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Transplantation and Cellular Therapy Jan 2024The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data... (Meta-Analysis)
Meta-Analysis
The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I = 0%) and 5% (95% CI, 0% to 21%; I = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I = 68%) and 40% (95% CI, 3% to 85%; I = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.
Topics: Adult; Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Lymphoma; Organ Transplantation; Adaptor Proteins, Signal Transducing; Antigens, CD19; Cytokine Release Syndrome; Immunosuppressive Agents; Cell- and Tissue-Based Therapy
PubMed: 37279856
DOI: 10.1016/j.jtct.2023.05.018 -
European Journal of Haematology Dec 2023The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency-approved chimeric antigen...
Cost-effectiveness analysis of transplant-ineligible relapsed or refractory diffuse large B-cell lymphoma treatment options-Experience of the efficiency frontier approach.
OBJECTIVES
The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency-approved chimeric antigen receptor T-cell (CAR-T) therapies (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel]) for the third-line onwards (3+L), and targeted therapies (polatuzumab vedotin-bendamustine-rituximab [pola-BR], tafasitamab-lenalidomide [Tafa-L]) for the second-line (2L) onwards. As associated rising treatment costs represent an economic burden, the cost-effectiveness of transplant-ineligible R/R DLBCL interventions was assessed from a German healthcare payer's perspective, using the efficiency frontier (EF) approach.
METHODS
A systematic literature review was performed to determine the clinical benefit concerning median overall survival (OS) of bendamustine-rituximab (BR), rituximab-gemcitabine-oxaliplatin (R-GemOx), axi-cel, liso-cel, tisa-cel, pola-BR, and Tafa-L. First-year treatment costs (drug and medical services costs) were calculated. Results were merged on two-dimensional graphs illustrating 2L and 3+L EFs.
RESULTS
Second-line EF is formed by BR (median OS 11.49 months, €23 958) and Tafa-L (45.7, €104 541), 3+L EF is formed by R-GemOx (12.0, €29 080), Tafa-L (15.5, €104 541), and axi-cel (18.69, €308 516). These interventions build the respective cost-effectiveness thresholds for novel interventions.
CONCLUSIONS
Using the EF approach, the currently most cost-effective interventions (based on cost-effectiveness ratios) in the indication of R/R DLBCL were identified to guide international reimbursement decisions.
Topics: Humans; Cost-Effectiveness Analysis; Bendamustine Hydrochloride; Rituximab; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Immunotherapy, Adoptive; Antigens, CD19
PubMed: 37644352
DOI: 10.1111/ejh.14095 -
International Journal of Cardiology Jan 2021Cancer immunotherapy is a success story of translational medicine that has led to improved survival in patients with different difficult-to-treat types of cancer, such...
Cancer immunotherapy is a success story of translational medicine that has led to improved survival in patients with different difficult-to-treat types of cancer, such as metastasized melanoma, non-small cell lung cancer or renal cell carcinoma. These novel therapeutic agents exert their antitumor effects by activating the patients' immune system against cancer cells. Immunotherapy can be divided into active agents, such as anti-tumour vaccines or adoptive T-cell transfer, and passive immunotherapies like monoclonal antibodies, checkpoint inhibitors, cytokine therapy, bispecific T-cell engagers. After initial experimental use, broad clinical application revealed a number of important cardiovascular side effects of immunotherapeutics, which limit treatment options and decrease patients' prognosis and quality of life. With the rising rate of new immunotherapeutics at a hand, the number of patients receiving cancer immunotherapy will constantly increase, resulting in improved long-term survival rates. This review aims to summarize available cancer immunotherapies, their mechanism of action, currently known cardiovascular toxicities and their treatment. Further optimization of patient care will depend on the combined efforts by oncologists, cardiologists and cardiac surgeons to identify patients at risk and the implementation of interdisciplinary screening and treatment strategies. It is therefore crucial to familiarize heart specialists with novel cancer therapeutics and their potential adverse effects.
