Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and Tisagenlecleucel are the first in class anti-CD19 CART cells currently available for relapsed-refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25) patients with relapsed-refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR T-cell associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated CART cell therapy. They can lead to significant morbidity and preclude widespread use of this treatment modality. Treatment related deaths from severe CRS and cerebral edema have been reported. There is a significant heterogeneity in the side-effect profile of different CART cell products under investigation and there is a need to develop standardized guidelines for toxicity grading and management. Here, we summarize the current literature on pathogenesis, clinical presentation, and management of CRS and neurotoxicity. The different grading systems of CRS and management protocols used in different trials have made it difficult to compare the outcomes of different CART cell therapies. Several prevention strategies such as predictive biomarkers of CRS and neurotoxicity and modified CART cells with 'built-in' safety mechanisms are being studied, which has the potential to greatly expand the safety and applicability of CART cell treatment across various malignancies.

SARS-CoV-2 infection: The role of cytokines in COVID-19 disease

“…Cytokine Target Clinical effect Reference Tocilizumab IL-6 Block Il-6 receptor, and revert the cytokine storm production Luo et al [84] Xu et al [95] Dholaria et al [96] Zhang et al [ [44]. SARS-CoV-2 appears to act on the activation and maturation of IL-1β, which in turn activates other proinflammatory cytokines, such as IL-6 and TNF-α [45][46][47].…”

“…The cytokine storm, including elevated levels of IL-6, has also been associated with cardiac damage in these patients [94]. With regard to the important role of IL-6 in the SARS-CoV-2-induced cytokine storm and its evasion, it has been reported that the monoclonal antibody tocilizumab acts by blocking the receptor of IL-6 and has been reported to reverse cytokine hyperproduction [84,[95][96][97], inflammation, and pulmonary fibrosis [98,99]. In fact, a multicenter clinical trial is under way in China on the usefulness of tocilizumab to treat patients with COVID-19 (NCT04252664 & NCT04257656), and it has already been included in clinical practice guidelines in China and Italy [100,101].…”

Weathering the Cytokine Storm in COVID-19: Therapeutic Implications

“…Anti-IL-6 agents are a class of drugs with anti-inflammatory properties that act by targeting either the IL6 receptor or IL-6 itself. Studies have shown that tocilizumab, an IL-6 receptor antibody, could reverse CRS in the setting of chimeric antigen receptor T-cell therapy for cancer [36]. Because of the greatly elevated serum levels of IL-6 in patients with COVID-19 [3], its off-label used in the early stage of the diseases suggests a favorable impact on the course of COVID-19 [37].…”

Response to CAR T cell therapy can be explained by ecological cell dynamics and stochastic extinction events

“…CAR T cell therapy can cause severe cytokine release syndrome (CRS), or a characteristic immune cell-associated neurologic syndrome (ICANS). Both are associated with significant morbidity and mortality [36][37][38] , and are characterized by high levels of inflammatory cytokines and, to a lesser extent, by high numbers of CAR T cells in the blood 6 . Both forms of toxicity occur in predictable distributions across patient populations 39 .…”