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International Immunopharmacology Jan 2023Multiple myeloma (MM) is the second most common hematological malignancy without cure, and Chimeric Antigen Receptor T Cell (CAR-T) therapy has been shown great...
BACKGROUND
Multiple myeloma (MM) is the second most common hematological malignancy without cure, and Chimeric Antigen Receptor T Cell (CAR-T) therapy has been shown great promising in MM. Unlike previous published studies mainly focusing on efficacy and safety, this study aims to summarize time points in the process of CAR-T therapy in MM and establish a standardized time-related CAR-T therapy platform to provide a reference for CAR-T treatment in MM.
METHODS
All the literatures were retrieved from PubMed, Web of Science, Embase, American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA). Relevant median detection time of efficacy and safety-related indicators of CAR-T therapy in MM were extracted from included literatures, and median values were applied to represent detection time points of indicators. Notably, the median values were not the certain and optimal detection time points, while the significance is that indicators could be detected more frequently around the median values to obtain the ideal results.
RESULTS
This review presented the median detection time points of efficacy and safety-related indicators of CAR-T therapy in MM according to the chronological order. For short-term effects on inflammation status within 1 month after CAR-T initiation, the median time points of cytokine release syndrome onset, immune effector cell-associated neurotoxicity syndrome onset, neutrophils recovery and CAR-T expansion peak were 4.5, 8, 10 and 12 days, respectively. For medium-term effects on clinical response in MM beyond 1 month and up to 3 months following CAR-T infusion, the median time points of minimal residual disease negativity, the reduction of serum light chain to minimum, platelet recovery and the reduction of M protein to minimum were 30, 30, 44 and 90 days, respectively.
CONCLUSIONS
This systematic review summarized the median detection time points of efficacy and safety-related indicators of CAR-T therapy in MM and constructed the time-related CAR-T therapy platform, providing an evidence-based standard for establishment of CAR-T treatment regimen in MM.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Immunotherapy; T-Lymphocytes
PubMed: 36700772
DOI: 10.1016/j.intimp.2022.109592 -
Journal of Experimental & Clinical... Jan 2023CAR-T cells are widely recognized for their potential to successfully treat hematologic cancers and provide durable response. However, severe adverse events such as... (Review)
Review
CAR-T cells are widely recognized for their potential to successfully treat hematologic cancers and provide durable response. However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity are concerning. Our goal is to assess CAR-T cell clinical trial publications to address the question of whether administration of CAR-T cells as dose fractions reduces toxicity without adversely affecting efficacy. Systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematologic cancers. Studies published in English were considered. Studies in children (age < 18), solid tumors, bispecific CAR-T cells, and CAR-T cell cocktails were excluded. Data was extracted from the studies that met inclusion and exclusion criteria. Review identified a total of 18 studies that used dose fractionation. Six studies used 2-day dosing schemes and 12 studies used 3-day schemes to administer CAR-T cells. Three studies had both single dose and fractionated dose cohorts. Lower incidence of Grade ≥ 3 CRS and neurotoxicity was seen in fractionated dose cohorts in 2 studies, whereas 1 study reported no difference between single and fractionated dose cohorts. Dose fractionation was mainly recommended for high tumor burden patients. Efficacy of CAR-T cells in fractionated dose was comparable to single dose regimen within the same or historical trial of the same agent in all the studies. The findings suggest that administering dose fractions of CAR-T cells over 2-3 days instead of single dose infusion may mitigate the toxicity of CAR-T cell therapy including CRS and neurotoxicity, especially in patients with high tumor burden. However, controlled studies are likely needed to confirm the benefits of dose fractionation.
Topics: Child; Humans; Immunotherapy, Adoptive; Hematologic Neoplasms; Neurotoxicity Syndromes; Cytokine Release Syndrome; T-Lymphocytes
PubMed: 36627710
DOI: 10.1186/s13046-022-02540-w -
Bone Marrow Transplantation Apr 2023Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD... (Review)
Review
Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD portends a high risk of death and effective management is not well established. CD19-targeted CAR-T cell therapy has been utilized, but the risks and benefits are unknown. We report the first case of diffuse large B-cell lymphoma (DLBCL) PTLD treated with lisocabtagene maraleucel and present a systematic literature review of SOTRs with PTLD treated with CD19 CAR-T therapy. Our patient achieved a complete response (CR) with limited toxicity but experienced a CD19 relapse 8 months after infusion despite CAR-T persistence. Literature review revealed 14 DLBCL and 2 Burkitt lymphoma PTLD cases treated with CD19 CAR-T cells. Kidney (n = 12), liver (n = 2), heart (n = 2), and pancreas after kidney (n = 1) transplant recipients were analyzed. The objective response rate (ORR) was 82.4% (14/17), with 58.5% (10/17) CRs and a 6.5-month median duration of response. Among kidney transplant recipients, the ORR was 91.7% (11/12). Allograft rejection occurred in 23.5% (4/17). No graft failure occurred. Our analysis suggests that CD19 CAR-T therapy offers short-term effectiveness and manageable toxicity in SOTRs with R/R PTLD. Further investigation through larger datasets and prospective study is needed.
