Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia DOI Creative Commons
Tommaso Balestra, Lisa M Niswander, Asen Bagashev

et al.

Leukemia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) induce constitutive kinase signaling targetable by the JAK1/2 inhibitor ruxolitinib under current clinical investigation. While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates children with relapsed/refractory B-ALL, ~50% CD19CART-treated patients relapse again, many CD19 loss. We previously reported preclinical activity thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against -overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART would superior first validated potent TSLPRCART-induced inhibition proliferation vitro CRLF2- rearranged lines vivo DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished proliferation, blunted cytokine production, and/or facilitated relapse, which was abrogated time-sequenced/delayed co-exposure. Importantly, co-administration prevented fatal cytokine-associated toxicity PDX mice. Upon withdrawal, functionality recovered clearance subsequent rechallenge. These translational studies demonstrate effective two-pronged therapeutic strategy mitigates acute CART-induced hyperinflammation provides potential anti-leukemia ‘maintenance’ prevention for -rearranged DS-ALL.

Language: Английский

Novel strategies to manage CAR-T cell toxicity DOI

Arthur Mulvey,

Lionel Trueb,

George Coukos

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Language: Английский

Citations

3
Mechanisms and management of CAR T toxicity DOI Creative Commons
Christopher Ferreri, Manisha Bhutani

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: May 21, 2024

Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large lymphoma, follicular mantle and multiple myeloma. Despite unprecedented efficacy, CAR can cause a multitude of adverse effects which require monitoring management at specialized centers contribute to morbidity non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity distinct from ICANS, hemophagocytic lymphohistiocytosis-like hematotoxicity that lead prolonged cytopenias infectious complications. This review will discuss the current understanding underlying pathophysiologic mechanisms provide guidelines grading such toxicities.

Language: Английский

Citations

13
Riding the storm: managing cytokine-related toxicities in CAR-T cell therapy DOI Creative Commons
Andrew D Hughes, David T. Teachey, Caroline Diorio

et al.

Seminars in Immunopathology, Journal Year: 2024, Volume and Issue: 46(3-4)

Published: July 16, 2024

Abstract The advent of chimeric antigen receptor T cells (CAR-T) has been a paradigm shift in cancer immunotherapeutics, with remarkable outcomes reported for growing catalog malignancies. While CAR-T are highly effective multiple diseases, salvaging patients who were considered incurable, they have unique toxicities which can be life-threatening. Understanding the biology and risk factors these led to targeted treatment approaches mitigate them successfully. three particular interest cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), hemophagocytic lymphohistiocytosis (HLH)-like (IEC-HS). Each is characterized by storm hyperinflammation; however, differ mechanistically regard cytokines that drive pathophysiology. We summarize current state field CAR-T-associated toxicities, focusing on underlying how this informs toxicity management prevention. also highlight several emerging agents showing promise preclinical models clinic. Many established do not appear impact anti-tumor function CAR-T, opening door additional wider applications.

Language: Английский

Citations

10
Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review DOI
Arthur Géraud, Thomas Hueso, Ariane Laparra

et al.

European Journal of Cancer, Journal Year: 2024, Volume and Issue: 205, P. 114075 - 114075

Published: May 4, 2024

Language: Английский

Citations

9
Weal and woe of interleukin-18 in the T cell therapy of cancer DOI Creative Commons
Christoph Kessel, Claudia Rössig, Hinrich Abken

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(1), P. e010545 - e010545

Published: Jan. 1, 2025

Chimeric antigen receptor (CAR) T cell therapy of solid cancer remains below expectations; adding cytokine help through IL-18 has shown remarkable efficacy in first clinical trials. As is also a powerful driver hyperinflammatory conditions, we discuss to what extent unleashing double-edged sword CAR therapies.

Language: Английский

Citations

1
CAR T-cell toxicities: from bedside to bench, how novel toxicities inform laboratory investigations DOI Open Access
Fabiana Perna, Samir Parekh, Caroline Diorio

et al.

