CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities

Abstract

Engineered T cell therapies such as chimeric antigen receptor (CAR) expressing T cells (CAR-T cells) have great potential to treat many human diseases; however, inflammatory toxicities associated with these therapies present safety risks and can greatly limit its widespread use. This article briefly reviews our current understanding of mechanisms for inflammatory toxicities during CAR T-cell therapy, current strategies for management and mitigation of these risks and highlights key areas of knowledge gap for future research.

Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice

“…These potentially life-threatening responses are associated, respectively, with targeted cell lysis and related electrolyte imbalance. Myeloid cells exposed to CAR-T treatment rapidly release inflammatory mediators, proteins, and cytokines such as GM-CSF, C-reactive protein, IL-6, and IL-1b [ 38 , 39 ]. A series of organ-specific adverse reactions can be exacerbated by CRS, for example, hyperthermia, myalgia, abdominal pain, dyspnea, hypotension, arrhythmia, erythema, pruritus, renal failure, and granulocytopenia.…”

“…Our experience with vaccines to prevent SARS-CoV-2 infection at an international level shows that they have a highly favorable safety profile, with some rare fatal events, considering the vast number of people vaccinated worldwide in the post-marketing setting. It must be highlighted that the biopharmaceutical technology that led, in a very short time, to the development of COVID vaccines (i.e., mRNA vaccines) comes from cancer immunotherapy research [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Commonly detected toxic responses following cancer vaccine administration include myalgia, cough, chills, fever, pain at the injection site, asthenia, flu-like syndrome, and respiratory abnormalities [ 20 ,…”

T-cell Redirecting Therapies for the Treatment of B-cell Lymphomas: Recent Advances

“…The main early toxicities relative to CAR T-cells treatment are inflammatory toxicities, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), and cytopenias [7,8]. Following infusion, CAR T-cells recognize the target that activates them and induces the secretion of various inflammatory factors (GM-CSF, IL-6, IL-1b, C-reactive Protein [7,8]. CRS of grade ≥ 3 was observed in 11% of patients with Yescarta ® and 23% with Kymriah ® .…”

“…Grade ≥ 3 ICANS was present in 32% and 12% of each respective treatment [4,5] (Table 2). The management of these toxicities depends on the intensity of the symptoms and consists of anti-inflammatory and symptomatic treatments [7]. Currently, tocilizumab, an IL-6 receptor antagonist, is the only FDA-approved therapy for CRS treatment.…”

“…Corticosteroids are also prescribed in cases where tocilizumab is insufficient to contain symptoms of severe CRS. Furthermore, other anti-inflammatory molecules have been studied, such as siltuximab, an IL-6 antagonist, or anakinra, an antibody-based IL-1 receptor (IL-1R) antagonist that can cross the blood-brain barrier (BBB) [7,8]. The occurrence of ICANS may be simultaneous with or independent of CRS.…”