Topics: Cancer Vaccines; Carcinoma, Non-Small-Cell Lung; Humans; Immunotherapy; Lung Neoplasms; Quality of Life
PubMed: 32800915
DOI: 10.1016/j.ijcard.2020.08.033 -
Clinical Lymphoma, Myeloma & Leukemia Feb 2022immunotherapy (IT), including checkpoint inhibitors (CIs) and Chimeric Antigen Receptor T cell therapy (CAR-T) revolutionized the treatment of relapsing or refractory... (Review)
Review
BACKGROUND
immunotherapy (IT), including checkpoint inhibitors (CIs) and Chimeric Antigen Receptor T cell therapy (CAR-T) revolutionized the treatment of relapsing or refractory (r/r) lymphoma. Several preliminary experiences evaluated concomitant administration of radiotherapy and IT.
METHODS
we performed a systematic review of current literature as of March 30, 2020. A total of 1090 records was retrieved, 42 articles were selected on the basis of title and abstract and, after the removal of analyses with no original data or insufficient clinical information, 28 papers were included in the review.
RESULTS
previous studies were mostly represented by case reports/series or small cohorts. Nonetheless, combination of radiotherapy and CIs or CAR-T led to promising outcomes, resulting in extremely high rates of complete response and improving progression free and overall survival compared with data from recent clinical trials. Combination of RT and CIs had a fair toxicity profile with no reports of severe side effects. Within the limits of the small cohorts retrieved, RT seems a superior option compared with systemic treatment as a 'bridge' to CAR-T and could as well reduce severe complications rates. Radiotherapy could elicit immune response against lymphoma, as demonstrated by multiple cases of abscopal effect and its inclusion in anti-neoplastic vaccines protocols.
CONCLUSION
The results of this review warrant the evaluation of combination of RT and immunotherapy in larger and preferably prospective and randomized cohorts to confirm these preliminary impressive outcomes. The optimal dose, fractionation and timing of RT still have to be clarified.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphoma; Neoplasm Recurrence, Local; Prospective Studies
PubMed: 34728169
DOI: 10.1016/j.clml.2021.09.005 -
Biomedicine & Pharmacotherapy =... May 2024Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues... (Review)
Review
Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues like poor trafficking, limited penetration, and insufficient persistence within the tumor microenvironment (TME). CAR-T cells are engineered to express receptors that target specific cancer antigens, enhancing their ability to recognize and eliminate cancer cells. This review paper explores the intricate interplay between CAR-T therapy and radiotherapy (RT), investigating their synergistic potential. Radiotherapy, a standard cancer treatment, involves using high doses of radiation to target and damage cancer cells, disrupting their ability to grow and divide. We highlight that RT modulates the TME, augments antigen presentation, and promotes immune cell infiltration, bolstering CAR-T cell-mediated tumor eradication. Molecular insights shed light on RT-induced alterations in tumor stroma, T cell recruitment promotion, and induction of immunogenic cell death. Noteworthy, strategies, such as combining hypofractionated radiotherapy with myeloid-derived suppressor cell blockade, underscore innovative approaches to enhance CAR-T cell therapy in solid tumors. Bridging indications for RT and CAR-T cells in hematological malignancies are discussed, emphasizing scenarios where RT strategically enhances CAR-T cell efficacy. The paper critically evaluates the RT as a bridge compared to traditional chemotherapy, highlighting timing and dosage considerations crucial for optimizing CAR-T therapy outcomes. In summary, the paper provides valuable insights into the intricate molecular mechanisms activated by RT and innovative strategies to improve CAR-T cell therapy, fostering a deeper understanding of their combined potential in cancer treatment.
Topics: Humans; Neoplasms; Tumor Microenvironment; Immunotherapy, Adoptive; Animals; Receptors, Chimeric Antigen; Combined Modality Therapy; Radiotherapy
PubMed: 38574625
DOI: 10.1016/j.biopha.2024.116532 -
The Oncologist Mar 2022Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom...
