INTERLEUKIN-12

Steven K. Clinton; Eduardo Canto; Michael A. O'Donnell

doi:10.1016/S0094-0143(05)70242-1

Clinicians are now keenly aware of the typical sequence of events that follow the characterization of novel immunoregulatory growth factors and cytokines by the biotechnology industry and their academic collaborators. Interferons and interleukin-2 received enormous media and public attention as breakthrough drugs for the treatment of human cancer based on provocative early in vitro and laboratory animal successes; however, subsequent clinical trials with recombinant cytokines demonstrated that orchestrating a patient's immune system to fight an advanced malignancy was a challenging and often baffling process. Despite frequent and severe toxicities in human studies, the occasional dramatic and prolonged response observed in selected patients fueled continued clinical development. Perseverance by clinical investigators and corporate supporters and a willing patient population ultimately resulted in the approval of these agents for a limited range of oncologic applications. Interest in interleukin-12 (IL-12) therapy has also varied since it was identified and cloned a decade ago.17,32,70 Enthusiam for IL-12 in the wake of dramatic anticancer properties demonstrated in rodents subsequently declined after disappointing clinical studies and the widely publicized deaths of several patients participating in trials of recombinant IL-12.5,9,16,56 The accumulating experience provides a foundation for laboratory and clinical studies examining novel approaches for cancer therapy employing IL-12. Clinical research opportunities include the following:1Combinations with highly immunogenic peptides and proteins derived from tumor antigens2Combinations with highly specific antibody constructs targeting tumor antigens3Combinations with other cytokines and chemokines to modulate antitumor immune responses more precisely4Augmentation of cell-based immune therapies5The development of efficient vectors for localized gene therapy6Combinations with nonimmunologic cancer therapies such as chemotherapy and radiotherapy This article focuses on the role of IL-12–based therapy for human bladder cancer. The application of intravesicular bacille Calmette-Guérin (BCG) for the treatment of superficial high-grade bladder cancer has clearly demonstrated that immune-based therapies can dramatically alter the course of disease and can provide durable cures.26,27,28 The possibility that more effective immune-based strategies for superficial bladder cancer may be developed and extended to more advanced disease provides the basis for additional studies with IL-12.

INTERLEUKIN-12

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