has consulted for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, and Celgene; received institutional research funding from Merck, Bristol Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM; and received honoraria from Merck and Bristol Myers Squibb

has consulted for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, and Celgene; received institutional research funding from Merck, Bristol Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM; and received honoraria from Merck and Bristol Myers Squibb. months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, NFIB 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very UM-164 limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #”type”:”clinical-trial”,”attrs”:”text”:”NCT02038946″,”term_id”:”NCT02038946″NCT02038946. Visual Abstract Open in a separate window Introduction Follicular lymphoma (FL) typically has an indolent disease course, but is not considered curable with conventional therapies.1 Most patients experience relapse after frontline therapy, and although newer therapies such as PI3K inhibitors and the immunomodulatory drug lenalidomide may lead to frequent responses in patients with relapsed or refractory (R/R) disease, most patients will subsequently relapse. 2-5 Therefore there is a need for novel, effective, and safe therapies for R/R FL. FL appears to be inherently immunosensitive, as evidenced by the success of allogeneic hematopoietic cell transplantation (HCT),6,7 as well as occasional responsiveness to other immunotherapeutic brokers such as ipilimumab and pidilizumab.8,9 Nivolumab, a fully human IgG4 monoclonal antibody against programmed death-1 (PD-1), blocks signaling induced by the binding of PD-1 to its ligands programmed death-ligand 1/ligand 2 (PD-L1/L2), which releases inhibition of T cells and restores antitumor immune responses.10 Nivolumab is indicated for the treatment UM-164 of several tumor types.10 In CheckMate 039, a phase 1 study targeting several lymphoid malignancies, nivolumab showed promising activity in R/R FL, with an objective response rate (ORR) of 40% (4 of 10 patients).11 Responses were durable, with response durations 1.5 years for 1 patient with complete remission (CR) and 6 months for patients with partial remission (PR). This study also suggested a favorable safety profile for nivolumab in R/R FL, similar to that observed in patients with solid tumors and classical Hodgkin lymphoma.12 On the basis of these encouraging results, we conducted a phase 2 study to evaluate the efficacy and safety of nivolumab in patients with R/R FL and previous rituximab treatment. The mechanistic basis of responsiveness to PD-1 blockade in FL has yet to be elucidated. Most FL tumor cells do not express PD-L1/L2,11,13-15 but PD-L1 has been found on nonmalignant tumor-infiltrating immune cells.11,15 Meanwhile, tumor-infiltrating T cells showed high PD-1 expression and suppressed cytokine signaling.15 Thus, responses to nivolumab could provide important insights into the mechanism of PD-1 blockade in FL. Indeed, the host immune response has been recognized as an important determinant of sensitivity of FL to conventional therapy. In 1 study, 2 gene expression signatures of nonmalignant tumor-infiltrating immune cells, termed immune-response 1 (IR-1) and immune-response 2 (IR-2), were associated with favorable and poor survival prognoses in FL, respectively.16 Studies have also found that the degree of infiltrating macrophages and T cells may be prognostic in FL,17 and progression of disease within 24 months was associated with reduced intratumoral immune infiltration.18 In this study, therefore, we examined pretreatment biomarkers as potential predictors of response to nivolumab. Methods Study design and patient population CheckMate 140 (“type”:”clinical-trial”,”attrs”:”text”:”NCT02038946″,”term_id”:”NCT02038946″NCT02038946) was a UM-164 single-arm, open-label, phase 2 trial in patients aged 18 years with R/R FL after failure of at least 2 prior lines of therapy, each of which had to contain a CD20 antibody or an alkylating agent, and at least 1 had to include rituximab. Patients were excluded if they had.

has consulted for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, and Celgene; received institutional research funding from Merck, Bristol Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM; and received honoraria from Merck and Bristol Myers Squibb
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