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International Journal of Molecular... Sep 2023The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and... (Review)
Review
The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and CAR-T cell therapies in relapsed/refractory (R/R) haematological malignancies. A systematic literature review was performed until 21 November 2022. Inclusion criteria: cohort studies/clinical trials aimed at evaluating the efficacy and/or safety of the combination of CAR-T cell therapy with PD-1/PD-L1 inhibitors in R/R haematological malignancies, which had reported results. Those focusing only on ICI or CAR-T separately or evaluating the combination in other non-hematological solid tumours were excluded. We used a specific checklist for quality assessment of the studies, and then we extracted data on efficacy or efficiency and safety. A total of 1867 articles were identified, and 9 articles were finally included (early phase studies, with small samples of patients and acceptable quality). The main pathologies were B-cell acute lymphoblastic leukaemia (B-ALL) and B-cell non-Hodgkin's lymphoma (B-NHL). The most studied combination was tisagenlecleucel with pembrolizumab. In terms of efficacy, there is great variability: the combination could be a promising option in B-ALL, with modest data, and in B-NHL, although hopeful responses were received, the combination does not appear better than CAR-T cell monotherapy. The safety profile could be considered comparable to that described for CAR-T cell monotherapy.
Topics: Humans; Immune Checkpoint Inhibitors; Receptors, Chimeric Antigen; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Hematologic Neoplasms; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37834228
DOI: 10.3390/ijms241914780 -
Leukemia & Lymphoma 2023Relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is a challenging disease with low rates of remission and survival in adult patients. Anti-CD19... (Meta-Analysis)
Meta-Analysis
Differences in efficacy and safety among CAR-Ts anti-CD19/CD22, anti-CD19, and anti-CD22, in adult patients with relapse/refractory B-cell acute lymphoblastic leukemia: a meta-analysis and systematic review.
Relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is a challenging disease with low rates of remission and survival in adult patients. Anti-CD19 Chimeric Antigen Receptor T-cells (CAR-Ts) therapies have been approved for these patients. Dual-target CAR-Ts against CD19 and CD22 have recently been developed to improve the efficacy of the single-target therapy; however, extent of the improvement using this dual-target therapy has yet to be determined. We performed a meta-analysis of the outcome and safety of CAR-Ts, comparing anti-CD19 vs anti-CD22 vs dual-target anti-CD19/CD22 CAR-Ts, to elucidate the differences and limitations of these therapies in adult patients with R/R B-ALL. our results suggest that anti-CD19/CD22 CAR-Ts generate lower incidence of relapse and neurotoxicity, but similar results were obtained regarding complete remission, minimal residual disease, overall survival, and cytokine release syndrome compared with single-target anti-CD19 and anti-CD22 CAR-Ts.
Topics: Humans; Adult; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Lymphoma, B-Cell; Antigens, CD19; Acute Disease; Sialic Acid Binding Ig-like Lectin 2
PubMed: 37548560
DOI: 10.1080/10428194.2023.2243357 -
Expert Review of Hematology 2024This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab.
METHODS
PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies.
RESULTS
The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy.
CONCLUSIONS
The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.
Topics: Humans; Immunotherapy, Adoptive; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Bispecific; Recurrence; Antigens, CD19
PubMed: 38135295
DOI: 10.1080/17474086.2023.2298732 -
International Journal of Molecular... May 2024Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell)... (Meta-Analysis)
Meta-Analysis Review
An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis.
Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.
Topics: Multiple Myeloma; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Treatment Outcome; Quality of Life; Neoplasm Recurrence, Local; Cytokine Release Syndrome
PubMed: 38732213
DOI: 10.3390/ijms25094996 -
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 -
Journal of Geriatric Oncology Mar 2024Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy is transforming the care of patients with relapsed/refractory multiple myeloma... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy is transforming the care of patients with relapsed/refractory multiple myeloma (MM). Unfortunately, despite being a disease of older adults these patients remain under-represented in most pivotal clinical trials. We performed a systematic review and proportion meta-analysis of prospective clinical trials and observational studies of anti-BCMA CAR-T therapy in patients with MM with the aim to determine the efficacy and safety of this therapy in older adults (≥65 years).
MATERIALS AND METHODS
We searched the Pubmed, Scopus, Web of Science (WOS), Ovid, Embase, CENTRAL, and CINAHL databases through September 9, 2022 and abstracts from the American Society of Hematology (ASH) Annual Meeting 2022. Primary outcome measures included overall response rate (ORR), rates of cytokine release syndrome (CRS), and immune cell-effector-associated neurotoxicity syndrome (ICANS). study was registered with PROSPERO (study number: CRD42022334287).
RESULTS
After screening 2218 references, 14 studies were included for data extraction, with a total of 558 patients, 26.2% (n = 146) of whom were older adults. The pooled ORR amongst this population was 93%, which was comparable to the ORR of 86% amongst younger patients. In older adults, the rates of CRS (any grade) and grade ≥ 3 were 95% and 21%, respectively. For younger patients, the pooled rate of CRS (any grade) and grade ≥ 3 CRS was 91% and 20%, respectively. The rate of ICANS (any grade) in older adults was 15%, which was higher than that observed in those <65 years.
CONCLUSION
Older adults experience comparable outcomes to younger patients with anti-BCMA CAR-T therapy, albeit with numerically higher rates of neurotoxicity.
