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

Basic Concepts and Indications of CAR T Cells DOI
J. Berg, Heinz Laübli, Nina Khanna

et al.

Hämostaseologie, Journal Year: 2025, Volume and Issue: 45(01), P. 014 - 023

Published: Feb. 1, 2025

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer immunotherapy, particularly for hematological malignancies. This personalized approach is based on genetically engineering cells derived from the patient to target antigens expressed—among others—on malignant cells. Nowadays they offer new hope where conventional therapies, such as chemotherapy and radiation, have often failed. Since first FDA approval in 2017, CAR rapidly expanded, proving highly effective against previously refractory diseases with otherwise a dismal outcome. Despite its promise, continues face significant challenges, including complex manufacturing, management of toxicities, resistance mechanisms that impact long-term efficacy, limited access well high costs, which continue shape ongoing research clinical applications. review aims provide an overview therapy, fundamental concepts, applications, current future directions

Language: Английский

Citations

1
Evolving strategies for addressing CAR T-cell toxicities DOI Creative Commons
Alexander W. Rankin, Brynn B. Duncan, Cecily Allen

et al.

Cancer and Metastasis Reviews, Journal Year: 2024, Volume and Issue: 44(1)

Published: Dec. 15, 2024

Abstract The field of chimeric antigen receptor (CAR) T-cell therapy has grown from a fully experimental concept to now boasting multitude treatments including six FDA-approved products targeting various hematologic malignancies. Yet, along with their efficacy, these therapies come side effects requiring timely and thoughtful interventions. In this review, we discuss the most common toxicities associated CAR T-cells date, highlighting risk factors, prognostication, implications for critical care management, patient experience optimization, ongoing work in toxicity mitigation. Understanding current state standards practice is order improve manage potential both novel as they are applied clinic.

Language: Английский

Citations

1
Hemophagocytic lymphohistiocytosis post chimeric antigen receptor T cell therapies DOI
Jingming Wang, Huiwen Jiang, Yinqiang Zhang

et al.

Expert Review of Clinical Immunology, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 13

Published: Dec. 27, 2024

Besides cytokine release syndromes (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), HLH-like (IEC-HS) is increasingly recognized across CAR-T recipients. This emergent fatal difficult to separate from other disorders during the early phase, urgently requires more integrated diagnostic therapeutic frameworks.

Language: Английский

Citations

1
INSPIRED Symposium Part 4B: Chimeric Antigen Receptor T Cell Correlative Studies—Established Findings and Future Priorities DOI Creative Commons
John A. Ligon, Sneha Ramakrishna, Francesco Ceppi

et al.

Transplantation and Cellular Therapy, Journal Year: 2023, Volume and Issue: 30(2), P. 155 - 170

Published: Oct. 18, 2023

Language: Английский

Citations

2
Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy DOI Open Access

CADTH

Canadian Journal of Health Technologies, Journal Year: 2024, Volume and Issue: 4(5)

Published: May 2, 2024

What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) therapy. The US FDA Health Canada approved tocilizumab, an anti-interleukin-6 antagonist, for management of severe life-threatening cases CRS. Corticosteroids also play important role in CRS mainstay ICANS management. Decision-makers interested understanding use anticytokine drugs (i.e., anakinra, siltuximab) and/or corticosteroids following CAR Did We Do? identified summarized literature comparing clinical effectiveness safety therapy with alternative care treatment as usual treating preventing ICANS. searched evidence-based recommendations treat prevent A research information specialist conducted a search peer-reviewed grey sources published between January 1, 2019 February 26, 2024 CRS; March 4, One reviewer screened citations inclusion based on predefined criteria, critically appraised included studies, narratively findings. Find? This report presents findings 3 retrospective chart review 2 prospective cohort 4 consensus guidelines. Limited low-quality evidence from studies high risk bias suggested that early tocilizumab corticosteroids, prophylactic anakinra may reduce high-grade without negative impact immunotherapy outcomes. guidelines recommend higher-grade CRS, grade 1 if symptoms persist days more. could be added conjunction there is no improvement persistent after For absence concurrent supportive preferred option ICANS, while recommended In presence per should continued until 1. did not identify any regarding efficacy compared usual. therapy, both prevention Does Mean? Despite limited evidence, suggest some potential benefits immunotherapy-related toxicities. Guidelines offer guidance other less related available evidence. When using this inform decisions, decision-makers consider low quality. To improve certainty findings, need more robust trials larger sample sizes, lower bias.

