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BACKGROUNDAxicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B cell lymphomas in the ZUMA-5 trial.METHODSHere, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 patients with follicular lymphoma (FL).RESULTSIn univariate and multivariate analyses, pretreatment inflammatory markers, including TNF-α and IL-12p40, as well as total metabolic tumor volume (TMTV), associated with disease progression. Conversely, T-naive-like product phenotype associated with improved outcome, particularly in patients with high TMTV. These covariates improved risk stratification when combined with the FL International Prognostic Index. Postinfusion, CAR T cell expansion associated with improved outcome, while serum inflammatory and immunomodulatory markers, including TNF-α, associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or posttreatment CD19 expression on tumor was not associated with outcome.CONCLUSIONThese findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches.TRIAL REGISTRATIONClinicalTrials.gov NCT03105336.FUNDINGKite, a Gilead Company.

TRIAL REGISTRATION. ClinicalTrials.gov NCT03105336.

BACKGROUND. Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent В cell lymphomas in the ZUMA-5 trial. METHODS. Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 patients with follicular lymphoma (FL). RESULTS. In univariate and multivariate analyses, pretreatment inflammatory markers, including TNF-2 and IL-12p40, as well as total metabolic tumor volume (TMTV), associated with disease progression. Conversely, T-naive-like product phenotype associated with improved outcome, particularly in patients with high TMTV. These covariates improved risk stratification when combined with the FL Intemational Prognostic Index. Postinfusion, CAR T cell expansion associated with improved outcome, while serum inflammatory and immunomodulatory markers, including TNF-0, associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type | and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or posttreatment CD19 expression on tumor was not associated with outcome. CONCLUSION. These findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches.

Chimeric antigen receptors (CARs) are engineered to target T cells specifically to tumor cells, resulting in the engineered T cell killing the tumor cell. This technology has been developed to target a range of cancers, with the most notable successes in the treatment of B-cell malignancies where four approved therapies, all targeting CD19, are on the market. These four products differ in the costimulation domains, with axicabtagene ciloleucel (Yescarta) and brexucabtagene autoleucel (Tecartus) both utilizing the CD28 costimulation domain whilst tisagenlecleucel (Kymriah) and lisocabtagene maraleucel (Breyanzi) both utilizing the 4-1BB costimulation domain. There are clearly defined differences in how the CD28 and 4-1BB domains signal, yet it is difficult to ascertain which domain affords a superior mechanism of action given many other differences between these products, including overall CAR architecture and manufacturing methods. Additionally, while in vitro and preclinical in vivo studies have compared CARs with different costimulation domains, it remains a challenge to extrapolate differences observed in this biology across different experimental systems to the overall product performance. While there has been extensive preclinical and clinical work looking at CARs with a variety of targeting domains and architectures, this review will focus on the differences between the four marketed anti-CD19 CAR-Ts, with an additional focus on the impact of hinge and transmembrane domain on CAR activity and interaction with the target cell as well as other proteins on the surface of the T-cell.

The IκB Kinase (IKK)-related kinases TBK1 and IKKɛ have essential roles as regulators of innate immunity by modulating interferon and NF-κB signaling. Recent work has also implicated these non-canonical IKKs in malignant transformation. IKKɛ is amplified in ∼30% of breast cancers and transforms cells through the activation of NF-κB. TBK1 participates in RalB-mediated inflammatory responses and cell survival, and is essential for the survival of non-small cell lung cancers driven by oncogenic KRAS . The delineation of target substrates and downstream activities for TBK1 and IKKɛ has begun to define their role(s) in promoting tumorigenesis. In this review, we will highlight the mechanisms by which IKKɛ and TBK1 orchestrate pathways involved in inflammation and cancer.

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al.Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel–related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable.

Aberrant nuclear factor (NF)-κB activation is frequently observed in human cancers. Genome characterization efforts have identified genetic alterations in multiple components of the NF-κB pathway, some of which have been shown to be essential for cancer initiation and tumor maintenance. Here, using patient tumors and cancer cell lines, we identify the NF-κB regulator, TRAF2 (tumor necrosis factor (TNF) receptor-associated factor 2), as an oncogene that is recurrently amplified and rearranged in 15% of human epithelial cancers. Suppression of TRAF2 in cancer cells harboring TRAF2 copy number gain inhibits proliferation, NF-κB activation, anchorage-independent growth and tumorigenesis. Cancer cells that are dependent on TRAF2 also require NF-κB for survival. The phosphorylation of TRAF2 at serine 11 is essential for the survival of cancer cells harboring TRAF2 amplification. Together, these observations identify TRAF2 as a frequently amplified oncogene.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel ( P  = 0.0002 for B cell GES; P  = 0.0165 for CD19 expression) but not SOC ( P  = 0.9374 for B cell GES; P  = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression ( P  = 8.56 × 10 –9 for B cell GES high; P  = 0.0019 for B cell GES low; P  = 3.85 × 10 –9 for CD19 gene high; P  = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel. Analysis of the pivotal phase 3 ZUMA-7 trial identifies tumor gene expression signatures that are uniquely predictive of anti-CD19 CAR T cell response and event-free survival in second-line treatment for patients with relapsed or refractory large B cell lymphoma.

Background and Objective Axicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin’s lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin’s lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure. Methods A population cellular kinetic model (NONMEM ® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 10 6 anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin’s lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types. Results Axi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration–time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids. Conclusions No covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose–exposure relationship. Clinical Trial Registration NCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).

BackgroundWe aimed to develop an actionable and feasible prospective clinical model to estimate toxicity risk to assist chimeric antigen receptor (CAR) T-cell therapy providers with the management of patients with relapsed and/or refractory large B-cell lymphoma.MethodsWe conducted an observational, retrospective cohort study using secondary data from 390 patients treated with the CD19 CAR T-cell therapy axicabtagene ciloleucel under two prospective clinical trials, ZUMA-1 and ZUMA-7; these clinical trials enrolled patients with relapsed/refractory large B-cell lymphoma between 2015 and 2019. Using machine learning and statistical methods, we developed a classification model for identifying patients unlikely to experience early cytokine release syndrome (CRS) and neurological events (NE) of any grade.ResultsWe found the use of prophylactic corticosteroids to be an important factor in remaining CRS-free and NE-free within the first 3 days post-treatment (p<0.001). We identified a top model for no early CRS/NE using a set of six pre-lymphodepletion clinicopathologic features: number of lines of prior systemic therapy, age, baseline tumor burden (as measured by sum of the product of the diameters), C-reactive protein, aspartate transaminase, and hemoglobin, which achieves a positive predictive value of 0.71 in the holdout validation cohort. Additionally, we find that predicted probabilities generated from the model are strongly associated with incidence of Grade 2 or higher NE.ConclusionsWe illustrated that routine clinicopathologic variables can be used to identify patients at low risk of developing early post-treatment CRS and/or NE. Such knowledge can be used to help treating centers prospectively manage patient care, including consideration of outpatient treatment.