Abstract: Introduction: Classical Hodgkin lymphoma (cHL) is characterized by Reed Sternberg (RS) cells surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. Recent studies suggest that Hodgkin RS cells have developed mechanisms that exploit the programmed cell death-1 (PD-1) pathway to evade immune detection. In cHL, chromosome 9p24.1 gain is a frequent structural alteration that increases the gene dosage of the PD-1 ligands, PD-L1 and PD-L2, and their induction via JAK/STAT signaling. Epstein-Barr Virus (EBV) infection also increases the expression of the PD-1 ligands in EBV-positive cHL. Ligand binding to PD-1 receptor-positive activated T cells induces T cell exhaustion, a reversible inhibition of T cell activation and proliferation. Nivolumab (BMS-936558, Bristol-Myers Squibb) is a fully human IgG4 monoclonal PD-1 blocking antibody that potentiates anti-tumor T cell activity, and exhibits clinical efficacy in several solid tumors. We hypothesized that nivolumab may augment anti-tumor activity in patients with relapsed or refractory (R/R) cHL, including those who had failed brentuximab vedotin (BV), and evaluated the PD-1 blocking antibody. These are the first analyses being reported with PD-1 antibody for the treatment of cHL. Methods: Patients with R/R cHL were included as an independent cohort in a dose escalation and cohort expansion phase I study of nivolumab in lymphoma and multiple myeloma (MM). Results for patients with non-Hodgkin lymphoma and MM are reported separately. Patients with cHL received nivolumab 3 mg/kg every 2 weeks until confirmed tumor progression or excessive toxicity. Responses were evaluated using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. Results: Twenty-three patients were enrolled with R/R cHL. Patients were heavily pre-treated, 87% had received ≥ 3 prior treatment regimens, 78% had prior autologous stem cell transplant (ASCT), and 78% had prior BV treatment. Drug-related adverse events (AEs) of any grade occurred in 78% of patients, the most common of which were rash (22%), decreased platelet count (17%), diarrhea, nausea, pruritus, fatigue, and pyrexia (each at 13%). Drug-related grade 3/4 AEs occurred in 22% of patients. Three patients experienced 1 serious AE each (grade 3 myelodysplastic syndrome [MDS], grade 3 pancreatitis, and grade 2 lymph node pain). The objective response rate (ORR) was 87% (20/23), with 4 patients (17%) achieving a complete response (CR) and 16 (70%) obtaining a partial response (PR). The remaining 3 patients (13%) had stable disease (SD). All 23 patients had a reduction in tumor burden at 1 or more efficacy assessments during treatment with nivolumab (Figure). Among the 18 patients who had previously failed BV, the ORR was 89% (16/18), with 6% (1/18) achieving CR and 83% (15/18) PR. Progression-free survival (PFS) rate at 24 weeks was 86% (95% CI, 62-95%). The median overall survival (OS) has not been reached (range, 21+ to 75+ weeks). Six of 23 patients elected to discontinue study treatment to undergo stem cell transplantation, 2 patients discontinued due to toxicities (MDS and thrombocytopenia in 1 patient; pancreatitis in 1 patient), 4 patients discontinued due to disease progression, and 11 patients continue on study as of June 16, 2014. In a subset of study patients (10/23), PD-L1 and PD-L2 copy numbers in RS cells were assessed using fixed tumor biopsy specimens and a 3-probe fluorescence in situ assay (PD-L1,PD-L2, and control centromeric probe). In all tumors, RS cells had copy gains of PD-L1 and PD-L2, as a result of either polysomy or amplification; these tumors also exhibited increased protein expression of PD-L1. RS cells were also largely positive for pSTAT3, indicative of active JAK/STAT signaling. Conclusions In patients with R/R cHL, nivolumab-mediated PD-1 blockade is safe and tolerable with a safety profile similar to that in solid tumors. The frequent and long-lasting responses in heavily pretreated, R/R patients, including those who have failed BV, highlight the importance of the PD-1 pathway in cHL, and the genetically defined sensitivity to PD-1 blockade in this disease. Based on these results, the FDA granted nivolumab breakthrough status in relapsed cHL and a large, multinational, phase II trial of this therapy is underway. Figure 1 Figure 1. Disclosures Armand: Merck: Consultancy. Off Label Use: Nivolumab was tested for the treatment of hematologic malignancies.. Ansell:Bristol-Myers Squibb: Research Funding. Lesokhin:Bristol-Myers Squibb: Consultancy, Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding. Borrello:Bristol-Myers Squibb: Research Funding. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R & D: Membership on an entity's Board of Directors or advisory committees.

Abstract: Expression of the PD-1 receptor on T cells has been shown to provide an important inhibitory signal that down-modulates peripheral effector responses in normal tissues and tumors. Furthermore, PD-1 up-regulation on chronically activated T cells can maintain them in a partially reversible inactive state. The function of PD-1 in the very early stages of T-cell response to antigen in vivo has not been fully explored. In this study, we evaluate the role of PD-1 and its 2 B7 family ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), in early fate decisions of CD8 T cells. We show that CD8 T cells specific for influenza hemagglutinin (HA) expressed as a self-antigen become functionally tolerized and express high levels of surface PD-1 by the time of their first cell division. Blockade of PD-1 or B7-H1, but not B7-DC, at the time of self-antigen encounter mitigates tolerance induction and results in CD8 T-cell differentiation into functional cytolytic T lymphocytes (CTLs). These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T-cell–fate decisions.

Abstract: Introduction Programmed cell death-1 (PD-1) is an immune checkpoint receptor that inhibits T cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported in various lymphoid malignancies, and may allow these tumors to circumvent host anti-tumor immunity. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, potentiates T cell activity, and has clinical efficacy in various solid tumors. We hypothesized that nivolumab might also have clinically important anti-tumor activity in patients with lymphoid malignancies. Methods This open-label study enrolled patients with relapsed or refractory lymphoid malignancies including B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), multiple myeloma (MM), and classical Hodgkin lymphoma (cHL). Patients were treated using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every two weeks for up to two years. Responses were assessed using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. The preliminary results for the cHL patients will be reported separately. Results Twenty-nine patients with B-NHL, 2 patients with primary mediastinal B-cell lymphoma; 23 patients with T-NHL; 27 patients with MM; and 1 with chronic myelogenous leukemia were enrolled. Patients were heavily pretreated with 67%, 69%, and 78% of MM, B-NHL, and T-NHL patients, respectively, having received ≥ 3 prior treatment regimens. Previous autologous stem cell transplantation was reported for 56% of MM, 14% of B-NHL, and 9% of T-NHL patients. Prior brentuximab treatment was reported in 7% of B-NHL and 26% of T-NHL patients. When this pre-planned interim analysis was performed, six patients had been treated at the 1 mg/kg dose with 2 dose-limiting toxicities (DLTs) occurring in the same patient: grade 3 pneumonia and pneumonitis. At the 3mg/kg dose, seven patients were treated with one patient experiencing two DLTs: grade 3 eosinophilia and diplopia. Additional patients were enrolled in the cohort expansion at 3 mg/kg. Drug-related adverse events (AEs) occurred in 72%, 65%, and 52% of B-NHL, T-NHL, and MM patients, respectively. Serious AEs in B-NHL patients were pneumonitis (7%), acute respiratory distress syndrome, dermatitis, diplopia, enteritis, eosinophilia, mucosal inflammation, pyrexia and vomiting, each occurring in 3%. In the T-NHL patients, serious AEs were pneumonitis, rash, and sepsis, each occurring in 4%, and in MM patients, serious AEs were pneumonitis, myositis, and increased creatine phosphokinase, each occurring in 4%. The incidence and severity of drug related AEs were similar across tumor types. Efficacy results are shown for each tumor type in the table. The overall response rate (ORR) and complete response (CR) rate in patients with B-NHL were 28% and 7%, respectively, including an ORR of 36% in patients with diffuse large B-cell lymphoma (DLBCL), and 40% in patients with follicular lymphoma (FL). In patients with T-NHL, ORR was 17% (no CR), including an ORR of 40% in the 5 patients with peripheral T cell lymphoma. No objective responses were observed in MM. Analysis of PD-L1 expression and correlation to clinical outcome is being performed and will be presented. Conclusions Nivolumab administered at a dose of 3 mg/kg every two weeks was tolerable and the safety profile was similar to that of the agent in solid tumors. Objective responses were observed in DLBCL, FL, mycosis fungoides (MF), and peripheral T cell lymphoma (PTCL). Durable stable disease was observed in relapsed MM. The results of this phase 1 study have led to phase 2 studies in DLBCL and FL, which are ongoing. Table: Efficacy Results Tumor N Complete Response n (%) Partial Response n (%) Stable Disease (SD) n (%) Progression Free Survival Rate at 24 Weeks (%) Diffuse Large B Cell Lymphoma (DLBCL) 11 1 (9) 3 (27) 3 (27) (24) Follicular Lymphoma (FL) 10 1 (10) 3 (30) 6 (60) (68) Other B Cell Lymphoma 8 0 0 5 (63) (38) Primary Mediastinal B Cell Lymphoma 2 0 0 2 (100) (0) Mycosis Fungoides (MF) 13 0 2 (15) 9 (69) (39) Peripheral T Cell Lymphoma (PTCL) 5 0 2 (40) 0 (30) Other T Cell Lymphoma 5 0 0 1 (20) (0) Multiple Myeloma (MM) 27 0 0 18 (67) (15) Chronic Myelogenous Leukemia 1 0 0 1 (100) (100) Disclosures Lesokhin: Bristol-Myers Squibb: Consultancy, Research Funding. Ansell:Bristol-Myers Sqibb: Research Funding. Armand:Merck: Consultancy. Cohen:Celgene: Member, Independent Response Adjudication Committee Other; Onyx: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other. Lebovic:Genentech, Allos, Celgene, Onyx, Millennium: Consultancy, Research Funding, Speakers Bureau. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R & D: Membership on an entity's Board of Directors or advisory committees. Borrello:Bristol-Myers Squibb: Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding.