Patients Receiving Chimeric Antigen Receptor T-cell Therapy Research Articles

Patient-reported outcomes after CAR T-cell therapy in patients with hematological malignancies.

The remarkable improvement in survival among individuals with hematological malignancies receiving chimeric antigen receptor (CAR) T-cell therapy has highlighted the growing unmet need to incorporate patient-centered assessments in management guidelines for these patients. That CAR T-cell therapy is associated with unique toxicities and relatively high symptom burden in the first few weeks after cell infusion is well known. Magnifying the patient's voice by using patient-reported outcomes (PROs) might support personalized intervention in the acute-care setting, optimize the use of medical resources, improve satisfaction with therapy, and enhance survival benefit. However, various factors impede PRO use in routine patient care: (1) the feasibility of PRO assessment during the acute phase of treatment, especially in patients experiencing neurological toxicities, is not well established; (2) although PROs are widely used in drug- development trials, the assessment tools used in clinical trials primarily inform quality-of-life or safety comparisons among study arms and are rarely the proper tools for assessing and capturing clinically meaningful adverse events that should be monitored in routine patient care; (3) PRO data that could guide how best to monitor and capture the delayed effects of CAR T-cell therapy in long-term survivors are limited. There is a pressing need to overcome these barriers to integrating evidence-based PROs into standard-of-care guidelines for patients receiving CAR T-cell therapy. In this review, we present the current state of PRO utilization in CAR T-cell therapy. We also discuss practical approaches and future directions for successful implementation of PROs in the care of patients receiving CAR T-cell therapy.

Early Prediction of Treatment Response By Circulating Tumor DNA Profiling in Patients with Diffuse Large B-Cell Lymphoma Receiving CAR T-Cell Therapy

Introduction Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) are characterized by a particularly poor prognosis. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has improved outcomes of patients with r/r DLBCL, yet a substantial proportion of patients still experiences relapse or progression after CAR T-cell treatment. Identifying patients at high risk of CAR T-cell therapy resistance or future lymphoma progression remains challenging. Here, we explored the value of circulating tumor DNA (ctDNA) as a prognostic biomarker at baseline and early into treatment in DLBCL patients undergoing standard-of-care CAR T-cell therapy, without the need for matched tumor genotypes. We further investigated associations between ctDNA and other known clinical risk factors. Methods We applied targeted next-generation sequencing (NGS) to a total of 53 samples from r/r DLBCL patients receiving CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel, n=16) at the University Medical Center Freiburg (Germany), using a modified version of the AVENIO ctDNA analysis workflow (Roche; Research Use Only) that covered ~314kb and targeted 466 distinct genes recurrently mutated in DLBCL (based on the CAPP-Seq workflow, Kurtz DM et al. J Clin Oncol 2018). Tumor genotypes were assessed noninvasively from plasma samples obtained at baseline before lymphodepletion with matched germline controls. Concentrations of ctDNA were quantified at baseline and early after CAR T-cell therapy at day 7-10. Initial treatment response was assessed by conventional PET-CT obtained 4-6 weeks after treatment based on the Lugano criteria. Results At baseline prior to lymphodepletion, we detected somatic mutations in 100% of plasma samples by noninvasive genotyping, with a median of 19.5 mutations per patient (range: 3-97). The most frequently mutated genes were IGHV, IGLL5, BCL2, MYC, BTG1, CREBBP, and TP53. Patients with high baseline ctDNA concentrations (mean allele frequency [AF] >= 1%) showed shorter progression-free survivial (PFS) and overall survival (OS) than patients with ctDNA levels below this threshold (median PFS: 86.5 days vs. not reached, p=0.04, HR: 6.3, 95% CI: 1.7-23.6; median OS: 219 days vs. not reached, p=0.048, HR: 4.1, 95% CI 1.0-16.6, Figure 1). Pretreatment ctDNA levels were significantly correlated with LDH concentrations ( p=0.049, r=0.5). We further found significantly higher ctDNA concentrations in patients with transformed DLBCL (vs. non-transformed, p=0.008) and in those with 3 or more prior treatment lines (vs. 1-2, p=0.04). At day 7-10 after CAR T-cell therapy, ctDNA levels dropped a median of 10-fold compared to the pretreatment time point ( p=0.008). Patients achieving a complete (CMR) or partial metabolic response (PMR) by PET-CT after 4-6 weeks showed a significant decrease of ctDNA ( p=0.001), while those with a stable (SD) or progressive disease (PD) had no significant ctDNA reduction at day 7-10 after CAR T-cell infusion. Vice versa, while 100% of patients with a >1.5-log-fold drop of ctDNA level between the pretreatment and interim time point revealed a CMR or PMR in early PET-CT scans, only 62% of patients with a smaller ctDNA decline responded to treatment according to PET-CT. Conclusions Our data suggests, together with previously published studies (Sworder BJ et al., Cancer Cell, 2023; Frank MJ et al. J Clin Oncol, 2021), that ctDNA profiling may allow robust noninvasive genotyping, accurate risk-stratification, and early prediction of clinical outcomes in r/r DLBCL patients undergoing CAR T-cell therapy. Although limited by small sample size, this pilot study highlights a potential future role of ctDNA measurements for personalized treatment selection and guidance in clinical trials.

