriate cytokine levels in tumors while minimizing toxicities associated with their systemic spread. This project will overcome these limitations by developing and evaluating a novel delivery strategy, based on linking cytokines with the biodegradable polysaccharide chitosan for the local, sustained delivery of pro-inflammatory and T cell activating cytokines to the tumor microenvironment.
|Jayanthi, Srinivas; Koppolu, Bhanu prasanth; Smith, Sean G et al. (2014) Efficient production and purification of recombinant human interleukin-12 (IL-12) overexpressed in mammalian cells without affinity tag. Protein Expr Purif 102:76-84|
|Kurtz, Samantha L; Ravindranathan, Sruthi; Zaharoff, David A (2014) Current status of autologous breast tumor cell-based vaccines. Expert Rev Vaccines 13:1439-45|