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Introduction One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells leading to adverse events. These are classified as cytokine release syndrome (CRS) and CAR T Related Encephalopathy Syndrome (CRES). Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R) DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients with R/R DLBCL treated with commercial axi-cel were included in this study. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B-ALL who were treated with 19-28z CAR T cells. We observed several cytokines which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected, including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2 (ANG1/ANG2). We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. CRS and CRES were prospectively graded using revised Lee criteria and the CARTOX group respectively. Results A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years (range 43-73). Grades 1-3 CRS were observed in 45%, 40% and 5% of patients respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) and r=0.53 (p=0.033) respectively (Fig. 1b). Patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grades 1-2 CRES. There were no significant correlations between serum cytokine levels and CRES. Conclusion In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and ANG2/ANG1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. In select cases, monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP (Fig.1c). We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events.

Background A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokineś analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. Results 41 patients were identified. Median age was 64 years old (76% male). Non-severe (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that wasnt evident from standard biomarkers. Conclusions We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically.