Current and emerging pharmacotherapies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis-like syndrome due to CAR T cell therapy

ABSTRACT

Introduction

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of multiple hematologic malignancies. Engineered cellular therapies now offer similar hope to transform the management of solid tumors and autoimmune diseases. However, toxicities can be serious and often require hospitalization.

Areas covered

We review the two chief toxicities of CAR T therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and the rarer immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. We discuss treatment paradigms and promising future pharmacologic strategies. Literature and therapies reviewed were identified by PubMed search, cited references therein, and review of registered trials.

Expert opinion

Management of CRS and ICANS has improved, aided by consensus definitions and guidelines that facilitate recognition and timely intervention. Further data will define optimal timing of tocilizumab and corticosteroids, current foundations of management. Pathophysiologic understanding has inspired off-label use of IL-1 receptor antagonism, IFNγ and IL-6 neutralizing antibodies, and janus kinase inhibitors, with data emerging from ongoing clinical trials. Further strategies to reduce toxicities include novel pharmacologic targets and safety features engineered into CAR T cells themselves. As these potentially curative therapies are used earlier in oncologic therapy and even in non-oncologic indications, effective accessible strategies to manage toxicities are critical.

KEYWORDS:

• Chimeric antigen receptor T cell
• CAR T
• CRS
• cytokine release syndrome
• ICANS
• management
• prevention
• immune effector cell-associated neurotoxicity syndrome

Article highlights

• First-line respective treatments for the two chief and potentially fatal toxicities of chimeric antigen receptor (CAR) T cell therapy – cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) – are tocilizumab, an IL-6 receptor-binding antibody currently first-line for CRS but ineffective for ICANS and often insufficient in more severe CRS cases, and corticosteroids, currently first-line for ICANS but limited by corticosteroid-refractory cases and the desire to spare corticosteroid exposure.

• IL-6 binding antibody (e.g. siltuximab) may have benefit in ICANS through its ability to prevent circulating IL-6 from crossing the blood-brain barrier and is being investigated in phase II study with interim results suggesting early treatment may reduce progression to high-grade CRS and ICANS (NCT04975555).

• IL-1 receptor antagonism (e.g. anakinra) is supported by the similarity of clinical parameters, cytokines, and chemokines in severe CRS/ICANS to those seen in hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and multiple recent interim phase II reports suggest efficacy of prophylactic or early anakinra in reducing incidence and severity of ICANS (NCT04148430, NCT04205838, NCT04150913) with additional phase II studies ongoing (NCT04359784, NCT04432506).

• Interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibodies (e.g. emapalumab and lenzilumab, respectively) may reduce macrophage and monocyte production of pathogenic inflammatory cytokines downstream of CAR T cell antigen-mediated activation, and a phase I trial of lenzilumab recently completed (NCT04314843).

• Inhibition of downstream janus kinases (JAKs) may be a means to effectively counter the plurality of pathogenic cytokines in CRS, ICANS, and IEC-HS, and preliminary analysis of a recent randomized placebo-controlled phase II trial of prophylactic itacitinib has demonstrated reduced incidence and severity of CRS and ICANS (NCT04071366).

• Additional strategies to dampen signaling downstream of CAR T antigen stimulation, including inhibition of other kinases (e.g. Bruton’s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), or dasatinib-sensitive kinases), or to engineer safety mechanisms into CAR T cells themselves (including capacity for switch-like control by small-molecules) are also being explored, with cytoreducing agents (e.g. chemotherapy) remaining an option to eliminate or drastically reduce the number of CAR-T cells in refractory severe toxicities.

Declaration of interest

M V Maus is an inventor on patents related to adaptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab) and University of Pennsylvania (some licensed to Novartis). They also receive Grant/Research support from: Kite Pharma, Moderna. M V Maus has served as a consultant for multiple companies involved in cell therapies. They also hold Equity in 2SeventyBio, A2Bio, Cargo, Century Therapeutics, Neximmune, Oncternal, and TCR2. Additionally, they are on the Board of Directors at 2Seventy Bio. Finally, M V Maus has been or is a Consultant for: A2Bio, Adaptimmune, Agenus/Mink Therapeutics, Allogene, Arcellx, Astellas, AstraZeneca, Atara, Bayer, BendBio, BMS, Cabaletta Bio (SAB), Cargo, Cellectis (SAB), CRISPR therapeutics, In8bio (SAB), Intellia, GSK, Kite Pharma, Neximmune, Novartis, Oncternal, Sanofi, Sobi, Synthekine, TCR2 (SAB), and Tmunity

M J Frigault received consulting honoraria from BMS, Kite/Gilead, Novartis, JnJ/Legend, Iovance, SOBI, Incyte.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by a grant to Z E Walton (NIH T32AR007258).