BCMA-Directed CAR-T Cell Therapy Is Associated with a Higher Risk of Infections: A Systematic Review and Meta-Analysis

Background: Chimeric antigen receptor (CAR) T-cell therapy is a rapidly evolving immunotherapy for hematological malignancies. With increasing access to this modality, there is an urgent need for a comprehensive understanding of infectious complications to optimize prophylaxis and improve clinical outcomes. We conducted a systematic review and meta-analysis to assess the incidence and characteristics of infectious complications in adult patients receiving CAR T-cell therapy. Methods: The study was registered on PROSPERO and we searched 5 electronic databases from inception to 2022. Each author independently screened titles, reviewed full texts to identify eligible studies and extracted data from included studies using Covidence, a data extraction tool for conduction of standard systematic reviews. A random effects model was used, and proportions were used as a measure of outcome. We assessed heterogeneity using I^2 statistic. Risk of bias assessments were conducted using the RoB 2.0 for RCTs and ROBINS I tool for non-RCTs. Results: Our search identified 12,441 studies of which 363 underwent full-text review (Figure 1). 33 studies were eligible for inclusion in the analysis and enrolled a total of 2866 patients. The pooled incidence of an infectious event in adult patients after CAR T-cell therapy was 38% (95%CI 0.31, 0.46; p<0.01; I2 = 98%]. No significant difference was noted in the incidence among studies with a longer follow up duration compared to studies with follow up of £ 30 days [40% (95% CI 0.30-0.50) vs 32% (95% CI 0.24-0.40), p=0.20 respectively]. BCMA-directed CAR T-cell therapies used for management of multiple myeloma had a significantly higher incidence of infectious complications compared to CD19 targeted agents, 64% (95% CI 0.53-0.74, I2 = 65%) versus 39% (95% CI 0.30-0.49; I2 = 98%; p <0.01) respectively, Figure 2. Clostridium difficile and Escherichia coli were the most common pathogens causing bacterial infections, while cytomegalovirus was the most commonly identified viral pathogen affecting these patients. Conclusion: In this study, BCMA-directed CAR T-cell therapies were associated with a significantly higher risk of infectious complications. The results of this study can guide the development of strategies to prevent and manage infectious complications in this patient population.

Infection epidemiology in relation to different therapy phases in patients with haematological malignancies receiving CAR T-cell therapy.

We described the real-life epidemiology and causes of infections on the different therapy phases in patients undergoing chimeric antigen receptor (CAR) T-cells directed towards CD19+ or BCMA+ cells. All consecutive patients receiving CAR T-cell therapy at our institution were prospectively followed-up. We performed various comparative analyses of all patients and subgroups with and without infections. Ninety-one adults mainly received CAR T-cell therapy for acute leukaemia (53%) and lymphoma (33%). We documented a total of 77 infections in 47 (52%) patients, 37 (48%) during the initial neutropenic phase and 40 (52%) during the non-neutropenic phase. Infections during the neutropenic phase were mainly due to bacterial (29, 78%): catheter infections (11 [38%] cases), endogenous source (5 [17%]), and Clostridioides difficile (5 [17%]). Patients receiving corticosteroids after CAR T-cell therapy had a higher risk of endogenous infection (100% vs. 16%; p = .006). During the non-neutropenic phase, bacterial infections remained very frequent (24, 60%), mainly with catheter source (8, 33%). Respiratory tract infections were common (17, 43%). Infections after CAR T-cell therapy were frequent. During the neutropenic phase, it is essential to prevent nosocomial infections and balance the use of antibiotics to lower endogenous bacteraemia and Clostridial infection rates.

Myocardial strain is associated with adverse cardiac events in patients treated with chimeric antigen receptor (CAR) T-cell therapy.

Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T-cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy-related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T-cell therapy. To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. Patients who had an echocardiogram within 6 months prior to receiving CAR T-cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. Among 75 CAR T-cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p = .021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p = .012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48-0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p = .024) was associated with a higher risk of CE. Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T-cell therapy.

Treatment patterns for extramedullary multiple myeloma and outcomes with CAR-T therapy and bispecific antibodies.

