'The last bridge'- How patients experience the CAR T-cell therapy. A qualitative study.

PURPOSE: CAR T-cell therapy gives patients new hope, who are diagnosed with relapsed or refractory B-cell lymphoma or B-cell leukaemia. To date, there is no scientific knowledge about the experiences of patients with CAR T-cell therapy, their process of treatment decision making or how they handle potential side effects. The study aims at deepening the understanding of the patient's experiences, indicating how to improve nursing care for this patient population. METHOD: A qualitative study was carried out. Episodic guideline-based interviews were conducted with 14 patients who had received CAR T-cell therapy. The data analysis was performed according to the Grounded Theory. The study took place at a German university hospital. RESULTS: Data analysis showed five sequential phases including the following concepts: 'living with cancer recurrence', 'deciding on CAR T-cell therapy', 'waiting for the reinfusion of the CAR T-cells', 'experiencing CAR T-cell therapy' and 'recovering and staying healthy'. The decision for CAR T-cell therapy was characterised by the lack of alternatives and uncertainty about the outcome and side effects. CONCLUSIONS: Before, during and after CAR T-cell therapy, patients are faced with major challenges for which they need nursing support and guidance. These include preparation for CAR T-cell therapy, handling of side effects and preparation for discharge home.

Improving the safety of CAR-T-cell therapy: The risk and prevention of viral infection for patients with relapsed or refractory B-cell lymphoma undergoing CAR-T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy, an innovative immunotherapeutic against relapsed/refractory B-cell lymphoma, faces challenges due to frequent viral infections. Despite this, a comprehensive review addressing risk assessment, surveillance, and treatment management is notably absent. This review elucidates immune response compromises during viral infections in CAR-T recipients, collates susceptibility risk factors, and deliberates on preventive strategies. In the post-pandemic era, marked by the Omicron variant, new and severe threats to CAR-T therapy emerge, necessitating exploration of preventive and treatment measures for COVID-19. Overall, the review provides recommendations for viral infection prophylaxis and management, enhancing CAR-T product safety and recipient survival.

Current perspectives on resistance to chimeric antigen receptor T-cell therapy and strategies to improve efficacy in B-cell lymphoma.

Although chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with chemo-refractory B-cell lymphoma, a significant portion is refractory or relapse. Resistance is a major barrier to improving treatment efficacy and long-term survival in CAR T-cell therapy, and clinicians have very limited tools to discriminate a priori patients who will or will not respond to treatment. While CD19-negative relapses due to loss of target antigen is well described, it accounts for only about 30% of cases with treatment failure. Recent efforts have shed light on mechanisms of CD19-positive relapse due to tumor intrinsic resistance, T-cell quality/manufacturing, or CAR T-cell exhaustion mediated by hostile tumor microenvironment. Here, we review the latest updates of preclinical and clinical trials to investigate the mechanisms of resistance and relapse post CAR T-cell therapy in B cell lymphoma and discuss novel treatment strategies to overcome resistance as well as advances that are useful for a CAR T therapist to optimize and personalize CAR T-cell therapy.

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.

Sequential antigen loss and branching evolution in lymphoma after CD19- and CD20-targeted T-cell-redirecting therapy.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T cells and CD20 targeting T-cell-engaging bispecific antibodies (bispecs) have been approved in B-cell non-Hodgkin lymphoma lately, heralding a new clinical setting in which patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19- and CD20-directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline on 28 longitudinally collected specimen from 7 patients, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T-cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T-cell therapy and reported the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20+ subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as not only an evolutionary bottleneck selecting for antigen loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.

Identifying and addressing unmet clinical needs in primary cutaneous B-cell lymphoma: A consensus-based paper from an ad-hoc international panel.

Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners.

Tumor microenvironment and CAR-T cell immunotherapy in B-cell lymphoma.

Chimeric receptor antigen T cell (CAR-T cell) therapy has demonstrated effectiveness and therapeutic potential in the immunotherapy of hematological malignancies, representing a promising breakthrough in cancer treatment. Despite the efficacy of CAR-T cell therapy in B-cell lymphoma, response variability, resistance, and side effects remain persistent challenges. The tumor microenvironment (TME) plays an intricate role in CAR-T cell therapy of B-cell lymphoma. The TME is a complex and dynamic environment that includes various cell types, cytokines, and extracellular matrix components, all of which can influence CAR-T cell function and behavior. This review discusses the design principles of CAR-T cells, TME in B-cell lymphoma, and the mechanisms by which TME influences CAR-T cell function. We discuss emerging strategies aimed at modulating the TME, targeting immunosuppressive cells, overcoming inhibitory signaling, and improving CAR-T cell infiltration and persistence. Therefore, these processes enhance the efficacy of CAR-T cell therapy and improve patient outcomes in B-cell lymphoma. Further research will be needed to investigate the molecular and cellular events that occur post-infusion, including changes in TME composition, immune cell interactions, cytokine signaling, and potential resistance mechanisms. Understanding these processes will contribute to the development of more effective CAR-T cell therapies and strategies to mitigate treatment-related toxicities.

