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." Although efforts have been made to diminish toxicity or enhance efficacy the only substantive advance in combination therapy has been the application of tumor-infiltrating lymphocytes and the antibody to CTLA4. A deeper understanding of the "limiting" toxicity associated with mild flu-like symptoms and more debilitating cytokine "storm" not forthcoming. Here we propose the notion that the systemic syndrome associated with IL-2 administration is due to global cytokine-induced autophagy and temporally limited tissue dysfunction. The possible role of autophagy inhibitors to enhance efficacy and limit toxicity as well as possible problems with this approach are considered.
Chavez
Antonio Romo de Vivar
AR
University of Pittsburgh Cancer Institute, Pennsylvania, USA.
Buchser
William
W
Basse
Per H
PH
Liang
Xiaoyan
X
Appleman
Leonard J
LJ
Maranchie
Jodi K
JK
Zeh
Herbert
H
de Vera
Michael E
ME
Lotze
Michael T
MT
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D011379:Prognosis
D000970:Antineoplastic Agents; D007376:Interleukin-2