8022 Background: Extramedullary Multiple Myeloma (EMM) is an aggressive entity with a dismal prognosis. Immune effector therapies (IETs), including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibodies (BsAb), have demonstrated excellent efficacy in relapsed/refractory MM with limited data for efficacy in EMM. Here, we report the treatment outcomes for patients with EMM. Methods: We identified 299 patients with EMM diagnosed between 01/01/2000 and 12/31/2021 after excluding solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia. The IMWG criteria were used for response definition. Results: Of the 299 patients, 204 (68%) patients had secondary EMM (sEMM) and 95 (32%) patients had primary EMM (pEMM). For sEMM (n=204), the median progression free survival (PFS) with initial therapy was 2.9 (95% CI: 2.4-3.2) months. Initial treatment strategies for sEMM were heterogenous and demonstrated in the table; 44% patients achieved ≥partial response (PR) with initial treatment for sEMM. The median PFS in patients with ≥PR was 5.8 (95%CI: 4.5-6.9) months vs 1.8 (95%CI: 1.4-2; p &lt;0.0001) months for &lt;PR. For patients with pEMM (n=95), the median PFS was 12.9 (95% CI: 6.7-18) months; the median PFS was 17.4 (95%CI: 12.9-25.4) months for patients with ≥PR versus 1 month (95%CI: 0.8-2) in patients with &lt;PR. Thirty patients (all sEMM and triple class refractory) were treated with IET after development of EMM: 18 with BCMA-directed CAR-T, 10 with BsAbs, and 2 with both CAR-T and BsAbs. In patients receiving CAR-T therapy, 75% (15/20) achieved ≥PR with 40% (n=8) achieving MRD negative (by flowcytometry) complete response. Fifteen (75%) patients receiving CAR-T had progressive disease (PD); 7 with systemic and EMM PD and 4 patients each with isolated EMM or systemic PD. The median PFS for patients treated with CAR-T was 4.9 months [3.1- not reached (NR)]. Among patients achieving a ≥PR with CAR-T, the median PFS was 5.8 (95%CI: 4.7-NR) months vs 1.4 months [(95%CI: 0.8-NR), p&lt;0.001] for &lt;PR. Among patients treated with BsAbs (10-BCMA, 1 each against FcRH5 and GPRC5D), 33% (4/12) achieved a ≥PR. Ten (83%) patients had PD on BsAb; 8 with both EMM and systemic PD and 1 patient each with isolated EMM or PD. The median PFS with BsAb was 2.9 months (95%CI: 2.2-NR). Conclusions: Patients with EMM continue to have dismal outcomes with conventional therapies. High response rates were noted with CAR-T therapy, but these tend to be short-lived. [Table: see text]

Circulating tumor DNA and association with CAR-T cell therapy response in gastric and pancreatic cancer patients.

4053 Background: Circulating tumor DNA (ctDNA) is a form of cell free DNA that can be used to detect and measure cancer molecular residual disease (MRD) before and after systemic therapy. There are no data pertaining to the assessment of MRD in patients with solid tumors treated with chimeric antigen receptor T-cell (CAR-T) therapy. Here, we evaluated a tumor-informed ctDNA assay in the setting of gastric and pancreatic malignancies treated with claudin18.2 (CT041)-targeted CAR-T cell therapy (NCT04404595). Methods: A single-center review between 7/1/2021 – 1/1/2023 identified 10 patients with pancreatic or gastric carcinoma who received CAR-T CT041 cell therapy. Eight patients were ctDNA positive prior to treatment and had blood samples serially drawn before and after CAR-T cell therapy. Banked plasma was analyzed for ctDNA using a tumor-informed Signatera, mPCR-NGS ctDNA assay (Natera, Inc.). The correlative prognostic value of ctDNA to predict response after CAR-T cell therapy was analyzed by RECIST 1.1 criteria. Results: Pre- and post-treatment serial ctDNA was available for 8 of 10 (3/5 gastric and 5/5 pancreatic cancer) patients and all 8 were ctDNA positive prior to CAR-T CT041 cell therapy. The median nadir of ctDNA was on day 14 after CT041 infusion.Of the 8 patients with detectable ctDNA, 5 (62.5%) became undetectable at some time after CT041 therapy, while 3 (37.5%)remained ctDNA positive throughout treatment. The disease control rate (DCR) was 80% for anytime negative ctDNA patients (4/5). Of patients with responsive disease after CT041 CAR-T, 2/3 (67%) achieved undetectable ctDNA and 1/3 (33%) had a ctDNA reduction by 95%. Both patients with stable disease developed undetectable ctDNA. In those patients with progressive disease, 1/3 (33%) had a negative anytime ctDNA. One patient with a complete response had undetectable ctDNA and target lesion response, then later developed progressive disease detectable by ctDNA 3 months prior to radiography. Overall survival was higher (9.1 months vs. 3.7 months) in those who achieved anytime undetectable ctDNA. Conclusions: Tumor-informed ctDNA correlates with response to CAR-T cell therapy in gastrointestinal malignancies. Ongoing clinical trials of CT041 CAR-T cell therapy will continue ctDNA analysis prospectively. Characteristics of initially ctDNA positive patients receiving CAR-T therapy. Clinical trial information: NCT04404595 . [Table: see text]

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Perception of Prognosis, Quality of Life, and Distress in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

