Editors' ChoiceImmunotherapy

The Enemy of the Enemy of My Enemy Is a Therapeutic Target

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Science Translational Medicine  19 Jun 2013:
Vol. 5, Issue 190, pp. 190ec100
DOI: 10.1126/scitranslmed.3006748

Some people work a lifetime in fields in which a single mistake can be catastrophic: air traffic control, open-heart surgery, parachute making. In the lifetime of a human body, failure to prevent any of its constituent 100 trillion cells from becoming cancerous can be catastrophic. Faced with such standards of perfection, the human body uses an arsenal of mechanisms to constantly surveil and thwart would-be cancer cells. Such mechanisms may be intrinsic to the cell—such as apoptotic checkpoints or replicative senescence—or extrinsic—such as immune surveillance. On the road to malignancy, a cell must overcome each of these defenses, and reconstituting each vanquished defense constitutes a potential therapeutic strategy.

In the 2 June 2013 issue of the New England Journal of Medicine, Hamid et al. report the results of a phase 1 clinical trial in melanoma of the monoclonal antibody to PD-1, lambrolizumab. PD-1 is thought to negatively regulate immune response; thus, anti-PD-1 therapies may enhance antitumor immune response within an immunosuppressive microenvironment.

The authors enrolled a total of 135 patients with advanced melanoma. Seventy-nine percent of patients treated with lambrolizumab reported drug-related adverse events, and 13% reported grade 3 or 4 drug-related adverse events. The incidence of immune-related adverse events was lower than those reported for trials targeting the negative immune regulator, CTLA-4. The confirmed response rate based on Response Evaluation Criteria In Solid Tumors (RECIST) was 38%. Perhaps more importantly, prior exposure to other immunotherapies neither reduced the response rate nor increased the toxic effects of lambrolizumab. Moreover, some patients responded to lambrolizumab after having disease progression after treatment with chemotherapy or BRAF-targeted therapy.

Therapeutic opportunities are afforded by strengthening any of the multiple intrinsic antitumor mechanisms that are concurrently subjugated by a tumor. The study by Hamid et al. supports the therapeutic efficacy of strengthening immunosurveillence mechanisms. Immunotherapies target distinct cellular processes from alternative strategies, such as antiproliferative agents, perhaps explaining why response to lambrolizumab was observed in patients who progressed after other therapies. This insight may suggest additional research into combination therapies targeting distinct antitumorigenic cellular processes. In addition, although only a subset of patients respond to immunotherapies, patient selection criteria for identifying responders are severely lacking. Thus, although immunotherapies appear to constitute a viable weapon in the anticancer quiver, the precision with which such medicines are applied may be improved through additional research into combination therapies and patient selection criteria.

O. Hamad et al., Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. NEJM, 2 June 2013 (10.1056/NEJMoa1305133). [Abstract]

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