Blood Advances, Journal Year: 2024, Volume and Issue: 8(16), P. 4348 - 4358

Published: June 11, 2024

Language: Английский

Citations

4
Immune Effector Cell-associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) DOI Creative Commons
Jerry C. Lee, W. Thomas Johnson, Melissa Hines

et al.

Hematology/Oncology Clinics of North America, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a complication of adoptive cell therapy. Presenting with clinical manifestations hyperinflammation and surrogate indicators such as elevations in serum ferritin hepatic transaminases, decreasing counts, hypofibrinogenemia, IEC-HS resembles primary other forms secondary lymphohistiocytosis. Nonetheless, this an iatrogenic resulting from the induction hyperinflammatory pathways during T-cell-mediated anticancer targeting. Distinct cytokine release syndrome, IEC-associated neurotoxicity hematotoxicity, can be life-threatening. Identification IEC-HS, optimization treatment strategies, use supportive care are critical to improving outcomes.

Language: Английский

Citations

0
Emapalumab for severe cytokine release syndrome in solid tumor CAR-T: a case report DOI Creative Commons

Tyler Ruemmele,

Rodney Macedo, Mark N. Stein

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: April 1, 2025

Chimeric Antigen Receptor T (CAR-T) cell therapy significantly and rapidly changed the treatment paradigm for lymphoma, myeloma leukemia, recent approvals of first cellular immunotherapies in melanoma synovial sarcoma demonstrate potential success this approach solid tumors. Though therapeutic CAR-T is impressive, severe cytokine release syndrome (CRS) remains an ongoing challenge. Here we report a patient who received investigational product metastatic castration-resistant prostate cancer developed multi-drug refractory, life-threatening CRS, which was successfully treated with interferon (IFN)-γ antagonist emapalumab. Within 12 hours after dose emapalumab, there dramatic improvement hemodynamic status weaned off all four vasopressors. The associated decrease IFN-γ CXCL10 levels but no other cytokines. Not only emapalumab drug effective at treating case refractory it did not appear to reduce activity product, as vector copy numbers remained persistent patient's PSA low. This demonstrates clinical use treat tumor while potentially preserving efficacy therapy. Further studies larger populations are needed evaluate CRS.

Language: Английский

Citations

0
Case Report: Successful use of emapalumab in adult B-cell acute lymphoblastic leukemia experiencing severe neurotoxicity and hemophagocytic lymphohistiocytosis-like features after CAR-T cell therapy DOI Creative Commons
Beatrice Manghisi,

Giulia Cotilli,

Marilena Fedele

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 4, 2025

Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) are increasingly recognized. Immune HLH-like (IEC-HS) describes symptoms attributable to therapy, often presenting as CRS resolves. Treatments for IEC-HS adapted from primary HLH, corticosteroids, the recombinant human interleukin (IL)-1 antagonist anakinra Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, promising but underexplored in adult cases. We report B-cell acute lymphoblastic leukemia (B-ALL) patient treated brexucabtagene autoleucel (brexu-cel). The developed CRS, refractory neurotoxicity, worsening multiorgan failure markers. Treatment included tocilizumab, high-dose anakinra, siltuximab, Despite aggressive management, hyperinflammation persisted. Emapalumab was initiated on day +11, resulting normalization of biochemical parameters full neurological recovery by +21. recovered underwent allogeneic stem transplantation. This case highlights role emapalumab managing persistent adults, underscoring need targeted interventions severe complications.

Language: Английский

Citations

0
INSPIRED Symposium Part 3: Prevention and Management of Pediatric Chimeric Antigen Receptor T Cell-Associated Emergent Toxicities DOI Creative Commons
Kevin O. McNerney, Emily M. Hsieh, Haneen Shalabi

et al.

Transplantation and Cellular Therapy, Journal Year: 2023, Volume and Issue: 30(1), P. 38 - 55

Published: Oct. 10, 2023

Language: Английский

Citations

9