Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression.

Administration of high-dose interleukin-2 (HDIL-2) has durable antitumor effects in 5% to 10% of patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multiorgan dysfunction characterized by a cytokine-induced systemic autophagic syndrome. Here, we hypothesized that the autophagy inhibitor chloroquine would enhance IL-2 immunotherapeutic efficacy and limit toxicity.

Pharmacologic administration of interleukin-2.

The development of biologic therapies for patients with cancer has in part been impeded by the extraordinary complexity and intrinsic feedback mechanisms promoting homeostasis in tissue injury, repair, inflammation, and immunity. Recombinant interleukin 2 (IL-2) therapy was initiated in 1984 based on its role as the prototypic T-cell growth factor, with novel roles deduced late after its FDA approval in regulating not only effector T cells but also regulatory T cells. Complicating its application, even in the most sophisticated centers, has been the manageable but difficult toxicities attendant on its use in spite of clear evidence of complete responses in 5-10% of treated patients with melanoma and renal cell carcinoma with extraordinary durability lasting now for almost 25 years, thus tantamount to "cures.

Ethyl pyruvate administration inhibits hepatic tumor growth.

EP is a potent inhibitor of HMGB1 release that has significant anti-inflammatory activities and exerts a protective effect in animal models of inflammation. As inflammation is linked to cancer growth, we hypothesized that EP would have anti-tumor activity and explored its effects in a liver tumor model. Mice injected intraportally with MC38 colorectal cancer cells led to the growth of visible hepatic tumors within 2 weeks.

The biology of interleukin-2 efficacy in the treatment of patients with renal cell carcinoma.

Renal cell carcinoma (RCC) is the eighth most common malignancy in adults in the United States. More than 50% of individuals present with metastatic disease and conventional chemotherapeutic strategies have been associated with poor response rates. Immunotherapy with Interleukin (IL)-2, however, induces durable remission, achieving >10 year recurrence free survival in 5-10% of patients with advanced RCC.