Overcoming the Challenge of Cytokine Release Syndrome in CAR T-Cell Therapy

Cytokine Release Syndrome, CAR-T Therapy: Cytokine Release Syndrome, CAR-T TherapyAlthough chimeric antigen receptor (CAR) T-cell therapies have led to lasting remissions in cancer patients who had no other treatment options and a select few have even earned regulatory approval, concerns about safety remain. Currently, two CAR T-cell therapies, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are in clinical use for patients with relapsed or refractory large B-cell lymphoma and one product, brexucabtagene autoleucel, was approved in July 2020 for relapsed or refractory mantle cell lymphoma. However, Rawan Faramand, MD, in the Department of Blood and Marrow Transplantation and Cellular Immunotherapy at the H. Lee Moffitt Cancer Center and Research Institute, explained to Oncology Times that the “widespread” use of these therapies is “limited” by toxicities such as cytokine release syndrome (CRS) and/or neurotoxicity, which are still observed despite treatment with corticosteroids and interleukin 6 (IL-6) antagonists. For example, in the pivotal ZUMA-1 trial for axi-cel, one in 10 patients developed grade 3 or worse CRS and three in 10 developed grade 3 or worse neurotoxicity (Lancet Oncol 2019;20:31-42). Similarly, in the pivotal JULIET trial for tisa-cel, two of 10 patients developed grade 3 or 4 CRS and one of 10 developed grade 3 or 4 neurotoxicity (N Engl J Med 2019;380:45-56). Even if successful, treatment of CRS with corticosteroids, which may be indicated if tocilizumab or other IL-6 inhibitors fail, may compromise the effectiveness of CAR T-cell therapy because corticosteroids impair the function of the very cells needed for CAR T-cell therapy to work: T cells (Nat Rev Clin Oncol 2018;15:47-62). And according to Wei and colleagues, “proper recognition and management of CRS may not only alleviate toxicity but also improve the likelihood of therapeutic benefit” (Signal Transduct Target Ther 2020;5:134). Overcoming the Challenge A recent retrospective study in Clinical Cancer Research indicates that looking at patient and tumor characteristics before CAR T-cell administration may help clinicians identify patients who are at risk of developing CRS (2020;26:4823-4831). “We believe that earlier identification of patients who are high risk of developing toxicities will allow us to design risk-adapted clinical trials to mitigate these toxicities,” explained Faramand, co-primary author of the study. “Furthermore, earlier identification of patients at low risk of toxicities would allow for some patients to be treated in the outpatient setting. “Since patients who are eligible for CAR T-cell therapy have relapsed/refractory disease with limited treatment options,” she continued, “they would still benefit from therapy, but we would encourage enrollment of these patients in clinical trials.” Study Details The study by Faramand and colleagues comprised 75 patients with large B-cell lymphoma who received commercial axi-cel at H. Lee Moffitt Cancer Center. Of the cohort, 70 patients had relapsed or refractory disease after two lines of systemic therapy, making them eligible for receipt of commercial axi-cel, which was approved in October 2017 for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. The remaining five patients received axi-cel through an expanded access treatment protocol (NCT03153462). Before receipt of lymphodepleting chemotherapy, patients had their serum cytokine and catecholamine levels measured and tumors biopsied. Serum cytokine and catecholamine levels were measured again on the day of CAR T-cell therapy administration and every day following until patients were discharged from the hospital. In all, 48 patients (64%) needed bridging therapy, with chemotherapy being the most common bridging therapy received (26 patients). Other bridging therapies included radiation with or without chemotherapy (10 patients) and high-dose steroids alone (11 patients). Among the 75 patients, 72 (96%) developed some degree of CRS and 12 (16%) had grade 3 or worse CRS, which included three patients (4%) who died from CRS. Neurotoxicity was also common, with 50 patients (67%) having neurotoxicity of any grade and 23 (31%) grade 3 or worse. Tocilizumab was given to 43 patients (57%) and steroids to 41 patients (55%) to manage toxicities. In all, 29 patients had a complete response and seven had a partial response at 90 days after CAR T-cell administration, which translated to a 53 percent response rate. By comparison, a long-term analysis of the pivotal ZUMA-1 trial showed an 83 percent response rate for axi-cel and a similar frequency of grade 3 or worse CRS and neurotoxicity (Lancet Oncol 2019;20:31-42). Nearly half of the patients in the current study, however, would have been ineligible for the ZUMA-1 trial, as they had comorbidities, suggesting that these patients are more representative of the real-world population. The patients in the current study were also permitted to have bridging chemotherapy, which was not allowed in ZUMA-1. Characteristics Identified A multivariate analysis revealed that IL-6 was the only characteristic before CAR T-cell therapy that was significantly correlated with development of severe CRS (P=0.03898). No other characteristics, including age, Eastern Cooperative Oncology Group status, or stage, were linked to development of severe CRS. Higher peak levels of noradrenaline were linked to development of grade 3 or higher CRS (P=0.0234) in a univariate analysis. Also, elevated levels of the catecholamine noradrenaline were seen in patients with more severe CRS. Preclinical evidence suggests that T-cell–activated macrophages release high levels of catecholamines, which in turn promote an inflammatory response (Nature 2018;564:273-7). Gene expression analysis of tumor samples taken before CAR T-cell therapy also showed an association between development of severe neurotoxicity and lower T-cell type score (P<0.001) and higher macrophage score (P<0.01). A Closer Look A closer evaluation of the patients with elevated levels of IL-6 revealed that these patients had especially aggressive disease, given that all had stage III/IV disease and needed bridging chemotherapy. Also, 89 percent of patients with IL-6 levels of 40 pg/mL or greater died within 90 days of receiving CAR T-cell therapy and more than half developed grade 3 or higher CRS. In fact, only one patient with IL-6 levels of 40 pg/mL or greater was alive at data cutoff, which the study researchers attributed, at least in part, to “early and aggressive” management of CRS. Specifically, the patient had grade 2 CRS the day after CAR T-cell infusion and developed resistance after treatment with tocilizumab and one dose of dexamethasone. Even though high-dose methylprednisolone is indicated only for grade 4 CRS, per institutional and the CAR T-cell therapy-associated TOXicity working group guidelines, the patient received the drug because he had high-risk features of toxicity, such as bulky disease. CRS eventually resolved and the patient achieved a partial response, as shown by day 30 scans. The patient with elevated IL-6 levels whose CRS was successfully managed also showcased the potential of using real-time cytokine monitoring to better manage toxicities. Faramand explained that the assay used to analyze IL-6 levels has a turnaround time of less than 2 hours, making the results available to the providers in “real time.” “We found that real-time cytokine monitoring may help guide the management of patients with severe toxicities,” Faramand noted. “These observations will need to be validated in larger studies.” Christina Bennett is a contributing writer.