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. For the vast majority of patients with advanced CRC (ie, for those in whom metastatic tumors are unresectable), treatment is palliative and typically involves chemotherapy, biologic therapy, and/or immune checkpoint inhibition. In recent years, the use of adoptive T-cell therapy (ACT), leveraging the body's own immune system to recognize and target cancer, has become increasingly popular. Unfortunately, while ACT has been successful in the treatment of hematological malignancies, it is less efficacious in advanced CRC due in part to a lack of productive immune infiltrate. This systematic review was conducted to summarize the current data for the efficacy and safety of ACT in advanced CRC. We report that ACT is well tolerated in patients with advanced CRC. Favorable survival estimates among patients with advanced CRC receiving ACT demonstrate promise for this novel treatment paradigm. However, additional stage I/II clinical trials are needed to establish the efficacy and safety of ACT in patients with CRC.
Topics: Cell- and Tissue-Based Therapy; Colorectal Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive
PubMed: 35274719
DOI: 10.1093/oncolo/oyab038 -
The AAPS Journal Apr 2021Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy that has recently become highly instrumental in the fight against life-threatening diseases. A variety...
Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy that has recently become highly instrumental in the fight against life-threatening diseases. A variety of modeling and computational simulation efforts have addressed different aspects of CAR T-cell therapy, including T-cell activation, T- and malignant cell population dynamics, therapeutic cost-effectiveness strategies, and patient survival. In this article, we present a systematic review of those efforts, including mathematical, statistical, and stochastic models employing a wide range of algorithms, from differential equations to machine learning. To the best of our knowledge, this is the first review of all such models studying CAR T-cell therapy. In this review, we provide a detailed summary of the strengths, limitations, methodology, data used, and data gap in currently published models. This information may help in designing and building better models for enhanced prediction and assessment of the benefit-risk balance associated with novel CAR T-cell therapies, as well as with the data need for building such models.
Topics: Computer Simulation; Humans; Immunotherapy, Adoptive; Machine Learning; Models, Immunological; Neoplasms; Receptors, Chimeric Antigen; Risk Assessment
PubMed: 33835308
DOI: 10.1208/s12248-021-00579-9 -
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 -
Reviews in Medical Virology Jul 2024Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis.
Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta-analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo-HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta-analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman-Tukey transformation was applied for analysis. In the meta-analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor-derived T-cell treatments exhibited a higher response rate (93.66%) compared to third-party sources (88.94%). HLA-matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft-versus-host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post-HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one-arm studies to provide robust evidence for clinical decision-making.
Topics: Humans; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; T-Lymphocytes; Treatment Outcome; Immunotherapy, Adoptive; Cytomegalovirus; Transplantation, Homologous
PubMed: 38878003
DOI: 10.1002/rmv.2558 -
World Journal of Gastroenterology Jul 2019Hepatocellular carcinoma (HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hepatocellular carcinoma (HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells (DCs) and cytokine-induced killer cells (CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored.
AIM
To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs, combined with different conventional treatments of HCC.
METHODS
We performed a literature search on PubMed and Web of Science up to February 15, 2019. Long-term efficacy (overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis.
RESULTS
A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio (RR) = 1.07; 95% confidence interval (CI): 1.01-1.13, = 0.02], 1 year (RR = 1.12; 95%CI: 1.07-1.17, < 0.00001), 3 years (RR = 1.23; 95%CI: 1.15-1.31, < 0.00001) and 5 years (RR = 1.26; 95%CI: 1.15-1.37, < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo (RR = 0.50; 95%CI: 0.36-0.69, < 0.0001) and 1 year (RR = 0.82; 95%CI: 0.75-0.89, < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe, feasible treatment.
CONCLUSION
Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients' prognosis by increasing overall survival and reducing cancer recurrence.
Topics: Carcinoma, Hepatocellular; Clinical Trials as Topic; Combined Modality Therapy; Cytokine-Induced Killer Cells; Dendritic Cells; Feasibility Studies; Humans; Immunotherapy, Adoptive; Liver Neoplasms; Neoplasm Recurrence, Local; Prognosis; Survival Analysis; Treatment Outcome
PubMed: 31367163
DOI: 10.3748/wjg.v25.i27.3649