Background: CAR T-cell is a potentially curative therapy for patients with hematologic malignancies but can cause life-threatening toxicities. Data on perceptions of prognosis and psychological distress are lacking. Methods: We conducted a cross-sectional study of patients receiving CAR T-cell therapy. Prior to hospitalization for CAR T-cell therapy, patients completed assessments of quality of life (QOL) (Functional-Assessment-of-Cancer-Therapy-General), anxiety and depression symptoms (Hospital-Anxiety-and Depression-Scale) and Post-Traumatic Stress Disorder symptoms (Post-Traumatic-Stress-Checklist). Patients also completed the Prognostic-Awareness-Impact-Scale (PAIS), which measures three domains: cognitive understanding of prognosis, emotional coping with prognosis, and adaptive response. Results: We enrolled 71.8% (102/142) of eligible patients. 34% of patients reported that their oncologist said their cancer is curable and 64% reported there was > 50% chance of cure (Figures 1 and 2). Overall, 26%, 30%, and 21% of patients reported clinically significant depression, anxiety, and PTSD symptoms, respectively. We found no association between patients’ cognitive understanding of prognosis and QOL or mood. Higher emotional coping with prognosis was associated with better QOL (b=0.72; SE=0.10; P=<0.001) and lower depression (b=-0.17; SE=0.02; P=<0.001), anxiety (b=-0.21; SE=0.02; P=<0.001), and PTSD (b=-0.43; SE=0.06; P=<0.001) symptoms. Higher adaptive response was associated with better QOL (b=0.19; SE=0.09; P=0.028) and lower depression (b=-0.05; SE=0.02; P=0.023), anxiety (b=-0.09; SE=0.02; P=<0.001), and PTSD (b=-0.19; SE=0.05; P=<0.001) symptoms. Conclusions: Patients undergoing CAR T-cell therapy report overly optimistic perception of their prognosis and have high rates of psychological distress. Higher emotional coping with prognosis and adaptive response were associated with better QOL and less psychological distress, underscoring the need to develop interventions to promote coping with this treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patient-Reported Outcomes after Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphomas

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As part of a larger study evaluating baseline biomarkers in prospective patients receiving CAR-T therapy at the Juravinski Hospital and Cancer Centre, we are reporting preliminary data on patient-reported health-related quality of life (HRQoL). Objective: To measure longitudinal HRQoL in patients receiving CAR-T therapy. We expected HRQoL to worsen in the first 30 days, but improve long term. Methods: A prospective cohort observational study was conducted. Patients with relapsed or refractory large B-cell lymphoma, who were eligible for CAR-T therapy, tisagenlecleucel, were consecutively approached to participate. Demographic data and disease characteristics were collected. Patients received lymphodepleting chemotherapy on days -5 to -3. CAR-T cells were infused on Day 0. CRS and ICANS were assessed using ASTCT criteria. HRQoL was measured using FACT-Lym (Hlubocky et al., Leuk. Lymphoma 2013); a validated 42-item questionnaire answered by the patient on a 5-point Likert scale on days 0 (baseline), day 30, and months 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma specific subscale (Lym-S). A score of 0 represents worst HRQoL and higher scores indicate an improvement (score range, 0-168). FACT-Lym Trial Outcome Index (TOI) is a combination of physical and functional well-being and Lym-S. Minimal important differences have been estimated using anchor (performance status and disease progression) and distribution methods for FACT-Lym (Carter et al., Blood 2008). Results: Among 34 patients registered to the study between January 2020 and June 2021, two did not receive their infusion due to progressive disease. Baseline demographics and disease characteristics are described in Table 1. Twenty-one (21/32, 65.7%) patients required bridging therapy prior to CAR-T infusion. Of the 32 patients who received CAR-T infusion, 22 (68.8%) received an outpatient CAR-T infusion; 18/22 (81.8%) were admitted to hospital. 26/32 (81.2%) developed any grade CRS; 6/32 (18.8%) developed grade 3 or 4 CRS. 6/32 (18.8%) developed grade 1 or 2 ICANS and no one developed grade 3 or 4 ICANS. Ten patients died and one withdrew. The remaining 23 patients were followed for one year. Ethics approval for the FACT-Lym questionnaire administration was pending when the first four patients were recruited. Of the 28 patients approached to complete the FACT-lym questionnaire, 26 (92.9%) completed a baseline and at least one follow-up. Fifteen (15/26, 57.7%) completed the 12-month questionnaire. Two remain on study protocol. Attrition was due to death in six patients, two were unknown, and one was due to withdrawal. The median (IQR) FACT-Lym score at baseline was 129 (106, 146), then worsened at day 30, 117.5 (97, 142), and unexpectedly did not improve beyond baseline by month 3, 128 (108, 156). Scores improved by month 6, 136 (114, 154) and month 12, 141.5 (100, 158). Figure 1 illustrates median change from baseline for FACT-Lym total scores and domains. Median change in FACT-Lym total scores at month 12 and FACT-TOI score at months 6 and 12 surpassed a minimal important difference. Conclusions: After initial worsening of HRQoL in patients who received CAR-T therapy, improvements were seen at 6 and 12 months. Future analyses will explore associations between HRQoL and baseline markers, toxicity and treatment response. These results will help enrich our understanding of the patient CAR-T experience and aid in complex and shared decision-making. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of infection in patients with hematological malignancies receiving CAR T-cell therapy: systematic review and meta-analysis

