scholarly journals Infection complications in febrile chimeric antigen receptor (CAR)‐T recipients during the peri‐CAR‐T cell treatment period examined using metagenomic next‐generation sequencing (mNGS)

2022 ◽  
Author(s):  
Jiali Nie ◽  
Li Yang ◽  
Liang Huang ◽  
Lili Gao ◽  
Ken He Young ◽  
...  
Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2842-2842
Author(s):  
Yue Huang ◽  
Houli Zhao ◽  
Mi Shao ◽  
Linghui Zhou ◽  
Guoqing Wei ◽  
...  

Abstract Background Minimal residual disease (MRD) is closely associated with risk stratification of hematological malignancies. Monitoring the MRD levels of patients during treatment and at time points after remission is critical for prevention of relapse. Chimeric antigen receptor T (CAR-T) cell therapy redirects genetically modified immune cells to fight against hematologic malignancies. However, given the high relapse rate after CAR-T cell therapy, MRD monitoring by traditional techniques cannot accurately quantify the disease burden, nor can they perform high-sensitivity in-depth monitoring. Further treatment options are still controversial at such a time point when the flow cytometry (FC) results show MRD < 0.01%, while tumor clones remain. Next-generation sequencing (NGS) - MRD screens out patient-specific T/B cell receptors and accurately and quantitatively monitor patient-specific tumor cells (up to 10E-6) to reveal accurate and highly sensitive MRD levels, plus provide more timely intervention criteria. Method Between June 2016 and June 2020, we retrospectively enrolled 27 patients who achieved complete remission at the first 4-week evaluation after CAR-T cell therapy. BM samples were harvested and stored before CAR-T cell infusion and 10-154 days after infusion. We evaluated 63 specimens in total 27 patients, plus tracked immunoglobulin (IG) sequencing rearrangement by next-generation sequencing (NGS) in 20 patients. Next, we classified 17 patients into high-risk (HR, NGS-MRD positive) and low-risk (LR, NGS-MRD negative) groups according to the lower limit of NGS detection (10E-6), as well as performed leukemia-free survival (LFS) and overall survival (OS) analysis. Results At least one trackable IG clonal sequence was identified in the pre-CAR-T BM specimens from 20/27 of the cases analyzed. The two diagnostic samples with low DNA quantity, in addition to five samples lacking a dominant index sequence were excluded from further analysis. We measured the MRD in 63 samples, using a threshold of 0.01%, the determination of the presence (or absence) of leukemia was concordant in 46/63 (73%) of the samples. Discordance between NGS and FC was identified in 17/63 samples (27%). Of the 20 patients for whom trackable sequences were identified, 17 with detectable clonal index sequences on +30 days were included in our subsequent analysis cohort (Figure 1). The baseline characteristics of the patients are presented in Table 1. NGS identified 9 out of the 17 patients (52.9%) whose level of MRD was > 0.01%, but MRD negative as measured by FC. This controversial group (n=9) had inferior LFS than those whose MRD was less than 0.01% by NGS (median, 56 days vs. 219 days, p = 0.037) (Figure 2A). The OS rate was comparable between the two groups (p = 0.129) (Figure 2B). Patients with positive NGS-MRD at day 30 had comparable LFS compared with those with negative NGS-MRD (p = 0.103) (Figure 3A). For subgroup analysis, we further analyzed the influence of HSCT on prognosis of HR and LR patients. Of the total 11 patients in HR group, seven non-HSCT subjects all relapsed within three months, with a median LFS of 38 days. In contrast, the remaining four HSCT patients in HR subgroup had a significantly better LFS than the non-HSCT patients (median, 495 days vs. 38 days, p = 0.003) (Figure 3B). These four patients also exhibited better OS to that of the non-HSCT group (median, 768 days vs 409 days, p = 0.006) (Figure 3C). As for the LR cohort, no significant difference was found in LFS and OS between the HSCT and non-HSCT groups (LFS: p = 0.782, OS: p = 0.782) (Median LFS and OS data not shown). All of the evidence demonstrated that NGS-MRD early after CAR-T is an efficient prognostic factor, especially for early relapse prediction. Early post-CAR-T NGS-MRD status may be recommended for HSCT timing. As such, for HR patients, whose NGS-MRD results were positive, timely HSCT may significantly improves the prognosis and therefore is highly recommended at an early point after CAR-T cell therapy. Conclusion NGS-MRD elaborately demonstrated the tumor dynamics. NGS-MRD evaluated early after CAR-T cell therapy is an efficient prognostic factor, and timely HSCT is highly recommended for NGS-MRD positive patients at an early point after CAR-T cell therapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


Immunotherapy ◽  
2020 ◽  
Vol 12 (18) ◽  
pp. 1341-1357
Author(s):  
Nashwa El-Khazragy ◽  
Sherief Ghozy ◽  
Passant Emad ◽  
Mariam Mourad ◽  
Diaaeldeen Razza ◽  
...  

Taking advantage of the cellular immune system is the mainstay of the adoptive cell therapy, to induce recognition and destruction of cancer cells. The impressive demonstration of this principle is chimeric antigen receptor-modified T (CAR-T)-cell therapy, which had a major impact on treating relapsed and refractory hematological malignancies. Despite the great results of the CAR-T-cell therapy, many tumors are still able to avoid immune detection and further elimination, as well as the possible associated adverse events. Herein, we highlighted the recent advances in CAR-T-cell therapy, discussing their applications beneficial functions and side effects in hematological malignancies, illustrating the underlying challenges and opportunities. Furthermore, we provide an overview to overcome different obstacles using potential manufacture and treatment strategies.


