First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas

Gopal, Ajay K.; Levy, Ronald; Houot, Roch; Patel, Sandip Pravin; Popplewell, Leslie; Jacobson, Caron A.; Mu, Xinmeng Jasmine; Deng, Shibing; Ching, Keith A.; Chen, Ying; Davis, Craig B.; Huang, Bo; Fly, Kolette D.; Thall, Aron; Woolfson, Adrian; Bartlett, Nancy L.

doi:10.1158/1078-0432.ccr-19-2973

Cited by 45 publications

(31 citation statements)

References 52 publications

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“…[33][34][35] Given its ability to improve the overall anti-tumour activity of CD19 CART therapy, in the ZUMA-11 clinical trial (NCT03704298), axicel is administered in combination with utomilumab, an agonistic monoclonal antibody targeting 4-1BB, capable of enhancing T cell and natural killer cell functions against lymphoma. 36 Another strategy to improve axi-cel overall performance could consist in strategies to reduce its notable toxicity. Recent data show that the use of dexamethasone can reduce the onset of severe CRS and ICANS without affecting axi-cel efficacy.…”

Section: Axicabtagene Ciloleucelmentioning

confidence: 99%

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

et al. 2020

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Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B-cell malignancies because they can achieve durable complete remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti-CD19 CART therapy for patients with relapsed and refractory aggressive large B-cell lymphomas. While long-term follow-up data show that about one-third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B-cell non-Hodgkin lymphomas, describes the most upto-date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!

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Section: Axicabtagene Ciloleucelmentioning

confidence: 99%

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

et al. 2020

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“…Agonistic anti-4-1BB monoclonal antibodies significantly improved the anti-lymphoma effects of anti-CD20 monoclonal antibodies in preclinical models [49,50]. Recently, through a first-in-human study, utomilumab in combination with rituximab demonstrated clinical activity in patients with B-cell non-Hodgkin lymphoma [51].…”

Section: Modulating Nk Cell Activitymentioning

confidence: 99%

Immuno-oncology for B-cell lymphomas

Choi

2021

Blood Res

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The goal of cancer immunotherapy is to restore and optimize the immune response against malignant clones through several stages, from recognition of tumor antigens to establishment of long-lived memory cell populations. Boosting the intrinsic anti-tumor immune responses of the patients’ own, several types of “active immunotherapies” have been tried in many types of malignancies, inspired by successful experiences of immune checkpoint inhibition even in Hodgkin lymphoma. However, in B-cell non-Hodgkin lymphomas, clinical usefulness of such “active immunotherapies” is relatively unsatisfactory considering the remarkable advances in “passive immunotherapy,” including CD19-targeting chimeric antigen receptor T-cell therapy. Understanding how tumor cells and immune cells interact and contribute to immune evasion processes in the tumor microenvironment (TME) is an important prerequisite for the successful restoration of anti-tumor immune responses. In this review, a recent understanding of the biology of the immune tumor microenvironment surrounding B-cell non-Hodgkin lymphomas will be introduced. In addition, novel therapeutic approaches targeting the immune microenvironment other than immune checkpoint blockade are discussed.

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“…A phase 1 study evaluated the activity of the anti-4-1BB antibody utomilumab in combination with rituximab in a total of 67 patients with CD20+ R/R B-NHL, including six MCL patients. The best overall response (BOR), including CR or PR, was observed in patients with MCL, FL, and DLBCL, with a favorable safety profile and clinical activity [172].…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Management of Drug Resistance in Mantle Cell Lymphoma

Roué

Sola

2020

Cancers

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Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis. As a result, MCL remains an incurable disease. In this review, we will present the molecular mechanisms of drug resistance learned from both preclinical and clinical experiences in MCL, detailing the main tumor intrinsic processes and signaling pathways associated to therapeutic drug escape. We will also discuss the possibility to counteract the acquisition of drug refractoriness through the design of more efficient strategies, with an emphasis on the most recent combination approaches.

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First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas

Cited by 45 publications

References 52 publications

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

Immuno-oncology for B-cell lymphomas

Management of Drug Resistance in Mantle Cell Lymphoma

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