Background Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment option for relapsed or refractory B-cell malignancies and multiple myeloma. Various factors —underlying immune dysfunction, prior chemotherapy, lymphodepletion, prolonged cytopenias, hypogammaglobulinemia and use of corticosteroids and tocilizumab— may contribute to the development of infectious complications. Research design and methods We conducted a systematic review and meta-analysis on the incidence of overall and severe (grade ≥3) infection in patients with hematological malignancies receiving CAR T-cells. Secondary outcomes included the specific rates of bacterial, viral and invasive fungal infection (IFI), and infection-related mortality. PubMed, Embase and Web of Science databases were searched from inception to May 27, 2022. Sensitivity analysis were performed according to the type of malignancy and study design (randomized clinical trials [RCTs] or observational studies). Results Forty-five studies (34 RCTs) comprising 3,591 patients were included. The pooled incidence rates of overall and severe infection were 33.8% (I2 = 96.31%) and 16.2% (I2 = 74.41%). The respiratory tract was the most common site of infection. Most events were bacterial or viral, whereas the occurrence of IFI was rare. The pooled attributable mortality was 1.8% (I2 = 43.44%). Conclusions Infection is a frequent adverse event in patients receiving CAR T-cell therapy. Further research should address specific risk factors in this population.

Prognostic Value of Radiomic Features of 18F-FDG PET/CT in Patients With B-Cell Lymphoma Treated With CD19/CD22 Dual-Targeted Chimeric Antigen Receptor T Cells.

ObjectiveIn the present study, we aimed to evaluate the prognostic value of PET/CT-derived radiomic features for patients with B-cell lymphoma (BCL), who were treated with CD19/CD22 dual-targeted chimeric antigen receptor (CAR) T cells. Moreover, we explored the relationship between baseline radiomic features and the occurrence probability of cytokine release syndrome (CRS).MethodsA total of 24 BCL patients who received 18F-FDG PET/CT before CAR T-cell infusion were enrolled in the present study. Radiomic features from PET and CT images were extracted using LIFEx software, and the least absolute shrinkage and selection operator (LASSO) regression was used to select the most useful predictive features of progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic curves, Cox proportional hazards model, and Kaplan-Meier curves were conducted to assess the potential prognostic value.ResultsContrast extracted from neighbourhood grey-level different matrix (NGLDM) was an independent predictor of PFS (HR = 15.16, p = 0.023). MYC and BCL2 double-expressor (DE) was of prognostic significance for PFS (HR = 7.02, p = 0.047) and OS (HR = 10.37, p = 0.041). The combination of NGLDM_ContrastPET and DE yielded three risk groups with zero (n = 7), one (n = 11), or two (n = 6) factors (p < 0.0001 and p = 0.0004, for PFS and OS), respectively. The PFS was 85.7%, 63.6%, and 0%, respectively, and the OS was 100%, 90.9%, and 16.7%, respectively. Moreover, there was no significant association between PET/CT variables and CRS.ConclusionsIn conclusion, radiomic features extracted from baseline 18F-FDG PET/CT images in combination with genomic factors could predict the survival outcomes of BCL patients receiving CAR T-cell therapy.

Association of Bridging Therapy Utilization with Clinical Outcomes in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

