Editors' ChoiceCancer

It takes two to tango

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Science Translational Medicine  13 May 2015:
Vol. 7, Issue 287, pp. 287ec77
DOI: 10.1126/scitranslmed.aab3976

For cancer, the age of combination therapy has dawned, and synergy is the name of the game. Tumor antigen–specific antibodies have paved the therapeutic path, but the promise of joining antibodies with immune-stimulating cytokines has failed to show clinical improvement over antibodies alone. Zhu et al. hypothesized that unsuccessful partnerships between the cytokine interleukin (IL)-2 and therapeutic antibodies have resulted from the cytokine’s rapid degradation in vivo. Here, the authors enhance IL-2 bioavailability by fusing it with a heterologous protein fragment, finally forcing the cytokine’s antitumor power to manifest.

The team fused mutated variants of a mouse IgG2a Fc region to mouse IL-2. Once-weekly administration of the Fc–IL-2 fusion protein and a melanoma-specific anti–TYRP-1 antibody (TA-99) tapped into the therapies’ synergistic effects—they halted tumor growth and enhanced survival while avoiding much of toxic effects of daily IL-2 administration. Enhanced survival was also observed in other solid-tumor mouse models when distinct antitumor antibodies were dosed with the IL-2 fusion protein, thus demonstrating the general nature of the therapeutic approach. Mechanistic studies revealed a complex interplay between immune cell recruitment and cytokine signaling in the treated tumors. Last, when the Fc–IL-2+TA99 combination was combined with adoptive T cell therapy, the authors observed a long-term survival response that lasted at least 3 months after treatment without relapse. The durable response was likely to be caused by Fc–IL-2–driven continued expansion of the infused T cells in the tumor.

Such designer therapeutics highlight how bioengineers can leverage their own synergy of biological knowledge and cutting-edge technology to transform medicine. Yet the powerful immunotherapy did not come without consequence. The authors observed treatment-associated splenomegaly as well as elevation in serum levels of liver enzymes and inflammatory cytokines. Also, a tumor-lysis syndrome might be even more pronounced if these combinations were applied to fully developed tumors, as would be the case in clinical settings. Humanizing the fusion protein and exploring dose-limiting efficacy and toxicology studies in full-grown tumors might balance the risk profile of Fc–IL-2, recruiting a new player to the cancer arena. And this one’s got moves.

E. F. Zhu et al., Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2. Cancer Cell 27, 489–501 (2015). [Abstract]

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