Improved Anti-Tumor Response of Chimeric Antigen Receptor T Cell (CART) Therapy after GM-CSF Inhibition Is Mechanistically Supported By a Novel Direct Interaction of GM-CSF with Activated Carts

Cox, Michelle J.; Kuhlmann, Charles J.; Sterner, Rosalie M.; Sakemura, Reona; Sinha, Sutapa; Hefazi, Mehrdad; Ahmed, Omar; Durrant, Cameron; Chappell, Dale; Roman, Claudia Manriquez; Schick, Kendall J.; Tapper, Erin E.; Horvei, Paulina; Ruff, Michael W.; Kay, Neil E.; Kenderian, Saad S.

doi:10.1016/j.bbmt.2019.12.227

Cited by 5 publications

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“…20 GM-CSF depletion results in modulation of myeloid cell behavior, a specific decrease in their inflammatory cytokines, and a reduction in tissue trafficking, 20 while enhancing T-cell apoptosis machinery. 21 These biological effects prevented both CRS and neuroinflammation after CART therapy in preclinical models and are being tested in a phase Ib/II clinical trial (NCT 04314843).…”

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confidence: 99%

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia

Temesgen

Assi

Shweta

et al. 2020

Mayo Clinic Proceedings

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Objective: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia. Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death. Results: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P¼.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab. Conclusion: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).

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confidence: 99%

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia

Temesgen

Assi

Shweta

et al. 2020

Mayo Clinic Proceedings

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“…Although the mechanism remains to be elucidated in full, we have observed improved lymphocyte proliferation and lymphocyte effector function in preclinical models with lenzilumab. 2,3 We agree that modulation of the monocyte-macrophage activity may provide a more favorable micro-environment for T cells resulting in reduced apoptosis.…”

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confidence: 60%

“…4 As already known, granulocytemonocyte colony-stimulating factor inhibition turned out to broadly modulate monocyte-macrophage activity by simultaneously reducing a spectrum of inflammatory cytokines, including tumor necrosis factor alpha. 3 We therefore suggest that the direct regulation of monocytemacrophage activity by lenzilumab, with subsequent broad cytokines shutdown, could provide a more favorable micro-environment where effector T cells could also be protected from cytokine-induced apoptosis. This would preserve a non-exhausted Tcell phenotype, being more effective against infections and performing more potently T-cell specific antiviral immunity to achieve viral clearance.…”

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confidence: 90%

“…The primary transmission route of the virion through respiratory aerosols is well documented. 3 There is an emerging recognition of potential transmission of SARS-CoV-2 through aerosolization of virusladen stools. 4 Air sampling for SARS-CoV-2 in hospital toilets used by patients has yielded positive results.…”

Section: Division Of Infectious Diseasesmentioning

confidence: 99%

“…2 In this setting, lenzilumab was shown to be effective in reducing chimeric antigen receptor T-cellemediated cytokine release syndrome and neuroinflammation at the same time, enhancing adoptive T cell therapy as well. 3 Previous preclinical data in SARS-CoVeinfected mice showed that inflammatory monocyte-macrophage response, secondary to dysregulated type-I interferon activity during SARS-CoV infection, results in lethal pneumonia and cytokine-induced apoptosis of T cells (specifically mediated by tumor necrosis factor alpha). 4 As already known, granulocytemonocyte colony-stimulating factor inhibition turned out to broadly modulate monocyte-macrophage activity by simultaneously reducing a spectrum of inflammatory cytokines, including tumor necrosis factor alpha.…”

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confidence: 99%

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In Reply — Clinical Benefit of Lenzilumab in Cases of Coronavirus Disease 2019

Temesgen

Kenderian

Badley

2021

Mayo Clinic Proceedings

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Advances in CAR T Therapy for Hematologic Malignancies

Freyer

Porter

2020

Pharmacotherapy

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The introduction of chimeric antigen receptor T‐cell (CAR T) therapy has resulted in a paradigm shift in the management of relapsed/refractory B‐cell malignancies. Patients with acute lymphoblastic leukemia and non‐Hodgkin’s lymphoma who had exhausted all meaningful treatment options now have an opportunity for long‐term remission and possibly cure. CAR T is rapidly expanding into the treatment paradigm for multiple myeloma with approvals expected in the near future. CAR T for chronic lymphocytic leukemia may not be far behind, while CAR T studies in Hodgkin lymphoma and acute myeloid leukemia are ongoing. Such therapeutic success brings challenges in toxicity management related to cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. Our understanding of these unique syndromes is evolving, with predictive models and additional treatment strategies on the horizon. This review aims to summarize the progress of CAR T therapeutics within malignant hematology thus far and highlight ongoing advances in the field.

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Improved Anti-Tumor Response of Chimeric Antigen Receptor T Cell (CART) Therapy after GM-CSF Inhibition Is Mechanistically Supported By a Novel Direct Interaction of GM-CSF with Activated Carts

Cited by 5 publications

References 0 publications

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia

In Reply — Clinical Benefit of Lenzilumab in Cases of Coronavirus Disease 2019

Advances in CAR T Therapy for Hematologic Malignancies

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