The Role of CAR T-Cell Therapy in Relapsed/Refractory Adult B-ALL.

CAR T-cell therapy is a recent therapeutic advancement that has transformed the management of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). To date, there are 2 FDA-approved CAR-T products for R/R B-ALL: tisagenlecleucel in patients aged <26 years and brexucabtagene autoleucel in those aged ≥18 years. This review summarizes the pivotal clinical trials that led to FDA approval of these 2 products and highlight emerging data addressing key questions pertinent to CAR-T utilization in the rapidly evolving landscape of R/R ALL management. These include optimal sequencing of CAR-T among other novel immunotherapeutic agents, the role of consolidation and maintenance following CAR-T, novel CAR-T constructs currently under clinical development, and strategies to optimize use of commercially available CAR-T products to improve patient outcomes.

Revolutionizing cancer treatment: an in-depth exploration of CAR-T cell therapies.

Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings.

A Cost-Effectiveness Analysis of Axicabtagene Ciloleucel versus Tisagenlecleucel in the Treatment of Diffuse Large B-cell Lymphoma Based on a Real-World French Registry.

INTRODUCTION: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are chimeric antigen receptor T-cell therapies that were evaluated in third and later line (3L+) relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in the ZUMA-1 and JULIET trials, respectively. As of October 2021, the DESCAR-T registry included 729 French patients with 3L+ r/r DLBCL who received axi-cel or tisa-cel. Using these data, propensity score matching was used to conduct an adjusted comparison between axi-cel and tisa-cel. Axi-cel was associated with statistically significant improvements in overall survival (OS) and progression-free survival (PFS), and significantly more frequent Grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (ICANS), compared with tisa-cel. There was no significant difference in Grade ≥ 3 cytokine release syndrome (CRS). The current analysis assessed the cost-effectiveness of axi-cel versus tisa-cel in the treatment of 3L+ r/r DLBCL using propensity score-matched data from the DESCAR-T registry. METHODS: A partitioned survival model was used to extrapolate costs and quality-adjusted life years (QALYs) over a lifetime. Survival curves for PFS and OS were based on independent mixture cure models fitted to digitized Kaplan-Meier data for the propensity score-matched DESCAR-T populations. Average duration of intensive care unit stays for each of axi-cel and tisa-cel in DESCAR-T were used to inform adverse event costs. Selected parametric survival distributions were based on clinical expert validation. Utility values were derived from ZUMA-1, and costs were obtained from French registries and published sources. List prices were used for both axi-cel and tisa-cel. Costs and outcomes were discounted at an annual rate of 2.5%. RESULTS: Axi-cel is associated with an incremental cost-effectiveness ratio of €15,520 per QALY compared with tisa-cel. CONCLUSION: Based on explicit willingness-to-pay thresholds applied in Europe, axi-cel is expected to be a cost-effective use of healthcare resources in real-world clinical settings compared with tisa-cel in 3L+ r/r DLBCL.

Costs of care during chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell lymphomas.

High upfront cost may be a barrier to adopting chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory B-cell lymphoma. Data on the real-world costs are limited. Using the Blue Cross Blue Shield Axis database, we evaluated 271 commercially insured patients who received CAR-T therapy for B-cell lymphoma (median age = 58 years; men = 68%; diffuse large B-cell lymphoma = 87%; inpatient CAR-T therapy = 85%). Our peri-CAR-T period of interest was from 41 days before to 154 days after CAR-T therapy index divided into seven 28-day intervals. Median total costs were $608 100 (interquartile range, IQR = $534 100-$732 800); 8.5% of patients had total costs exceeding $1 million. The median cost of CAR-T therapy products was $402 500, and the median out-of-pocket copayment was $510. Monthly costs were highest during the month of CAR-T therapy administration (median = $521 500), with median costs below $25 000 in all other 28-day intervals. Costs of CAR-T therapy use were substantial, largely driven by product acquisition. Future studies should examine the relationship between costs, access, and financial outcomes.

CAR T-Cell Therapy: A Promising Modality for Autoimmune Diseases.

Chimeric Antigen Receptor (CAR) T-cells have emerged as a promising immune effector cell-based therapy. With promising results and approval for the treatment of hematological malignancies, we discuss the scope of this novel therapeutic modality in systemic autoimmune diseases and immune-mediated inflammatory disorders refractory to conventional and biological disease-modifying agents.

Feasibility of collecting longitudinal patient-reported outcomes in individuals with relapsed or refractory large B-cell lymphoma who received chimeric antigen receptor T-cell (CART) therapy.

PURPOSE: Chimeric antigen receptor T-cell (CART) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute and long-term toxicities. To understand the patient perspective, we measured a patient-reported outcome (PRO), specifically, health-related quality of life (HRQoL), at multiple time points over one year. METHODS: This was a prospective feasibility study of a cohort of patients who were eligible for standard of care CART therapy, tisagenlecleucel. Demographic data and disease characteristics were collected. HRQoL was measured using FACT-Lym at baseline, and months 1, 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma subscale. RESULTS: Thirty-four of 35 patients approached, consented to participate. Two of them did not receive their infusion due to progressive disease. 50% were female and median age was 62 (23-77). Twenty-nine patients (91%) completed baseline FACT-Lym and 20 of 21 (95%) eligible patients completed 12-month FACT-Lym. 52% completed all 4 post-baseline FACT-Lym measures. Exploratory analyses for changes in FACT-Lym scores are reported. CONCLUSION: It is feasible to measure longitudinal PROs in patients who receive CART therapy. This study will inform future studies in evaluating the patient perspective on CART therapy.

