Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.

Ascierto, Paolo A.; Melero, Ignacio; Bhatia, Shailender; Bono, Petri; Sanborn, Rachel E.; Lipson, Evan J.; Callahan, Margaret K.; Gajewski, Thomas F.; Gomez‐Roca, Carlos; Hodi, F. Stephen; Curigliano, Giuseppe; Nyakas, Marta; Preusser, Matthias; Koguchi, Yoshinobu; Maurer, Matthew; Clynes, Raphael; Mitra, Priyam; Suryawanshi, Satyendra; Muñoz‐Couselo, Eva

doi:10.1200/jco.2017.35.15_suppl.9520

Cited by 226 publications

(171 citation statements)

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“…Clinically, combination treatment regimens also highlight potential mechanisms of resistance; for example, the activity of combined PD-1/CTLA-4 blockade in melanoma (54) and in RCC (107) strongly implicate CTLA-4 activity as a factor limiting the efficacy of PD-1 blockade in patients. Other clinically apparent mechanisms of resistance include LAG-3 expression (108), IDO expression (109–111), as well as many others (112). …”

Section: Mechanisms Of Resistance To Pd-1/pd-l1 Blockadementioning

confidence: 99%

Inhibitors of the PD-1 Pathway in Tumor Therapy

LaFleur

Muroyama

Drake

et al. 2018

The Journal of Immunology

124

102

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The programmed death 1 (PD-1) pathway delivers inhibitory signals that function as a brake for immune responses. This pathway limits the initiation and duration of immune responses, thereby protecting tissues from immune-mediated damage and autoimmune diseases. However, the PD-1 pathway also inhibits immune responses to tumors. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers with the hallmark of durability of response. Despite this success, most patients do not respond to PD-1 monotherapy, and some patients experience adverse events. In this review, we discuss the functions of the PD-1 pathway and its translation to cancer immunotherapy. We also consider current challenges and opportunities for PD-1 cancer immunotherapy, including mechanisms of response and resistance, identification of biomarkers of response to PD-1 therapy, characterization and treatment of PD-1 therapy–related adverse events, and development of safe and effective combination therapies.

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Section: Mechanisms Of Resistance To Pd-1/pd-l1 Blockadementioning

confidence: 99%

Inhibitors of the PD-1 Pathway in Tumor Therapy

LaFleur

Muroyama

Drake

et al. 2018

The Journal of Immunology

124

102

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“…Thus, it stands to reason that antagonistic anti-LAG-3 antibodies may improve efficacy in combination with anti-PD-1 therapies in the clinic (7,8,(27)(28)(29)(30). Currently, there are several LAG-3-targeting treatments in various phases of clinical development (31)(32)(33)(34). In particular, combination therapy of anti-LAG-3 (BMS-986016) plus anti-PD-1 (nivolumab) has shown promising clinical efficacy in patients with melanoma (33,34).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Burova

Hermann

Dai

et al. 2019

Molecular Cancer Therapeutics

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In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigenpresenting cell bioassay, REGN3767 alone, or in combina-tion with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.

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“…LAG-3 blocking could be achieved by LAG-3-Ig fusion protein or LAG-3 targeting antibody (relatlimab). The treatment of melanoma patients with relatlimab resulted in the ORR of 16% and DCR of 45% [140]. Interestingly, only 9% of patients had grade 3 or 4 adverse events that was comparable to the therapy with nivolumab.…”

Section: Other Ici In Malignant Melanomamentioning

confidence: 96%

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

Petrova

Arkhypov

Weber

et al. 2020

IJMS

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Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.

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Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.

Cited by 226 publications

References 0 publications

Inhibitors of the PD-1 Pathway in Tumor Therapy

Inhibitors of the PD-1 Pathway in Tumor Therapy

Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice

Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma

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