Editors' ChoiceCancer

Checkpoint Therapy to the Rescue

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Science Translational Medicine  17 Dec 2014:
Vol. 6, Issue 267, pp. 267ec214
DOI: 10.1126/scitranslmed.aaa3459

To prevent overactivation of the immune system, the programmed death 1 (PD-1) pathway works as a checkpoint to control T cell activation. The pathway is activated when the ligands PD-L1 and PD-L2 bind to the PD-1 receptor, resulting in T cell “exhaustion,” a reversible inhibition of T cell activation and proliferation. Tumors hijack this pathway by overexpressing PD-L1 to fly under the radar of the immune system. Patients with Hodgkin’s lymphoma frequently have amplification of the 9p24.1 locus, which contains PD-L1 and PD-L2, causing the ligands to be overexpressed on the surface of lymphoma cells in these patients and making Hodgkin’s lymphoma a candidate for immunotherapeutic approaches. Although most patients are curable with chemotherapy, patients who relapse after chemotherapy or fail to respond to it have considerably worse outcomes.

In a recent study by Ansell et al., 23 patients with relapsed or refractory Hodgkin’s lymphoma, 18 of whom had relapsed after a bone marrow transplant, were enrolled in a clinical trial to be treated with nivolumab, a PD-1 blocking antibody. Twenty of these patients achieved an objective response. At 24 weeks after the start of treatment, 86% of the patients’ cancers had not progressed. Only two patients had to discontinue the drug due to toxicity. The investigators evaluated PDL1 and PDL2 copy numbers in tumor samples obtained before treatment and identified amplification, relative copy gain, or polysomy of chromosome 9p. The samples also showed increased expression of nuclear pSTAT3, indicating activation of JAK-STAT signaling in all the samples tested.

This study demonstrates the effectiveness and safety of immunotherapy in relapsed or refractory Hodgkin’s lymphoma and suggests a possible link between genomic amplifications of the 9p24 locus and sensitivity to PD-1 blockade.

S. M. Ansell et al., PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 10.1056/NEJMoa1411087 (2014). [Full Text]

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