CAR T-cell therapy in cancer: Integrating nursing perspectives for enhanced patient care.

Chimeric antigen receptor (CAR) T-cell therapy represents a significant advancement in cancer treatment, particularly for hematologic malignancies. Various cancer immunotherapy strategies are presently being explored, including cytokines, cancer vaccines, immune checkpoint inhibitors, immunomodulators monoclonal antibodies, etc. The therapy has shown impressive efficacy in treating conditions such as acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma, often leading to complete remission in refractory cases. However, the clinical application of CAR T-cell therapy is accompanied by challenges, notably severe side effects. Effective management of these adverse effects requires meticulous monitoring and prompt intervention, highlighting the critical role of nursing in this therapeutic process. Nurses play a crucial role in patient education, monitoring, symptom management, care coordination, and psychosocial support, ensuring safe and effective treatment. As research advances and new CAR T-cell therapies are developed, the role of nursing professionals remains pivotal in optimizing patient outcomes. The continued evolution of CAR T-cell therapy promises improved outcomes, with nursing professionals integral to its success.

Advancements and Challenges in Personalized Therapy for BRAF-Mutant Melanoma: A Comprehensive Review.

Over the past several decades, advancements in the treatment of BRAF-mutant melanoma have led to the development of BRAF inhibitors, BRAF/MEK inhibitor combinations, anti-PD-1 therapy, and anti-CTLA4 therapy. Although these therapies have shown substantial efficacy in clinical trials, their sustained effectiveness is often challenged by the tumor microenvironment, which is a highly heterogeneous and complex milieu of immunosuppressive cells that affect tumor progression. The era of personalized medicine holds substantial promise for the tailoring of treatments to individual genetic profiles. However, tumor heterogeneity and immune evasion mechanisms contribute to the resistance to immunotherapy. Despite these challenges, tumor-infiltrating lymphocyte (TIL) therapy, as exemplified by lifileucel, has demonstrated notable efficacy against BRAF V600-mutant melanoma. Additionally, early response biomarkers, such as COX-2 and MMP2, along with FDG-PET imaging, offer the potential to improve personalized immunotherapy by predicting patient responses and determining the optimal treatment duration. Future efforts should focus on reducing the T-cell harvesting periods and costs associated with TIL therapy to enhance efficiency and accessibility.

Targeting GPRC5D for multiple myeloma therapy.

Given its nearly ubiquitous expression on plasma cells and limited expression on essential normal tissue, the G protein-coupled receptor class C group 5 member D (GPRC5D) presents a promising opportunity for utilization as an immunotherapy target in multiple myeloma (MM). The therapeutic strategies targeting GPRC5D, such as bispecific antibodies (BsAbs), chimeric antigen receptor (CAR) T cells, and antibody-drug conjugates (ADCs), have been prominently emphasized in relapsed/refractory MM (R/R MM) in recent years. Further clinical trials are necessary to confirm the long-term efficacy of GPRC5D-targeting immunotherapies alone, explore their potentials co-targeting with other specific antigens, or investigate their combinations with existing treatments to overcome MM resistance. This review provides an overview of current research progress in GPRC5D, encompassing its biological characteristics and translational journey from laboratory to clinical application.

Salivary gland swelling as a characteristic manifestation of local cytokine release syndrome after anti-CD19 chimeric antigen receptor T cell therapy: A case series.

Cytokine release syndrome (CRS) is the most common adverse event of chimeric antigen receptor T (CAR-T) cell therapy and is usually characterized by systemic symptoms such as fever, hypotension, and hypoxia. However, there have been several recent reports of local CRS characterized by cervical swelling. This localized syndrome can cause life-threatening laryngeal edema and requires early diagnostic treatment. Here we report 3 cases of local CRS where bilateral salivary gland swelling emerged following anti-CD19 CAR-T cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Following tocilizumab treatment for systemic CRS, all patients exhibited cervical swelling. Physical examinations revealed significant swelling of the bilateral submandibular glands, and computed tomography scans showed substantial enlargement of the bilateral parotid and submandibular glands. Immediate treatment with dexamethasone effectively managed the potentially life-threatening laryngeal or pharyngeal edema, thereby preventing severe airway obstruction. This study has demonstrated, for the first time to our knowledge, that salivary gland enlargement is a common finding in local CRS. This observation suggests that physicians should continue to closely monitor the risk of developing cervical edema leading to life-threatening airway obstruction after systemic CRS, even in patients treated with tocilizumab. If salivary gland swelling is observed, it would be better to consider prompt evaluation and dexamethasone administration.