Background: CAR T-cell therapy has altered the landscape of treatment options for patients with hematologic malignancies. Because CAR T-cell therapy involves manufacturing an autologous cellular product over a period of weeks, patients can receive bridging therapy while awaiting CAR T-cells. Currently there is no standard of care for use of bridging therapy. Moreover, data are lacking regarding the impact of bridging therapy use on clinical outcomes.Methods: We conducted a retrospective analysis of 236 patients who received CAR-T cell therapy at two tertiary care centers from 2/2016-12/2019. We abstracted clinical outcomes from review of the Electronic Health Record (EHR) including 1) overall response rate (ORR); 2) complete response (CR) rate; 3) progression-free survival (PFS); 4) overall survival (OS); 5) health care utilization (length of stay [LOS], intensive care unit [ICU] admission during admission for CAR T-cell therapy, and hospital readmission within 3 months of CAR T-cell infusion); and 6) rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [all grades and grade 3+]. We assessed the association of bridging therapy use with ORR, CR rate, rates of ICU admission and hospital readmission, and rates of CRS (any grade) and ICANS (any grade and grade 3+) using the chi square test. We assessed the association of bridging therapy use with LOS using the Wilcoxon-Mann-Whitney test given the distribution of LOS and with grade 3+ CRS using Fisher's Exact Test given the sample size of this outcome. To assess the association of bridging therapy use with PFS and OS, we used Cox multivariable regression analyses adjusting for age, sex, marital status, Charlson comorbidity index, lymphoma diagnosis, number of prior therapies, history of autologous stem cell transplant, time from relapse to CAR T-cell therapy, vein to vein time, Eastern Cooperative Oncology Group performance status (closest to day 0), LDH (> 500 vs <=500), CRP, ferritin, and platelet count (< 100 vs >=100) prior to CAR T-cell infusion, CAR T-cell product, total dose of steroids received (days 0-31), and receipt of tocilizumab.Results: Patients had a median age of 62.8 years (range: 19-82) and the majority were male (145/236, 61.4%). The most common diagnosis was de novo diffuse large B cell lymphoma (DLBCL) (101/236, 42.8%) and most patients received axicabtagene ciloleucel (axi-cel) (192/236, 81.4%). All patients received lymphodepletion with cyclophosphamide and fludarabine. Overall, 39.4% (93/236) received bridging therapy. Regimens utilized for bridging therapy included systemic chemotherapy (48/236, 20.3%), corticosteroids (25/236, 10.6%), radiation (10/236, 4.2%), and other systemic therapies (10/236, 4.2%). Among the entire cohort, ORR and CR rate were 85.2% (201/236) and 64.8% (153/236), respectively, and bridging therapy use was not associated with ORR (80.0% with bridging therapy vs. 88.8% without bridging therapy; χ 2=3.81; p=0.051) or CR rate (63.4% with bridging therapy vs. 65.7% without bridging therapy; χ 2=0.13; p=0.718). In univariate Cox regression analyses, bridging therapy was associated with worse PFS (HR=1.47; p=0.049) and worse OS (HR=1.85; p=0.006). In multivariable Cox regression models adjusting for covariates (Tables 1 and 2), bridging therapy use was not associated with PFS (HR=1.43; p=0.163) but was associated with worse OS (HR=2.23; p=0.006). Bridging therapy use was not associated with LOS (p=0.451), ICU admission (χ 2=0.22; p=0.638), hospital readmission (χ 2=0.95; p=0.329), CRS (all grades: χ 2=0.46; p=0.500; grades 3+: p=0.574), or ICANS (all grades: χ 2=0.13; p=0.719; grades 3+: χ 2=0.23; p=0.632).Conclusions: We identified that bridging therapy use is not associated with differences in response rates, PFS, health care utilization, or rates of CRS or ICANS but is associated with worse OS in patients receiving CAR T-cell therapy. These findings underscore the need for novel bridging therapy regimens to optimize outcomes in this patient population. [Display omitted] DisclosuresJacobson: Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Frigault: Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Arcellx: Consultancy; Iovance: Consultancy; Takeda: Consultancy; Editas: Consultancy; BMS: Consultancy.

Associations between Socioeconomic Status and Bispecific LV20.19 CAR T-Cell Therapy Outcomes

BackgroundSocioeconomic Status (SES) is recognized as a major contributor to health disparities in overall disease rate, morbidity, mortality, and quality of life (QOL). Specifically, low SES, independent of race, has a negative impact on solid and haematological cancer outcomes. Chimeric antigen receptor (CAR) T-cell cancer therapy is an increasingly utilized novel treatment option for the treatment of lymphoma; however its use is associated with cytokine release syndrome (CRS), neurotoxicity (NTX), and QOL impairments. Though the precise mechanism for these toxicities is unknown, adverse effects of CAR T-cell therapy are associated with neuroinflammatory markers that are upregulated in low SES populations. In this study, we hypothesized that patient response to a novel anti-CD20 and anti-CD19 (LV20.19) CAR T-cell treatment is affected by patient SES. Our second goal was to explore several possible biological mechanisms of the effects of SES on CAR T-cell therapy outcomes, including cytokines and kynurenine metabolites.MethodsThe current study population (N=15) is derived from a parent study evaluating patients treated with LV20.19 CAR T-cells on a Phase I/Ib clinical trial (NCT03019055). Patients provided blood samples and patient reported outcome (PRO) data 15 days before therapy (baseline), Day 14 post therapy (D14), D28, and D90. Cytokines were sent to Eve Technologies and quantified using an ELISA. Our analysis focused on 10 cytokines associated with CAR T-cell therapy neurotoxicity. Tryptophan (TRP) and kynurenine metabolites were quantified from serum samples using stable isotope-dilution liquid chromatography/mass spectrometry of the daughter ions (LC-MS-MS). Neurotoxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v5 and CRS was graded using Lee et al. (Blood; 2019) PROs included depression and anxiety (Inventory of Depression and Anxiety), sleep (Pittsburgh Sleep Quality Index; PSQI), fatigue (Fatigue Symptom Inventory; FSI), and pain (Brief Pain Inventory; BPI) intensity (BPII) and interference (BPIF). SES was assessed by household annual income either above or below the Wisconsin median annual income in 2021 of $54,660 (high SES as >$55,000, n=7; low SES as $10,001-55,000, n=8). SES groups were compared against therapy outcomes using Wilcox Ranked Sum test, Student's t-test, and mixed effects linear models with a random subject intercept and estimated marginal means, respectively.ResultsThere was no significant difference between SES groups based on age, education, or clinical response to therapy by D28 (Table 1). Baseline LDH was 3.4-fold higher in low compared to high SES patients (p=0.04). Most peak cytokine concentrations were higher in low SES patients with significant elevations (p<0.05) in G-CSF, I-309, IL-8, IP-10, MCP-2, and TNFa (9-fold, 3-fold, 3-fold, 2-fold, 2-fold, and 4-fold, respectively; Figure 1). Low SES patients also had significantly elevated neurotoxic pathway kyunerine metabolites (p<0.05; Figure 2) 3-hydroxyanthranilate (3-HAA) at D28 (8-fold) and quinolinic acid (QA) at baseline (5-fold), D14 (8-fold), and D28 (6-fold). Though incidences of CRS were only qualitatively higher in low SES patients (p=0.07), low SES patients experienced CRS significantly earlier (p=0.009; Table 2). Not enough patients experienced NTX for sufficient analysis. Patients with low SES indicated more pain intensity on D90 (BPII; p=0.021) and baseline pain interference (BPIF; p=0.08; Figure 3). Low SES patient reported worse sleep quality at D90 than high SES patients (p<0.05), and low SES average was higher than the PSQI threshold for “poor sleep” (5) at baseline, D28, and D90.ConclusionOur data show preliminary evidence that SES is associated with biological and clinical outcomes among patients receiving CAR T-cell therapy. In particular, we observed significantly higher concentrations of proinflammatory cytokine and neurotoxic kynurenine metabolites in low SES patients, as well as higher baseline LDH associated with higher tumor burden. Earlier CRS onset and increased pain were also seen in low SES patients, with qualitatively higher incidences of CRS, neurotoxicity, and poor sleep. Future work will focus on acquiring a larger sample to further delineate the impact of SES on cancer outcome disparities among CAR T-cell recipients, including but not limited to PROs, neurotoxicity, and survival. [Display omitted] DisclosuresShah: Umoja: Consultancy; Incyte: Consultancy; Kite: Consultancy; Epizyme: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Legend: Consultancy; Lily: Consultancy, Honoraria, Research Funding. Hillard: Formulate Bioscience: Current holder of stock options in a privately-held company; Phytecs, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Assessing CAR T-Cell Therapy Response Using Genome-Wide Sequencing of Cell-Free DNA in Patients With B-Cell Lymphomas

Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful. The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas. Whole blood was collected before and throughout CAR T-cell therapy until day 154. Low-coverage (∼0.4×), genome-wide cfDNA sequencing, similar to that established for noninvasive prenatal testing, was performed. The genomic instability number (GIN) was used to quantify plasma copy number alteration level. Twelve patients were enrolled. Seven (58%) patients achieved a complete response (CR); 2 (25%), a partial response. Median progression-free survival was 99 days; median overall survival was not reached (median follow-up, 247 days). Altogether, 127 blood samples were analyzed (median, 10 samples/patient [range 8-13]). All 5 patients who remained in CR at the time of last measurement had GIN <170 (threshold). Two patients who attained CR, but later relapsed, and all but one patient who had best response other than CR had last GIN measurement of >170. In 5 of 6 patients with relapsed or progressive disease, increasing GIN was observed before the diagnosis by imaging. The abundance of CAR T-cell construct (absolute number of construct copies relative to the number of human genome equivalents) also showed a trend to correlate with outcome (day 10, P = .052). These data describe a proof-of-concept for the use of multiple liquid biopsy technologies to monitor therapeutic response in B-cell lymphoma patients receiving CAR T-cell therapy.

Prognostic impact of total metabolic tumor volume in large B-cell lymphoma patients receiving CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy provides long-term remissions in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Total metabolic tumor volume (TMTV) assessed by 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) has a confirmed prognostic value in the setting of chemoimmunotherapy, but its predictive role with CAR T-cell therapy is not fully established. Thirty-five patients with R/R LBCL who received CAR T-cells were included in the study. TMTV and maximum standardized uptake value (SUVmax) were measured at baseline and 1-month after CAR T-cell infusion. Best response included 9 (26%) patients in complete metabolic response (CMR) and 16 (46%) in partial metabolic response (PMR). At a median follow-up of 7.6months, median PFS and OS were 3.4 and 8.2months, respectively. A high baseline TMTV (≥ 25 cm3) was associated with a lower PFS (median PFS, 2.3 vs. 8.9months; HR = 3.44 [95% CI 1.18-10.1], p = 0.02). High baseline TMTV also showed a trend towards shorter OS (HR = 6.3 [95% CI 0.83-47.9], p = 0.08). Baseline SUVmax did not have a significant impact on efficacy endpoints. TMTV and SUVmax values showed no association with adverse events. Metabolic tumor burden parameters measured by 18FDG-PET before CAR T-cell infusion can identify LBCL patients who benefit most from this therapy.

