Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer

Abstract

Bladder cancer is a highly recurrent disease in need of novel, durable treatment strategies. This study assessed the ability of an intravesical immunotherapy composed of a coformulation of the biopolymer chitosan with interleukin-12 (CS/IL-12) to induce systemic adaptive tumor-specific immunity. Intravesical CS/IL-12 immunotherapy was used to treat established orthotopic MB49 and MBT-2 bladder tumors. All mice receiving intravesical CS/IL-12 immunotherapy experienced high cure rates of orthotopic disease. To investigate the durability and extent of the resultant adaptive immune response, cured mice were rechallenged both locally (intravesically) and distally. Cured mice rejected 100% of intravesical tumor rechallenges and 50–100% of distant subcutaneous rechallenges in a tumor-specific manner. The ability of splenocytes from cured mice to lyse targets in a tumor-specific manner was assessed in vitro, revealing that lytic activity of splenocytes from cured mice was robust and tumor-specific. Protective immunity was durable, lasting for at least 18 months after immunotherapy. In an advanced bladder cancer model, intravesical CS/IL-12 immunotherapy controlled simultaneous orthotopic and subcutaneous tumors in 70% of treated mice. Intravesical CS/IL-12 immunotherapy creates a robust and durable tumor-specific adaptive immune response against bladder cancer. The specificity, durability and potential of this therapy to treat both superficial and advanced disease are deserving of consideration for clinical translation.

Delivering safer immunotherapies for cancer

“…injection of biodegradable polylactic acid microspheres exhibiting controlled release of IL-12 was safe and led to complete regression of transplanted lung tumors, prevented metastatic spread to the lung, and enabled animals to reject a subsequent re-challenge with live tumor cells, indicating the development of systemic antitumor immunity [163]. More recently, chitosan matrices have been similarly used to provide sustained localized dosing of IL-12 in several tumor models, including as a neoadjuvant treatment in a breast cancer model prior to surgical resection of the primary tumor [167–169]. Hanes et al used crosslinked gelatin/chondroitin sulfate microspheres as delivery vehicles for intratumoral delivery of IL-2 in models of brain or hepatic melanoma metastases [151].…”

Immunology‐Guided Biomaterial Design for Mucosal Cancer Vaccines

“…For example (Table ), while subcutaneous vaccination with negatively charged silica nanospheres was successful in eliciting T cell responses, if administered via mucosal routes, these would have most likely be immobilized in the mucus layer, thus releasing the soluble vaccine, which may elicit predominantly humoral response. The same applies to other examples illustrated in Table , including polycationic and mucoadhesive chitosan and a hydrophobic alkyne functionalized 4‐arm star polymer conjugate which formed microparticles …”

Intravesical Treatment Modalities in Bladder Cancer: Current and Future Perspectives

“…Through this therapy, it is possible to decrease the number of intravesical treatments required and the costs of frequent treatment and surveillance. This also shows a novel intravesical for the systemic transfer of immunity with the potential to treat locally advanced or metastatic disease [54]. Through this therapy, it is possible to decrease the number of intravesical treatments required and the costs of frequent treatment and surveillance.…”