Topics: Humans; Antigens, CD19; Epstein-Barr Virus Infections; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Lymphoproliferative Disorders; Neoplasm Recurrence, Local; Organ Transplantation; Receptors, Chimeric Antigen; Transplant Recipients
PubMed: 36575360
DOI: 10.1038/s41409-022-01907-z -
Journal For Immunotherapy of Cancer Dec 2022The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently... (Review)
Review
The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50-100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.
Topics: Child; Humans; Adolescent; T-Lymphocytes; Immunotherapy, Adoptive; Neoplasms; Hematologic Neoplasms; Treatment Outcome
PubMed: 36549782
DOI: 10.1136/jitc-2022-005678 -
JCO Oncology Practice Mar 2023Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse...
Development of a Core Set of Patient- and Caregiver-Reported Signs and Symptoms to Facilitate Early Recognition of Acute Chimeric Antigen Receptor T-Cell Therapy Toxicities.
PURPOSE
Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post-CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy.
METHODS
We performed a systematic review of phase II/III trials of US Food and Drug Administration-approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell-dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers.
RESULTS
From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments.
CONCLUSION
This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Caregivers; Receptors, Antigen, T-Cell; Outpatients; Cell- and Tissue-Based Therapy
PubMed: 36508702
DOI: 10.1200/OP.22.00501 -
Clinical Lymphoma, Myeloma & Leukemia Jan 2023Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities,... (Review)
Review
Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Prospective Studies; Transplantation, Autologous; Receptors, Antigen, T-Cell; Antigens, CD19; Lymphoma; Central Nervous System Neoplasms; Lymphoma, Non-Hodgkin; Neoplasms, Second Primary; Central Nervous System; Lymphoma, Large B-Cell, Diffuse
PubMed: 36328891
DOI: 10.1016/j.clml.2022.09.008 -
British Journal of Haematology Jan 2023
Meta-Analysis
Topics: Humans; Receptors, Chimeric Antigen; Standard of Care; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Cell- and Tissue-Based Therapy; Antigens, CD19; Receptors, Antigen, T-Cell
PubMed: 36281746
DOI: 10.1111/bjh.18506 -
Blood Advances Jan 2023Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and... (Meta-Analysis)
Meta-Analysis
Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Anti-CD19 chimeric antigen receptor (CAR) T cells, effective in systemic large B-cell lymphoma (LBCL), have shown responses in PCNSL and SCNSL in early reports, but with limited sample size. We, therefore, performed a comprehensive systematic review and meta-analysis of all published data describing CAR T-cell use in PCNSL and SCNSL. This identified 128 patients with PCNSL (30) and SCNSL (98). Our primary objectives were to evaluate CAR T-cell specific toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS]) as well as response rates in these 2 populations. Seventy percent of patients with PCNSL had CRS of any grade (13% grade 3-4) and 53% had ICANS of any grade (18% grade 3-4). Comparatively, 72% of the SCNSL cohort experienced CRS of any grade (11% grade 3-4) and 48% had ICANS of any grade (26% grade 3-4). Of the patients with PCNSL, 56% achieved a complete remission (CR) with 37% remaining in remission at 6 months. Similarly, 47% of patients with SCNSL had a CR, with 37% in remission at 6 months. In a large meta-analysis of central nervous system (CNS) lymphomas, toxicity of anti-CD19-CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.
Topics: Humans; Antigens, CD19; Central Nervous System Neoplasms; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasms, Second Primary; Neurotoxicity Syndromes
PubMed: 36260735
DOI: 10.1182/bloodadvances.2022008525 -
Frontiers in Genetics 2022In the tumor microenvironment, tumor-infiltrating immune cells (TIICs) are a key component. Different types of TIICs play distinct roles. CD8+ T cells and natural killer...
In the tumor microenvironment, tumor-infiltrating immune cells (TIICs) are a key component. Different types of TIICs play distinct roles. CD8+ T cells and natural killer (NK) cells could secrete soluble factors to hinder tumor cell growth, whereas regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) release inhibitory factors to promote tumor growth and progression. In the meantime, a growing body of evidence illustrates that the balance between pro- and anti-tumor responses of TIICs is associated with the prognosis in the tumor microenvironment. Therefore, in order to boost anti-tumor response and improve the clinical outcome of tumor patients, a variety of anti-tumor strategies for targeting TIICs based on their respective functions have been developed and obtained good treatment benefits, including mainly immune checkpoint blockade (ICB), adoptive cell therapies (ACT), chimeric antigen receptor (CAR) T cells, and various monoclonal antibodies. In recent years, the tumor-specific features of immune cells are further investigated by various methods, such as using single-cell RNA sequencing (scRNA-seq), and the results indicate that these cells have diverse phenotypes in different types of tumors and emerge inconsistent therapeutic responses. Hence, we concluded the recent advances in tumor-infiltrating immune cells, including functions, prognostic values, and various immunotherapy strategies for each immune cell in different tumors.
PubMed: 36246629
DOI: 10.3389/fgene.2022.988703 -
Expert Review of Anti-infective Therapy Nov 2022Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment option for relapsed or refractory B-cell malignancies and multiple myeloma.... (Meta-Analysis)
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. Underlying and treatment-related variables 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 27 May 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% (I = 96.31%) and 16.2% (I = 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% (I = 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.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Antigens, CD19; Hematologic Neoplasms; Neoplasms
PubMed: 36148506
DOI: 10.1080/14787210.2022.2128762