Language: Английский

Citations

0
Secondary hypogammaglobulinemia: diagnosis and management of a pediatric condition of clinical importance DOI
Daniel DiGiacomo, Sara Barmettler

Current Opinion in Pediatrics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Purpose of review Secondary hypogammaglobulinemia, or low serum immunoglobulins, is associated with a variety medications medical conditions and may be symptomatic lead to increased infectious risk. There limited data regarding the study acquired, secondary, hypogammaglobulinemia (SHG) in pediatrics. The date has suffered from methodologic issues including retrospective design, lack baseline immunoglobulin measurements, longitudinal follow-up. Recent findings emerging research on impact B-cell depleting therapies, specifically rituximab chimeric antigen T-cells, along other autoimmune malignant disease states, development SHG pediatric patients. This will also summarize relevant related SHG. Summary clinical relevance pediatrics increasingly appreciated. Improved understanding specific etiologies, risk factors, natural history have informed screening management recommendations.

Language: Английский

Citations

0
Immunotherapy-Related Neurotoxicity in the Central Nervous System of Children with Cancer DOI
Jiasen He, Jeremy Connors,

Andrew Meador

et al.

Neuro-Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 13, 2024

Abstract Significant gaps remain in our understanding of immunotherapy-related neurotoxicity pediatric patients, largely because much knowledge comes from studies adults. Accurately identifying the adverse effects immunotherapy children is also challenging, owing to variations terminology and grading systems. Moreover, manifestation differs greatly across different diseases, various modalities, dosages, delivery methods. Combining with other treatments might improve outcomes but introduces new complexities potential for increased toxicities. Additionally, patients intracranial malignancy have unique responses immunotherapies distinct compared those extracranial malignancy. Consequently, we must enhance pathophysiology, prevalence, severity, management immunotherapy’s neurotoxic this vulnerable group. This review consolidates current oncology, highlighting types including cytokine release syndrome (CRS), immune effector cell-associated (ICANS), tumor inflammation-associated (TIAN), among others. Furthermore, examine features associated adoptive cellular therapy (ACT), antibody-based therapies, checkpoint inhibitors (ICIs), oncolytic viruses (OV), cancer vaccines.

Language: Английский

Citations

0
CAR-T Cells for the Treatment of Central Nervous System Tumours: Known and Emerging Neurotoxicities DOI Creative Commons
Leonardo Palazzo, Valentina Pieri, Giulia Berzero

et al.

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(12), P. 1220 - 1220

Published: Nov. 30, 2024

The advent of chimeric antigen receptor (CAR)-T cells has recently changed the prognosis relapsing/refractory diffuse large B-cell lymphomas, showing response rates as high 60 to 80%. Common toxicities reported in pivotal clinical trials include cytokine release syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a stereotyped encephalopathy related myeloid cell activation blood-brain barrier dysfunction, presenting with distinctive cascade dysgraphia, aphasia, disorientation, attention deficits, vigilance impairment, motor symptoms, seizures, brain oedema. tremendous oncological efficacy CAR-T observed systemic malignancies is leading their growing use patients primary or secondary central nervous system (CNS) lymphomas solid tumours, including several CNS cancers. Early studies conducted adult paediatric tumours distinct profile neurotoxicity referred Tumour inflammation-associated (TIAN), corresponding local inflammation at tumour site manifesting focal neurological deficits mechanical complications (e.g., obstructive hydrocephalus). present review summarises available data on safety for haematological malignancies, emphasising known emerging phenotypes, ongoing challenges, future perspectives.

Language: Английский

Citations

0
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

Citations

0