Effects of Consolidation Therapy With Autologous Hematopoietic Stem Cell Transplantation After BCMA-CAR T-Cell Therapy on the Survival of Patients With Relapsed or Refractory Multiple Myeloma.

Despite the success of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory multiple myeloma (RRMM), failure after CAR T-cell therapy remains an unmet medical need. An effective consolidation therapy after CAR T-cell therapy may improve the prognosis of RRMM. To investigate the effects of consolidation therapy with autologous hematopoietic stem cell transplantation (AHCT) after B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy on the prognosis of RRMM patients. This retrospective study included 39 RRMM patients who received BCMA-targeted CAR T-cell therapy. Basic clinical, therapy, and outcome data were collected, and factors associated with survival were analyzed. Among the 39 RRMM patients included in the study, 15 had high-risk cytogenetics and 11 had extramedullary disease (EMD). All 39 patients reached peak CAR T-cell expansion within 28 days after infusion. Twenty-six patients developed cytokine release syndrome, including 12 grade 1 and 14 grade 2 cases. Survival analysis revealed that high-risk cytogenetics, high tumor load (International Staging System [ISS] stage III), and EMD were negatively associated with progression-free survival (PFS) and overall survival (OS). Thirteen patients received consolidation AHCT therapy 50-276 days after CAR T-cell therapy, with a median interval of 92 days. No serious complications occurred after consolidation AHCT. Survival analysis showed that consolidation AHCT effectively improved OS and PFS over maintenance chemotherapy. Moreover, Cox regression analysis identified low tumor load (ISS stage I/II) and consolidation AHCT as independent predictors of superior PFS and OS and high-risk cytogenetics as an independent risk factor for poor PFS. Consolidation AHCT after CAR T-cell therapy in RRMM patients can improve patient survival.

Proceedings of the 2024 Third Annual ASTCT-NMDP ACCESS Initiative Workshop.

The Third Annual Workshop of the American Society for Transplantation and Cellular Therapy (ASTCT) and National Marrow Donor Program (NMDP) ACCESS Initiative occurred on July 23 and 24, 2024. Content from the workshop is provided to inform the hematopoietic cell transplantation (HCT) and cellular therapy (CT) ecosystem about progress and direction of the collaborative. Highlights from the meeting are reviewed, including the inaugural Corporate Roundtable and Advocacy Day, new partnerships with non-profit organizations, and updates on projects from the Awareness, Poverty and Race and Ethnicity Inequity Committees. In addition, the Junior Faculty and Trainee Immersion Program-sponsored efforts in workforce diversity and physician advocacy are also presented. Lastly, continued education was provided on patient and caregiver participation as well as community engagement. As it enters its third year, the ASTCT-NMDP ACCESS Initiative will transition from foundation-building as a grass roots collaborative to intentional impact in reducing barriers and improving outcome disparities for all patients in need of HCT/CT. Enthusiasm for and participation in the ACCESS Initiative remain high and both are needed to sustain progress in achieving its goal in enabling all patients in need to receive HCT/CT.

Earlier intrathecal dexamethasone effectively alleviate immune effector cell-associated neurotoxicity syndrome.

Chimeric antigen receptor T cell (CAR-T) therapy is effective in treating relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, the side effects of immune effector cell-associated neurotoxicity syndrome (ICANS) remain a problem. The current frontline therapies for ICANS include steroids and supportive care. For the steroid-refractory and severe ICANS, several studies have reported excellent efficacy of intrathecal (IT) corticosteroids alone or in combination with chemotherapy. However, whether patients can benefit from IT dexamethasone (dex) before grade 3 or refractory ICANS remains unclear. In this study, the patients with ICANS (≥1) after CAR-T cell therapy were assigned to the IT group and non-IT group. Clinical information, laboratory parameters, and serum cytokine levels were analyzed. A significant and rapid reduction in inflammatory cytokines and biomarkers was observed after 24 h of IT dex treatment. With IT dex, 83.3 % (15/18) of patients recovered from neurotoxicity. Moreover, this option significantly shortens the recovery time of ICANS without affecting the efficacy of CAR-T cell therapy. Earlier initiation of IT dex is the optimal management of ICANS resulting from CAR-T cell therapy, but larger sample studies are needed to determine its efficacy in these settings.

