Editors' ChoiceCancer

Blocking an Immune Inhibitor: Small Step or Giant Leap?

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Science Translational Medicine  13 Jun 2012:
Vol. 4, Issue 138, pp. 138ec102
DOI: 10.1126/scitranslmed.3004423

Like obnoxious houseguests, tumors take over their resident tissues and thwart the body’s attempt to oust them. Indeed, cancers coopt endogenous immunosuppression strategies to prevent immune-mediated elimination. Experimental models of tumor immunotherapy have long tantalized researchers with the promise of awakening endogenous antitumor immunity. However, moving from models to patients has proven frustrating. Now, Topalian et al. and Brahmer et al. report that antibodies that block the immune inhibitory receptor system programmed death 1 (PD-1) and PD-L1 (ligand for PD-1) can safely reverse the immunosuppression that allows tumors to survive and grow.

The two new clinical studies show that immunotherapy can decrease tumor burden without causing autoimmunity. In addition, immune classification of solid-organ tumors has therapeutic relevance. Anti–PD-1 and anti–PD-L1 therapy were evaluated in patients with cancers that are thought to be immunotherapy-sensitive (melanoma and renal cell carcinoma) and others that have been resistant to immunotherapy in past attempts (non–small cell lung cancer). Of the 24% of patients who had an objective response in the anti–PD-1 antibody study by Topalian et al., response was not predicted as much by tumor origin (for example, melanoma versus lung cancer) as by the tumor’s expression of PD-L1. In the anti–PD-1 study by Brahmer et al., tumors that were PD-L1–positive responded in one third of patients, but there was an 18% death rate among patients in the highest-dose treatment arm compared with 0 to 5% with lower doses. Prior attempts at blocking inhibitory immune receptors had caused autoimmune disease in some patients, but in the current study, neither PD-1 nor PD-L1 therapy was associated with autoimmune phenomena.

As with all phase I clinical trials, critical details will need to be clarified in future studies. However, the observation that immunotherapy can yield a durable tumor response for greater than 1 year represents a giant leap forward for the concept of blockade of inhibitory immune receptors as cancer treatment.

S. L. Topalian et al., Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med., 2 June 2012 (10.1056/NEJMoa1200690). [Abstract]

J. R. Brahmer et al., Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med., 2 June 2012 (10.1056/NEJMoa1200694). [Abstract]

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