Background In patients with melanoma, ipilimumab (anti-CTLA-4) prolongs overall survival and nivolumab (anti-PD-1) produced durable tumor regressions in a phase 1 trial. Based on their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in advanced melanoma patients. Methods Patients received nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). Combined treatment was subsequently continued every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks. Results Fifty-three patients received concurrent nivolumab/ipilimumab and 33 received sequenced treatment. The objective response rate, for all concurrent-regimen patients was 40% (modified WHO criteria). Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease ≥24 weeks) was observed in 65% of patients. At the maximum tolerated dose (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 53% of patients achieved an objective response, all with ≥80% tumor reduction. Grade 3–4 related adverse events occurred in 53% of concurrent-regimen patients, but were qualitatively similar to historical monotherapy experience and were generally reversible. Among sequenced-regimen patients, 18% had grade 3–4 related adverse events and the objective response rate was 20%. Conclusions Concurrent nivolumab/ipilimumab had a manageable safety profile and achieved clinical activity that is distinct from published monotherapy data, with rapid and deep tumor regressions in a substantial number of patients.

Background Preclinical studies suggest that Reed–Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1–blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. Methods In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. Results Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. Conclusions Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.)

Summary The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a monoclonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer–testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.)

Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/ programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. MethodsPatients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. ConclusionPneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/ resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

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CONFLICT OF INTEREST STATEMENT VRB, BB, MDH, NHS, RJM, and KJB have no conflicts of interest to declare. MAP has had a consulting or advisory role with Amgen and Bristol-Myers Squibb, and receives research support from Bristol-Myers Squibb and Novartis (Inst). AML has a consulting or advisory role with Bristol-Myers Squibb, Janssen, Aduro, Efranat, Jounce, and Novartis, and receives research funding from Bristol-Myers Squibb (Inst), Janssen (Inst.), and Genentech (Inst). SW has a speaking arrangement with Novartis, Bayer-Onyx, Pfizer, and Mediavation. JDW has a consulting or advisory role with Bristol-Myers Squibb, Merck, MedImmune, Ziopharm, Polynoma, Polaris, Jounce, GlaxoSmithKline; receives honoraria from EMD Serono, Janssen Oncology, and research funding from Bristol-Myers Squibb (Inst), MedImmune (Inst), GlaxoSmithKline (Inst), Merck (Inst). MEL has consulted for BMS and Merck, and received research support from Bristol-Myers Squibb (Inst).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access AbstractBackground-Dermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the PD-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs is not known.

Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) may confer durable disease control in several malignancies. In some patients, immune checkpoint mAb cause cutaneous immune-related adverse events. Although the most commonly reported cutaneous toxicities are mild, a subset may persist despite therapy and can lead to severe or life-threatening toxicity. Autoimmune blistering disorders are not commonly associated with immune checkpoint mAb therapy. We report a case series of patients who developed bullous pemphigoid (BP), an autoimmune process classically attributed to pathologic autoantibody formation and complement deposition. Three patients were identified. Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of each patient and rash, and corresponding radiologic findings at the development of the rash and after its treatment, are described. Patients receiving anti-PD-1/PD-L1 mAb may develop immune-related bullous pemphigoid. This may be related to both T-cell and B-cell mediated responses. Referral to dermatology for accurate diagnosis and management is recommended.