[Characteristics and impact factors of SARS-CoV-2 infection in adult patients with relapsed/refractory B-cell non-Hodgkin lymphoma receiving chimeric antigen receptor T-cell therapy].

Objective: To explore the clinical characteristics and treatment of COVID-19 infection in patients with relapsed/refractory B-cell non-Hodgkin lymphoma before and after receiving chimeric antigen receptor T-cell therapy, and study the influencing factors of severe COVID-19 infection in these patients. Methods: The data of 59 patients with relapsed/refractory B-cell non-Hodgkin lymphoma who received chimeric antigen receptor T-cell therapy at the Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology and Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University between December 2017 and February 2023, and who were infected with novel coronavirus between December 2022 and February 2023 were retrospectively studied. Patients were divided into light, medium, severe, and critical groups, and the differences between the groups were analyzed using the chi-square test. A univariate logistic regression model was used to evaluate the contribution of each variable and its relationship with severe infection. The chi-square and Fisher's exact tests were used to analyze the differences between the B-cell aplasia and B-cell recovery (BCR) groups. Results: Of the 59 pre- and post-infusion infections, 39 (66.1%) led to mild COVID-19, 9 (15.3%) resulted in moderate COVID-19, 10 (16.9%) resulted in severe COVID-19, and 1 (1.7%) led to critical COVID-19. Moroever, age greater than 55 years, having received autologous hematopoietic stem cell transplantation, progressive disease status, and B-cell aplasia at the time of diagnosis of COVID-19 infection are factors affecting severe infection. Patients with B-cell aplasia had a more severe infection with COVID-19 (P<0.001), a longer duration (P=0.015), a longer antiviral therapy course (P<0.001), and a higher hospitalization rate (P<0.001) than the BCR group. Conclusion: Active prevention and treatment of COVID-19 infection remains a crucial issue requiring urgent attention in managing patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with chimeric antigen receptor T-cell therapy.

Characteristics of Primary Cutaneous Lymphoma in Italy: A Tertiary Care, Single-Center Study.

Data on primary cutaneous lymphomas (PCLs) patients in the Italian population are limited, and, despite the existence of several treatment options, the management of those patients remains challenging. Our study aimed to investigate the clinical and therapeutic features of PCL patients in a referral center in Italy. We conducted a retrospective study on 100 consecutive PCL patients between January 2017 and December 2022. The mean (SD) age of our cohort was 70.33 (14.14) years. Cutaneous T-cell lymphomas (CTCLs) represented 65% of all cases; the majority were mycosis fungoides (42%), followed by cases of Sezary syndrome (10%) and primary cutaneous anaplastic large cell lymphoma (4%). Cutaneous B-cell lymphomas (CBCLs) accounted for 35 % of PCLs, with 15 cases of primary cutaneous follicle center lymphoma, 10 cases of primary cutaneous diffuse large B-cell lymphoma leg type, and 9 cases of marginal zone B-cell lymphoma. A higher frequency of pruritus (p = 0.008) and higher peripheral blood levels of beta-2 microglobulin (p ≤ 0.001) and lactate dehydrogenase (p = 0.025) were found in CTCLs compared to those of CBCLs. Considering all therapeutic lines performed, treatments were extremely heterogeneous and skin-directed therapies represented the most frequently used approach. Our study confirms the distribution of PCL subtypes formerly reported in the literature and highlights the utility of real-life data in treatments to improve the current management of PCL patients.