CAR T-cell therapy for solid tumours

Chimeric antigen receptor (CAR) T-cell therapy has fundamentally changed the therapeutic landscape for haematological malignancies. CAR T-cell therapy involves the collection of a patient's T cells, ex-vivo genetic modification of the cells to encode a synthetic receptor that binds a specific tumour antigen, and then re-infusion of these cells back into the patient. The clinical success of CAR T-cell therapy in blood cancers has generated enthusiasm for testing the technology in solid tumours. However, the biology of solid tumours is more complex than that of haematological malignancies. Unfortunately, CAR T-cell therapy for solid tumours suffered a setback on June 2, 2021, when Tmunity Therapeutics stopped its phase 1 clinical trial in men with prostate cancer because two patients died from immune effector cell-associated neurotoxicity syndrome (ICANS). Tmunity Therapeutics had been developing prostate-specific membrane antigen (PSMA)-directed, TGF-β-insensitive CAR T cells. Prostate cancer cells secrete TGF-β as an immunosuppressive factor, so the investigators hypothesised that using a PSMA-directed CAR T cell with coexpression of a dominant-negative TGF-β receptor would enhance antitumour immunity in patients with prostate cancer. Early trial results had shown no dose-limiting toxicities, and only one, reversible, case of cytokine release syndrome (CRS). ICANS, however, although seen less frequently than CRS, has been reported in up to half of all patients receiving CAR T-cell therapy for various haematological cancers and thus was also a risk in solid tumour trials. ICANS needs prompt diagnosis and appropriate management to avoid rapid clinical deterioration. Unlike CRS, the precise underlying pathophysiology of ICANS remains poorly understood, and although the acute symptoms of CRS and ICANS are generally reversible with supportive care, steroids, and immunosuppressive drugs, they can be associated with substantial morbidity, with some patients requiring admission to an intensive care unit. In addition to CRS and ICANS, the development of CAR T-cell therapy for solid tumours faces many fundamental challenges, the most difficult being the identification of an ideal target antigen. Haematological cancers typically express a single, specific, tumour-associated antigen, whereas solid tumours have substantial antigen heterogeneity. Of concern, many antigens associated with solid tumours are also expressed on healthy tissue, raising the risk of off-target adverse events. Genetic modification technologies can help to circumvent this risk, but they are not a failsafe solution. Other major challenges include how to traffic the CAR T cells to the tumour bed because of a lack of appropriate cytokines in the tumour milieu; how to prevent CAR T cells from losing their effectiveness over time (so-called T-cell fitness); how to lymphodeplete the tumour to allow for CAR T-cell expansion in the absence of effective lymphodepleting chemotherapies; and, finally, how to overcome the hostile immunosuppressive conditions of the tumour microenvironment. A recent development might help to overcome two of these challenges. Using a new CAR T-cell technology called synthetic Notch (or synNotch), CAR T cells can be made to target specific cancers very precisely. Researchers at the Children's Hospital Los Angeles (Los Angeles, CA, USA) have developed a modified version of a CAR T cell for treating neuroblastoma. The synNotch protein on the surface of the T cell is designed to recognise an antigen called GD2. When it does, the synNotch protein then instructs the T cell to activate its CAR T-cell properties, enabling it to recognise a second antigen called B7H3. This gating property is key to minimising toxicity, as healthy cells sometimes express one of these antigens, but rarely both. Neuroblastoma, however, has both GD2 and B7H3 antigens. Interestingly, synNotch CAR T cells are metabolically more stable than regular CAR T cells, enabling them to target a tumour over a longer timeframe and overcome the problems associated with CAR T-cell fitness. The use of CAR T-cell therapy has yielded excellent early-to-mid-term results in patients with haematological cancers, but the transfer of this technology to solid cancers faces more substantive biological barriers and risks to patients. Despite many ongoing clinical trials, very few have reported any results and all are at early stages. Consequently, many unknowns remain. The potential is evident, but it will only be realised through carefully designed trials incorporating thorough patient monitoring and stringent stopping rules coupled to detailed preclinical translational research.

Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the TRANSCEND NHL 001 trial

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell–specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.

Prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy: A cross-sectional study

Background: We conducted a survey to investigate the prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy. Methods: In total, 130 eligible patients completed the Self-Rating Anxiety Scale and Self-Rating Depression Scale at week 4 after CAR-T cell infusion. We collected sociodemographic information during the same period. We studied factors associated with anxiety and depressive symptoms using logistic regression analysis. Results: The prevalence of anxiety and depressive symptoms at week 4 after infusion were 13.8% and 40.0%, respectively. A cutoff value of 50 or above indicates significantly anxiety and depressive symptoms. Binary logistic regression analysis showed that high school education and above (OR = 0.22, 95% CI = 0.06–0.78) and middle age (OR = 0.16, 95% CI = 0.03–0.90) were associated with lower risk of anxiety symptoms, and increased odds of depressive symptoms was associated with old age (OR = 11.39, 95% CI = 2.50–51.88), non-manual occupations before illness (OR = 3.72, 95% CI = 1.20–11.58), and higher healthcare expenditure (OR = 3.93, 95% CI = 1.50–10.33), while lower risk of depressive symptoms was associated with rural household location (OR = 0.25, 95% CI = 0.08–0.76) and being cared for by spouse (OR = 0.12, 95% CI = 0.02–0.63). Conclusions: Patients receiving CAR-T therapy with lower education background, old ages, urban household location, or who used to work as non-manual workers require more attention and psychological care. Support from a spouse and medical expense deductions from the government may help patients develop positive attitudes.

Gut Bacterial Diversity Associates with Efficacy of Anti-CD19 CAR T-Cell Therapy in Patients with Large B-Cell Lymphoma

Gut Bacterial Diversity Associates with Efficacy of Anti-CD19 CAR T-Cell Therapy in Patients with Large B-Cell Lymphoma