A Multicenter Real-life Prospective Study of Axicabtagene Ciloleucel versus Tisagenlecleucel Toxicity and Outcomes in Large B-cell Lymphomas.

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel's superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies.

Toward a comprehensive solution for treating solid tumors using T-cell receptor therapy: A review.

T-cell receptor therapy (TCR-T) has demonstrated efficacy, durability, and safety advantages in certain solid tumors (such as human papillomavirus-related tumors, synovial sarcoma, and melanoma). This study aimed to provide careful considerations for developing TCR-T for solid tumors. Therefore, in this review, we have summarized the current clinical application, advantage of TCR-T modalities and explored efficacy/safety-related parameters, particularly avidity, pharmacokinetics/pharmacodynamics, and indications, for solid tumors. Furthermore, we have investigated critical factors related to avidity, including antigen selection, T-cell receptor acquisition, optimization, and co-receptor engagement. Moreover, we have re-examined the expression of tumor antigens for a potentially higher coverage rate of solid tumors based on the current RNA-seq datasets. Finally, we have discussed the current limitations and future directions of TCR-Ts.

Dermatologic Adverse Events Associated With Chimeric Antigen Receptor T-Cell Therapy: A Pharmacovigilance Analysis of the FDA Reporting System.

Chimeric antigen receptor T-cell (CAR-T) therapy, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), has demonstrated significant efficacy in treating refractory or relapsed diffuse large B-cell lymphoma and B-cell acute lymphoblastic leukemia. Though adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well characterized, the dermatologic adverse event (DAE) profile is less thoroughly described. This study aims to provide the first comprehensive analysis of DAEs associated with axi-cel and tisa-cel using real-world data from the FDA Adverse Event Reporting System (FAERS) database. FAERS database reports citing axi-cel or tisa-cel in patients aged 16 years or older were included, excluding duplicate reports and off-label indications. Disproportionality analysis by reporting odds ratio (ROR) was utilized to detect increased reporting of drug-adverse event combinations. Of the 11,256,845 reports in the FAERS database, 5559 identified CAR-T therapy as the primary suspected drug. After exclusions, 3,666 reports were analyzed (2,168 for axi-cel and 1,498 for tisa-cel). Among these, 2.7% of axi-cel and 5.1% of tisa-cel cases reported DAEs. There was a statistically significant increased reporting of 2 DAE groups associated with CAR-T therapy: severe cutaneous eruptions (ROR 5.18, 95% CI 1.29, 20.76) and vascular cutaneous (ROR 2.91, 95% CI 1.51, 5.60). The median time to DAE onset was 3 days after CAR T-cell infusion. Death was a reported outcome in 11.9% and 13.0% of axi-cel and tisa-cel DAE cases, respectively, and in 50% and 25% of severe cutaneous eruptions and vascular cutaneous cases, respectively. This study reveals a significantly increased reporting rate of severe cutaneous eruptions and vascular cutaneous DAEs associated with CAR-T therapy, with both event groups associated with high mortality. These results emphasize the importance of monitoring dermatologic toxicities in clinical practice to ensure timely identification and management of potentially severe adverse events.

Cost-utility analysis of second-line axicabtagene ciloleucel versus standard of care in Japan based on the ZUMA-7 trial.

Aim: To perform a cost-effectiveness analysis comparing axicabtagene ciloleucel (axi-cel) with standard of care (SoC; salvage chemoimmunotherapy, followed by high-dose therapy with autologous stem cell rescue for responders) for second-line (2L) treatment of adults with relapsed or refractory large B-cell lymphoma (r/r LBCL) in the pivotal ZUMA-7 trial data from a Japanese payer perspective.Materials & methods: A three-state partitioned survival model was utilized using population and clinical inputs from the ZUMA-7 trial data over a lifetime horizon.Results: Axi-cel was associated with greater incremental quality-adjusted life-years (2.06) and higher incremental total costs ($48,685.59/¥6.9 million) leading to an incremental cost-effectiveness ratio of $23,590.34/¥3.3 million per quality-adjusted life-years compared with SoC.Conclusion: Axi-cel is a cost-effective treatment alternative to SoC for 2L treatment of adults with r/r LBCL.

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Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy.

Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy for treatment of myeloma. Targeted messenger RNA sequencing revealed the presence of CAR gene product in tumor cells. Whole-genome sequencing of samples of tumor and peripheral blood identified a single lentiviral insertion site within the second intron of the SSU72 gene. In addition, numerous genetic alterations that may have contributed to malignant transformation were identified in the tumor sample. (Funded by MedStar Georgetown University Hospital.).

Advances in CAR-T-cell therapy in T-cell malignancies.

Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.

Recent Advances in CAR-T Therapy.

Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a patient's T cells are programmed to act against tumor cells. We discuss the process of manufacturing CAR-T cells, the common side effects of therapy, and the recent emerging risk of T-cell malignancies after treatment.