Programa de inoculación de estrés para el manejo del malestar emocional asociado a la terapia de células CAR-T: caso clínico / Stress inoculation program for the management of emotional distress associated with CART Cell Therapy: A case study

Objetivo: se presenta un caso clínico de una paciente con linfoma B difuso candidata a recibir tratamiento de células CART, con la que se utiliza un programa de inoculación de estrés debido a las características de la enfermedad y del tratamiento médico, además de la incertidumbre asociada. Metodología: programa de diez sesiones de intervención que se divide en tres fases: conceptualización, que incluye el modelo teórico de estrés y de intolerancia a la incertidumbre; adquisición de estrategias y ensayo que incorpora técnicas de desactivación y cognitivas, planificación de actividades y entrenamiento en habilidades de comunicación; consolidación. Resultados: se evidencia una reducción del malestar emocional, de la sintomatología de ansiedad y bajo estado de ánimo, así como de los niveles de fatiga. Respecto a las estrategias de afrontamiento, tras la intervención psicológica se mantiene el estilo de preocupación ansiosa, aunque se observa un mejor uso de recursos asociados al afrontamiento de espíritu de lucha. Conclusión: la aplicación sistemática de programas para el manejo del estrés puede suponer una estrategia útil y efectiva para la mejora de la salud mental de los pacientes que van a someterse a tratamiento de células CART (AU)

Objective: A case report is presented of a patient with diffuse B lymphoma who is a candidate for CART cell therapy using a stress inoculation program due to the characteristics of the disease and medical treatment and the associated uncertainty. Methodology: psychological program intervention with 10 sessions, divided into three phases: Conceptualization, including the theoretical model of stress and uncertainty intolerance; strategy acquisition and rehearsal, incorporating deactivation and cognitive techniques, activity planning and communication skills training; consolidation. Results: there was a reduction in emotional distress, anxiety symptoms and mood, as well as fatigue levels. In terms of coping strategies, after the psychological intervention, the anxious worrying style is maintained, although a better use of the resources associated with coping with a fighting spirit is observed. Conclusion: Systematic application of stress management programs can be a useful and effective strategy for improving the mental health of patients undergoing CART cell treatment (AU)

Specific Targeting of STAT3 in B Cells Suppresses Progression of B Cell Lymphoma.

The signal transducer and activator of transcription 3 (STAT3), which regulates multiple oncogenic processes, has been found to be constitutively activated in lymphoma, suggesting its potential as a therapeutic target. Here, we constructed an anti-CD19-N-(4-carboxycyclohexylmethyl) maleimide N-hydroxysuccinimide ester (SMCC)-protamine (CSP)-STAT3 small interfering RNA (siRNA) conjugate and demonstrated that the CSP-STAT3 siRNA conjugate could specifically bind to normal B cells and A20 lymphoma cells in vitro. It decreased the STAT3 expression in B cell lymphoma cell lines (A20, SU-DHL-2 and OCI-Ly3), resulting in reduced proliferation of lymphoma cells featured with lower S-phase and higher apoptosis. Using an A20 transplantable lymphoma model, we found that the CSP-STAT3 siRNA conjugate significantly inhibited tumor growth and weight. Ki-67, p-STAT3, STAT3, and serum IL-6 levels were all significantly reduced in A20-bearing mice treated with CSP-STAT3 siRNA. These findings indicate that specifically targeting STAT3 siRNA to B cell lymphoma cell lines can significantly decrease STAT3 activity and inhibit tumor progression in vitro and in vivo, suggesting its potential utilization for cancer treatment.

Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown remarkable results against B-cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumor cells and activated T cells result in production of lactate. The export of lactate is facilitated by expression of monocarboxylate transporter (MCTs). CAR T cells express high levels of MCT-1 and MCT-4 on activation, while certain tumors predominantly express MCT-1. METHODS: Here, we studied the combination of CD19-specific CAR T-cell therapy with pharmacological blockade of MCT-1 against B-cell lymphoma. RESULTS: MCT-1 inhibition with small molecules AZD3965 or AR-C155858 induced CAR T-cell metabolic rewiring but their effector function and phenotype remained unchanged, suggesting CAR T cells are insensitive to MCT-1 inhibition. Moreover, improved cytotoxicity in vitro and antitumoral control on mouse models was found with the combination of CAR T cells and MCT-1 blockade. CONCLUSION: This work highlights the potential of selective targeting of lactate metabolism via MCT-1 in combination with CAR T cells therapies against B-cell malignancies.

[Expert Consensus on the prevention and treatment of indolent B-cell non-Hodgkin lymphoma with novel coronavirus infection].

Indolent B-cell non-Hodgkin lymphoma (B-iNHL) is a group of mature B-cell lymphomas that develop slowly. It is characterized by low immune function and could be risky when complicated with novel coronavirus infection (COVID-19). In order to guide the prevention and treatment of B-iNHL combined with COVID-19, China Anti-Cancer Association Hematological malignancies Committee, the Chinese Society of Hematology Medical Association and Chinese Chronic lymphoproliferative Diseases Working Group formed consensus on COVID-19 vaccination, prognosis, treatment and follow-up of B-iNHL patients for clinician reference.