Relatlimab plus nivolumab beneficial for previously untreated metastatic or unresectable melanoma

O’Rourke, Kate

doi:10.1002/cncr.34227

Cited by 6 publications

(5 citation statements)

References 2 publications

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“…The first anti LAG-3 antibody for clinical use is Relatlimab which is able to reactivate T lymphocytes in tumor tissues in a significant way ( 59 ). Two main randomized clinical trials have investigated the effects of Relatlimab in combination with Nivolumab in cancer patients: in a study on patients with melanoma refractory to therapy with PD-1 blocking agents, the combinatorial use of Relatlimab with Nivolumab showed significant antitumor efficacy with increased survival ( 60 ). A double blind randomized clinical trial, called Relativity-047, combined Relatlimab with Nivolumab in metastatic or unresectable melanoma patients ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology

Quagliariello,

Passariello,

Bisceglia

et al. 2024

Front. Cardiovasc. Med.

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BackgroundImmune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events.MethodsHuman cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens.ResultsBoth combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies.ConclusionsData of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

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Section: Discussionmentioning

confidence: 99%

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology

Quagliariello,

Passariello,

Bisceglia

et al. 2024

Front. Cardiovasc. Med.

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“…Furthermore, the combination also has a high clinical efficacy against leukemia [ 39 ]. Fortunately, in March 2022, nivolumab [ 40 ] in combination with relatlimab (Opdualag TM ) received approval in the some areas such as USA for the treatment of unresectable melanoma [ 41 ].…”

Section: The Features Of T Cell Exhaustionmentioning

confidence: 99%

Regulatory Mechanisms and Reversal of CD8+T Cell Exhaustion: A Literature Review

Zhu

Meng

et al. 2023

Biology

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CD8+T cell exhaustion is a state of T cell dysfunction during chronic infection and tumor progression. Exhausted CD8+T cells are characterized by low effector function, high expression of inhibitory receptors, unique metabolic patterns, and altered transcriptional profiles. Recently, advances in understanding and interfering with the regulatory mechanisms associated with T cell exhaustion in tumor immunotherapy have brought greater attention to the field. Therefore, we emphasize the typical features and related mechanisms of CD8+T cell exhaustion and particularly the potential for its reversal, which has clinical implications for immunotherapy.

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“…14,15 LAG-3 cell surface receptor is induced on effector T lymphocytes in response to antigenic stimulation and its expression is maintained at high levels on CD4 + and CD8 + T lymphocytes in response to persistent antigen stimulation, being upregulated in melanoma. 4,16 The classic ligands of LAG-3 are major histocompatibility complex class II molecules, which are abundantly expressed in cutaneous melanomas. 17 Considering its physiologic roles, LAG-3 has the potential to restrict the efficacy of PD-1 blockade in individuals who have not had previous treatment, whereas the adaptive elevation of LAG-3 expression may lead to resistance to treatment in patients undergoing anti-PD-1 therapy.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Nivolumab/Relatlimab-rmbw: A Novel Dual Combination Therapy to Treat Adult and Pediatric Patients With Unresectable or Metastatic Melanoma

Thomas,

Burns,

Pervanas

et al. 2023

American Journal of Therapeutics

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Background: Immune checkpoint inhibitors control effector mechanisms and work to restore downregulated T-cells in patients with melanoma. Examples of such include programmed death-1 inhibitors and lymphocyte-activating gene 3 inhibitors. The combination of nivolumab, a programmed death-1 inhibitor, and relatlimab-rmbw, a lymphocyte-activating gene 3 inhibitor, has shown antitumor activity and improved progression-free survival in patients with unresectable or metastatic melanoma. Mechanism of Action & Pharmacokinetics/Pharmacodynamics: The fixed-dose combination of nivolumab and relatlimab immunotherapy is approved for adults and pediatrics 12 years of age or older with metastatic or unresectable melanoma. Volume of distribution is 6.6 L for relatlimab and nivolumab, and half-life is 27 and 26 days, respectively. Clearance at steady state is 7.6 mL/h for nivolumab and 5.5 mL/h for relatlimab. Sex, age, race, and mild hepatic/renal impairment had no clinical effect on clearance. The exposure–response relationship and pharmacodynamic response for the safety and effectiveness of nivolumab/relatlimab-rmbw have not been fully characterized. Safety concerns include severe and fatal immune-mediated adverse reactions, infusion-related reactions, and complications of allogeneic hematopoietic stem cell transplantation, and fetal toxicity. Dosing is determined by patient's age and weight. Solution is infused over a 30-minute timeframe. Clinical Trials: In the RELATIVITY-047 trial, patients received nivolumab or nivolumab/relatlimab-rmbw. Results showed superiority of dual therapy over monotherapy with a progression-free survival of 10.1 months (95% CI, 6.4–15.7) compared with 4.6 months (95% CI, 3.4–5.6) and hazard ratio of 0.75 (95% CI, 0.62–0.92); P = 0.006, respectively. No safety concerns were observed compared with monotherapy with treatment-related adverse events occurring in 18.9% of patients on combination therapy compared with 9.7% on nivolumab alone. Therapeutic Advance: The novel mechanism and improvement in progression-free survival compared with standard of care highlight the therapeutic advancement of nivolumab/relatlimab-rmbw in the treatment of unresectable and metastatic melanoma.

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Relatlimab plus nivolumab beneficial for previously untreated metastatic or unresectable melanoma

Cited by 6 publications

References 2 publications

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology

Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1β and interleukin-6: biochemical implications in cardio-immuno-oncology

Regulatory Mechanisms and Reversal of CD8+T Cell Exhaustion: A Literature Review

Nivolumab/Relatlimab-rmbw: A Novel Dual Combination Therapy to Treat Adult and Pediatric Patients With Unresectable or Metastatic Melanoma

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