Author(s):  
Javad Masoumi ◽  
Abdollah Jafarzadeh ◽  
Jalal Abdolalizadeh ◽  
Haroon Khan ◽  
Jeandet Philippe ◽  
...  

2021 ◽  
Vol 7 (2) ◽  
pp. 156
Author(s):  
Will Garner ◽  
Palash Samanta ◽  
Ghady Haidar

Studies describing invasive fungal infections (IFIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. Although post-CAR-T-cell IFIs appear to be uncommon, they are associated with significant morbidity and mortality. Specific risk factors for IFIs in CAR-T-cell recipients have not been fully characterized and are often extrapolated from variables contributing to IFIs in patients with other hematologic malignancies or those undergoing hematopoietic cell transplant. Optimal prophylaxis strategies, including the use of yeast versus mold-active azoles, also remain ill-defined. Further research should investigate key risk factors for IFIs and establish an evidence-based approach to antifungal prophylaxis in these patients in order to improve clinical outcomes.


2021 ◽  
Vol 27 (3) ◽  
pp. S211-S212
Author(s):  
Eddie Stephens ◽  
Ansh Mehta ◽  
Tanya Persoon ◽  
Shannon Baker ◽  
Remy David ◽  
...  

Author(s):  
Niamh Carey ◽  
Conor Hickey ◽  
Laura Mc Cullagh ◽  
Michael Barry

IntroductionIn 2018, the National Centre for Pharmacoeconomics (NCPE) was commissioned to conduct a health technology assessment (HTA) of one of the first commercially available chimeric antigen receptor (CAR) T-cell therapies, tisagenlecleucel. CAR T-cells are a major advance in personalized cancer treatment, demonstrating promising outcomes in relapsed/refractory pediatric acute lymphoblastic leukemia (pALL). However, the results are based on short-term follow up, limiting their value in predicting long-term survival and leading to uncertainty about the most appropriate survival modeling method to employ. This study aimed to address these limitations by means of expert elicitation.MethodsAn expert elicitation method, the histogram technique, was employed. A predefined discrete numerical scale was presented in Microsoft Excel® and the expert was asked to place twenty crosses on a frequency chart. These crosses represented the expert's beliefs about the distribution of particular quantities. Each cross represented five percent of the probabilistic distribution. Individual distributions were then aggregated across experts using linear pooling.ResultsA total of seventeen experts were invited to take part; eight agreed to participate and five completed the exercise. Three experts did not consider tisagenlecleucel to be a “curative” therapy because patients had a higher risk of death, compared with the age- and sex-matched general population. The aggregated distributions indicated the five-year overall survival rate to be thirty-three percent (95% CI 8.65–56.88) in patients who do not receive a subsequent stem cell transplant and twenty percent (95% CI 2.38 -52.04) in those who do.ConclusionsThe results of this study will be used to calibrate CD19 CAR T-cell therapy survival estimates presented in HTA submissions to the NCPE to ensure more robust assessments. They will also be used to inform the construction of a de novo cost-utility model for examining the cost effectiveness of CD19 CAR T-cell therapies for relapsed/refractory pALL in the Irish healthcare setting.


Author(s):  
Roni Shouval ◽  
Ana Alarcon Tomas ◽  
Joshua A. Fein ◽  
Jessica R. Flynn ◽  
Ettai Markovits ◽  
...  

PURPOSE Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type ( P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi149-vi149
Author(s):  
Carlen Yuen ◽  
Kourosh Rezania ◽  
Thomas Kelly ◽  
Michael Bishop

Abstract INTRODUCTION Chimeric antigen receptor (CAR) T-cell therapy, including axicabtagene ciloleucel (axi-cel; Yescarta®) and tisagenlecleucel (tisa-cel; Kymriah®), are FDA approved for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Neurotoxicity (NT) associated with CAR T-cell therapy (immune effector cell-associated neurotoxicity syndrome [ICANS]) can be fatal. Timely data, in the form of an abbreviated bedside mini-mental status exam, is thought to lead to earlier identification of NT. However, existing literature validating this method is limited. MATERIALS AND METHODS In this retrospective study, patients with R/R DLBCL treated with commercial axi-cel or tisa-cel in our center from December 2017 to September 2018 were assessed for NT with the CTCAE v4 criteria and the CAR-T-cell-therapy-associated TOXicity (CARTOX-10) scoring system. RESULTS Twenty-six patients with R/R DLBCL were treated with CAR T-cell therapy (25 axi-cel/[Yescarta®] and 1 tisagenlecleucel [Kymriah®]). Twenty-three (88%) developed NT with 8 (31%) experiencing severe NT (Grade III-IV). Tremor and dysgraphia occurred in all patients with severe NT. Lower average CARTOX-10 score (p=< 0.01), dysgraphia (p< 0.01), inattention (p=.018), and disorientation (p=.01) were significantly associated in patients with severe NT. A trend towards significance was observed between tremor and severe NT (p=.08). All patients with severe NT had both dysgraphia and tremor 8/8 (100%) and 2/8 (25%) had concurrent dysnomia. Death occurred in 12/26 (46%) of patients due to disease progression (n=11) and cardiac failure due to myositis (n=1). CONCLUSION In our limited cohort, dysgraphia, inattention, and disorientation are heralding symptoms of severe NT in adult R/R DLBCL patients treated with commercial CAR T-cell therapy. Dysgraphia was the earliest presenting symptom in patients with severe CAR T-cell neurotoxicity and was likely a manifestation of motor dysfunction rather than a component of dysphasia. Further studies with a larger cohort are needed to validate our findings.


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