Topics: Humans; Aged; Multiple Myeloma; Receptors, Chimeric Antigen; Prospective Studies; Immunotherapy, Adoptive; Cell- and Tissue-Based Therapy; Observational Studies as Topic
PubMed: 37723045
DOI: 10.1016/j.jgo.2023.101628 -
Cytotherapy Sep 2022The existing evidence about the impact of bridging therapy (BT) on chimeric antigen receptor (CAR)-T cell therapy in patients with large B cell lymphoma (LBCL) is... (Meta-Analysis)
Meta-Analysis
Systematic review and meta-analysis of the association between bridging therapy and outcomes of chimeric antigen receptor T cell therapy in patients with large B cell lymphoma.
BACKGROUND
The existing evidence about the impact of bridging therapy (BT) on chimeric antigen receptor (CAR)-T cell therapy in patients with large B cell lymphoma (LBCL) is conflicting. Therefore, we reviewed all available evidence to examine the association between BT and CAR-T therapy outcomes by systematic review and meta-analysis approach.
METHODS
Two reviewers independently searched Embase, PubMed, Web of Science, and Cochrane library to identify all records that described BT for LBCL treated with CAR-T. We then applied a fixed- or random-effects meta-analysis to estimate the pooled hazard ratios (HRs) and rate ratio (RRs) for efficacy and safety endpoints and assessed differences across various BT modalities. The Newcastle-Ottawa Scale was used to evaluate study quality.
RESULTS
Twenty-six reports from 24 studies involving 2014 patients were included in the analysis. Pooled results showed that patients requiring BT had significantly worse 1-year overall survival rate (RR = 0.76, 95% confidence interval [CI] 0.68-0.85, P < 0.001), 1-year progression-free survival rate (RR = 0.71, 95% CI 0.60-0.85, P < 0.001), progression-free survival (HR = 1.35, 95% CI 1.07-1.69, P = 0.01), overall response rate (RR = 0.88, 95% CI 0.81-0.95, P = 0.001), complete response rate (RR = 0.78, 95% CI 0.65-0.93, P = 0.005), and grade ≥3 immune effector cell-associated neurotoxicity syndrome (RR = 1.43, 95% CI 1.10-1.87, P = 0.007), and tended to have poorer overall survival (HR = 1.42, 95% CI 0.99-2.02, P = 0.056) and grade ≥3 cytokine release syndrome (RR = 1.59, 95% CI 0.92-2.75, P = 0.096). Prolonged cytopenias were the common toxicity event associated with BT. Radiotherapy may serve as a promising BT option that can provide safe and effective disease control for patients with LBCL before CAR-T infusion. The inconsistency of patient baselines in the current study hindered further comparisons between different BT modalities. Most of the available evidence was rated as low quality because of concerns over low comparability.
CONCLUSION
BT appears to be associated with comparatively poor efficacy and safety outcomes after CAR-T infusion. However, due to the considerable heterogeneity between the BT and non-BT cohorts at disease baseline, no definitive conclusions can be made for the true impact of BT on CAR-T until further randomized studies are conducted.
Topics: Cell- and Tissue-Based Therapy; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Progression-Free Survival; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 35568624
DOI: 10.1016/j.jcyt.2022.03.009 -
The Oncologist Jun 2023T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in cutaneous melanoma. We conducted a systematic review and meta-analysis aiming to assess the primary efficacy of TCR-based adoptive cell therapy in cutaneous melanoma.
METHODS
We searched through PubMed electronic database from its inception until May 21, 2022. Primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). We conducted logistic regression analyses to identify potential predictive factors for tumor response.
RESULTS
From 187 patients, 50 showed an objective response (pooled ORR 28%; 95% CI, 20%-37%) and a pooled DCR of 38% (95% CI, 27%-50%). Median PFS was 2, 9 months (95% CI, 1.4-3.1). A trend toward higher PFS was demonstrated for patients treated with cancer/testis antigens targeting TCR-T cells (HR 0.91 95% CI, 0.64-1.3, P = .61) among whom, patients treated with NYESO-1 targeting TCR-T showed a significantly higher PFS (HR 0.63 95% CI, 0.64-0.98, P = .03). In addition, the number of infused cells was associated with a significantly higher likelihood of tumor response (OR 6.61; 95% CI, 1.68-21.6; P = .007).
CONCLUSION
TCR-T therapy shows promising results in terms of antitumor activity and survival similar to those reported for TILs with a significantly higher benefit for cancer/testis antigens targeting cells. Since TCR-based therapy shows advantages of great potential over classic ACT strategies, further research in solid cancers is warranted (PROSPERO ID CRD42022328011).
Topics: Male; Humans; Melanoma; Skin Neoplasms; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Melanoma, Cutaneous Malignant
PubMed: 37036865
DOI: 10.1093/oncolo/oyad078 -
International Journal of Molecular... Nov 2021The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer...
The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills strong interests in understanding the immunomodulatory effects of radiotherapy (RT), an area that was actually investigated more than a century ago but had been largely ignored for many decades. With the "newly" discovered immunogenic responses from RT, numerous endeavors have been undertaken to combine RT with IOs, in order to bolster anti-tumor immunity. However, the underlying mechanisms are not well defined, which is a subject of much investigation. We therefore conducted a systematic literature search on the molecular underpinnings of RT-induced immunomodulation and IOs, which identified the IFN-JAK-STAT pathway as a major regulator. Our further analysis of relevant studies revealed that the signaling strength and duration of this pathway in response to RT and IOs may determine eventual immunological outcomes. We propose that strategic targeting of this axis can boost the immunostimulatory effects of RT and radiosensitizing effects of IOs, thereby promoting the efficacy of combination therapy of RT and IOs.
Topics: Combined Modality Therapy; Humans; Immunotherapy; Interferons; Janus Kinases; Neoplasms; Radiotherapy; STAT Transcription Factors; Signal Transduction; T-Lymphocytes
PubMed: 34830176
DOI: 10.3390/ijms222212295 -
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