Editors' ChoiceImmunotherapy

Checkpoint inhibitors continue to check out

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Science Translational Medicine  29 Apr 2015:
Vol. 7, Issue 285, pp. 285ec69
DOI: 10.1126/scitranslmed.aab3135

T cells often fail to eradicate cancer—even when they successfully infiltrate tumors, they are often exhausted or suppressed by so-called immune checkpoints. A revolutionary new class of cancer immunotherapies—immune checkpoint blockers—reverses the inhibition and releases T cells to clear tumors. The latest good news for tumor immunotherapy is reported in three articles in The New England Journal of Medicine published to coincide with this year’s meeting of the American Association for Cancer Research.

The FDA has already approved biological agents that target two cell surface receptors— cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1)—that appear to act through distinct checkpoint pathways. Ipilimumab (Bristol-Myers Squibb) is an anti–CTLA-4 antibody approved as first-line treatment for advanced melanoma. Two different PD-1 inhibitors, nivolumab (Bristol-Myers Squibb) and pembrolizumab (Merck), are currently approved as second-line therapy for melanoma that is not responsive to anti–CTLA-4 treatment. Two of the current studies in the NEJM may be a step towards use of PD-1 inhibitors as first-line agents for advanced melanoma. Robert et al. performed a Phase 3 trial that compared pembrolizumab head-to-head with ipilimumab and reported that the anti–PD-1 antibody led to longer progression-free survival with fewer serious side effects. Phase 1 results from Postow et al. suggest that PD-1 inhibition with nivolumab may have even further survival benefits when given along with anti–CTLA-4 treatment, although they only compared the combination with anti–CTLA-4 monotherapy. A third study by Garon et al. extends beyond melanoma, reporting efficacy for pembrolizumab as a treatment for non–small cell lung cancer. Interestingly, this article observed that tumor expression of a PD-1 ligand correlated with anti–PD-1 efficacy, suggesting that expression of the PD-1 ligand may eventually serve as a biomarker to identify patients who are candidates for PD-1 blockade.

These three studies are the most recent in a series of successes of anti–PD-1 therapies for cancers in which traditional chemotherapies have been ineffective. Additional combination therapies and improved biomarkers may extend the benefits further. Important work lies ahead to determine why some tumors remain unresponsive to checkpoint inhibition.

E. B. Garon et al., Pembrolizumab for the treatment of non–small-cell lung cancer. N. Engl. J. Med. 10.1056/NEJMoa1501824 (2015). [Abstract]

C. Robert et al., Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 10.1056/NEJMoa1503093 (2015). [Abstract]

M. A. Postow et al., Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 10.1056/NEJMoa1414428 (2015). [Abstract]

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