How can we improve the successful identification of patients suitable for CAR-T cell therapy?

INTRODUCTION: In recent years, chimeric antigen receptor T (CAR-T) cell therapy has resulted in a breakthrough in the treatment of patients with refractory or relapsed hematological malignancies. However, the identification of patients suitable for CAR-T cell therapy needs to be improved. AREAS COVERED: CAR-T cell therapy has demonstrated excellent efficacy in hematological malignancies; however, views on determining when to apply CAR-T cells in terms of the evaluation of patient characteristics remain controversial. EXPERT OPINION: We reviewed the current feasibility and challenges of CAR-T cell therapy in the most common hematological malignancies and classified them according to the disease type and treatment priority, to guide clinicians and researchers in applying and investigating CAR-T cells furtherly.

Influencing factors and solution strategies of chimeric antigen receptor T-cell therapy (CAR-T) cell immunotherapy.

Chimeric antigen receptor T-cesll therapy (CAR-T) has achieved groundbreaking advancements in clinical application, ushering in a new era for innovative cancer treatment. However, the challenges associated with implementing this novel targeted cell therapy are increasingly significant. Particularly in the clinical management of solid tumors, obstacles such as the immunosuppressive effects of the tumor microenvironment, limited local tumor infiltration capability of CAR-T cells, heterogeneity of tumor targeting antigens, uncertainties surrounding CAR-T quality, control, and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy. These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach. In this paper, we comprehensively analyze recent preclinical and clinical reports on CAR-T therapy while summarizing crucial factors influencing its efficacy. Furthermore, we aim to identify existing solution strategies and explore their current research status. Through this review article, our objective is to broaden perspectives for further exploration into CAR-T therapy strategies and their clinical applications.

Systemic toxicity of CAR-T therapy and potential monitoring indicators for toxicity prevention.

Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects.

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy.

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

Current progress in CAR-based therapy for kidney disease.

Despite significant breakthroughs in the understanding of immunological and pathophysiological features for immune-mediated kidney diseases, a proportion of patients exhibit poor responses to current therapies or have been categorized as refractory renal disease. Engineered T cells have emerged as a focal point of interest as a potential treatment strategy for kidney diseases. By genetically modifying T cells and arming them with chimeric antigen receptors (CARs), effectively targeting autoreactive immune cells, such as B cells or antibody-secreting plasma cells, has become feasible. The emergence of CAR T-cell therapy has shown promising potential in directing effector and regulatory T cells (Tregs) to the site of autoimmunity, paving the way for effective migration, proliferation, and execution of suppressive functions. Genetically modified T-cells equipped with artificial receptors have become a novel approach for alleviating autoimmune manifestations and reducing autoinflammatory events in the context of kidney diseases. Here, we review the latest developments in basic, translational, and clinical studies of CAR-based therapies for immune-mediated kidney diseases, highlighting their potential as promising avenues for therapeutic intervention.

Enhanced platelet function through CAR-T cell therapy in relapsed/refractory multiple myeloma.

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91-87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11-22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0-2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy.

Case report: Bridging radiation therapy before chimeric antigen receptor T-cell therapy induces sustained remission in patients with relapsed/refractory double-expressor diffuse large B-cell lymphoma with localized compressive symptoms.

Background: High-risk double-expressor diffuse large B-cell lymphoma has an inferior prognosis following standard first-line therapy. After failure of second-line therapy, treatment options are limited if accompanied by localized compressive symptoms. Chimeric Antigen Receptor T cell (CAR-T) therapy preceded by bridging radiotherapy may be an effective emerging therapy. Case presentation: We report a 66-year-old female patient diagnosed with stage IV double-expressor diffuse large B-cell lymphoma. The patient achieved progressive disease after two cycles of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone and continued to develop cervical lymph node recurrence after second-line therapy. The patient was infused with CAR-T cells after receiving focal bridging radiotherapy and remained in complete response more than 9 months after treatment. In addition, the patients did not experience serious adverse reactions related to radiotherapy as well as CAR-T cell therapy. Conclusions: In this article, we describe a patient with double-expressor diffuse large B-cell lymphoma with localized compression symptoms after second-line treatment failure who benefited from CAR-T combined with focal bridging radiotherapy.

Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.

Background: On April 18, 2024, the U.S. Food and Drug Administration officially required updating of the "boxed warning" for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel. Methods: We extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset. Results: A total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed "unexpected signals," including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12-122.03) and plasma cell myeloma (12.45; 8.18-18.95) for ide-cel, and increased serum ferritin (24.98; 8.0-77.58) and large intestine perforation (18.57; 5.98-57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged ≥65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration. Conclusion: This study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.

Mesenchymal stem cell infusion for enhancing hematopoietic recovery and addressing cytopenias in CAR-T cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy. METHODS: We conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes. RESULTS: All patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells. CONCLUSIONS: Our findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells. HIGHLIGHTS: 1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs.

Antigen escape in CAR-T cell therapy: Mechanisms and overcoming strategies.

Chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating hematological malignancies and certain solid tumors. However, its efficacy is often hindered by negative relapses resulting from antigen escape. This review firstly elucidates the mechanisms underlying antigen escape during CAR-T cell therapy, including the enrichment of pre-existing target-negative tumor clones, antigen gene mutations or alternative splicing, deficits in antigen processing, antigen redistribution, lineage switch, epitope masking, and trogocytosis-mediated antigen loss. Furthermore, we summarize various strategies to overcome antigen escape, evaluate their advantages and limitations, and propose future research directions. Thus, we aim to provide valuable insights to enhance the effectiveness of CAR-T cell therapy.

Novel approaches to primary membranous nephropathy: Beyond the KDIGO guidelines.

Primary membranous nephropathy (PMN) is an immune-mediated glomerular disease. Rituximab (RTX) is recommended as a first-line immunosuppressive therapy and shows high clinical efficacy, but the optimal doses remain controversial. Approximately 20%-40% of PMN patients experience RTX resistance and failure. Reduced bioavailability, RTX internalization and attack, anti-RTX antibody production, autoreactive B-cell reservoirs and chronic and irreversible renal damage may contribute to this problem. Therefore, new treatment modalities are needed to compensate for this deficit. New interventions and new dose combinations are being proposed. Multiple drug combination therapies show comparable clinical efficacy to conventional treatments by blocking the production of disease-causing antibodies in multiple directions, and can reduce single-agent doses without increasing adverse effects. New therapies that directly target B cells, plasma cells, and antibody production have shown encouraging results. In addition, new techniques for sweeping antibodies and chimeric antigen receptor T-cell therapy also may be promising strategies for PMN. Immunoadsorption could be used as an auxiliary choice for severe cases. This article explores new treatments for PMN and highlights possible mechanisms for potential new technologies that offer new ideas for treatment.

Evaluating pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) is an uncommon non-Hodgkin lymphoma that is generally considered incurable. Covalent BTK inhibitors (cBTKi) are the cornerstone of treatment for relapsed or refractory (R/R) MCL, but treatment options are limited and prognosis is poor after cBTKi failure. Pirtobrutinib is a non-covalent BTK inhibitor that has demonstrated excellent efficacy and safety and represents an important new treatment in the evolving treatment landscape of R/R MCL. AREAS COVERED: This review will provide an overview of the therapeutic landscape of R/R MCL, characteristics of pirtobrutinib, and efficacy and safety data of pirtobrutinib in R/R MCL from pivotal clinical trials. PubMed and major hematology conference proceedings were searched to identify relevant studies involving pirtobrutinib. EXPERT OPINION: For patients with R/R MCL that has progressed after treatment with cBTKi, pirtobrutinib is an important and efficacious treatment that confers favorable outcomes. In the post-cBTKi setting, when chimeric antigen receptor (CAR) T-cell therapy is not available or feasible, pirtobrutinib is the preferred treatment for R/R MCL. How to sequence or combine pirtobrutinib with CAR T-cell therapy and other available or emerging therapies requires further investigation. Future studies should also explore the role of pirtobrutinib in earlier lines of therapy for MCL.