Intravesical immunotherapy of superficial bladder cancer with chitosan/interleukin-12.
Publication/Presentation Date
8-1-2009
Abstract
Intravesical BCG has been used successfully to treat superficial bladder cancer for three decades. However, 20% to 30% of patients will fail initial BCG therapy and 30% to 50% of patients will develop recurrent tumors within 5 years. Alternative or complementary strategies for the management of superficial bladder cancer are needed. Interleukin-12 (IL-12) is a potent T(H)1 cytokine with robust antitumor activity and the ability to potentiate immunologic memory. Unfortunately, intravesical IL-12 did not show antitumor efficacy in a recent clinical study of patients with recurrent superficial bladder cancer. We hypothesized that coformulation of IL-12 with chitosan, a biocompatible, mucoadhesive polysaccharide, could improve intravesical IL-12 delivery and provide an effective and durable alternative for the treatment of superficial bladder cancer. In antitumor studies, 88% to 100% of mice bearing orthotopic bladder tumors were cured after four intravesical treatments with chitosan/IL-12. In contrast, only 38% to 60% of mice treated with IL-12 alone and 0% treated with BCG were cured. Antitumor responses following chitosan/IL-12 treatments were durable and provided complete protection from intravesical tumor rechallenge. Urinary cytokine analysis showed that chitosan/IL-12 induced multiple T(H)1 cytokines at levels significantly higher than either IL-12 alone or BCG. Immunohistochemistry revealed moderate to intense tumor infiltration by T cells and macrophages following chitosan/IL-12 treatments. Bladder submucosa from cured mice contained residual populations of immune cells that returned to baseline levels after several months. Intravesical chitosan/IL-12 is a well-tolerated, effective immunotherapy that deserves further consideration for testing in humans for the management of superficial bladder cancer.
Volume
69
Issue
15
First Page
6192
Last Page
6199
ISSN
1538-7445
Published In/Presented At
Zaharoff, D. A., Hoffman, B. S., Hooper, H. B., Benjamin, C. J., Jr, Khurana, K. K., Hance, K. W., Rogers, C. J., Pinto, P. A., Schlom, J., & Greiner, J. W. (2009). Intravesical immunotherapy of superficial bladder cancer with chitosan/interleukin-12. Cancer research, 69(15), 6192–6199. https://doi.org/10.1158/0008-5472.CAN-09-1114
Disciplines
Medicine and Health Sciences
PubMedID
19638573
Department(s)
Department of Medicine
Document Type
Article