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Experimental Hematology & Oncology Aug 2023Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It is based on genetically modified T cells to express a CAR,... (Review)
Review
Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising advances in cancer treatment. It is based on genetically modified T cells to express a CAR, which enables the recognition of the specific tumour antigen of interest. To date, CAR-T cell therapies approved for commercialisation are designed to treat haematological malignancies, showing impressive clinical efficacy in patients with relapsed or refractory advanced-stage tumours. However, since they all use the patient´s own T cells as starting material (i.e. autologous use), they have important limitations, including manufacturing delays, high production costs, difficulties in standardising the preparation process, and production failures due to patient T cell dysfunction. Therefore, many efforts are currently being devoted to contribute to the development of safe and effective therapies for allogeneic use, which should be designed to overcome the most important risks they entail: immune rejection and graft-versus-host disease (GvHD). This systematic review brings together the wide range of different approaches that have been studied to achieve the production of allogeneic CAR-T cell therapies and discuss the advantages and disadvantages of every strategy. The methods were classified in two major categories: those involving extra genetic modifications, in addition to CAR integration, and those relying on the selection of alternative cell sources/subpopulations for allogeneic CAR-T cell production (i.e. γδ T cells, induced pluripotent stem cells (iPSCs), umbilical cord blood T cells, memory T cells subpopulations, virus-specific T cells and cytokine-induced killer cells). We have observed that, although genetic modification of T cells is the most widely used approach, new approaches combining both methods have emerged. However, more preclinical and clinical research is needed to determine the most appropriate strategy to bring this promising antitumour therapy to the clinical setting.
PubMed: 37605218
DOI: 10.1186/s40164-023-00435-w -
International Journal of Surgery... Nov 2023Hepatocellular carcinoma (HCC) is the third-most lethal malignant tumor worldwide. The rapid development of immunotherapy utilizing immune checkpoint inhibitors for... (Meta-Analysis)
Meta-Analysis
Clinico-characteristics of patients which correlated with preferable treatment outcomes in immunotherapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis.
BACKGROUND AND AIMS
Hepatocellular carcinoma (HCC) is the third-most lethal malignant tumor worldwide. The rapid development of immunotherapy utilizing immune checkpoint inhibitors for advanced HCC patients has been witnessed in recent years, along with numerous randomized clinical trials demonstrating the survival benefits for these individuals. This systematic review and meta-analysis aimed to identify specific clinico-pathological characteristics of advanced HCC patients that may lead to preferable responses to immunotherapy in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).
METHODS
The included clinical trials were retrieved from PubMed, Embase, the Cochrane library, and the Web of Science databases published in English between 1 January 2002 and 20 October 2022. A systematic review and meta-analysis for first-line and second-line phase II/III studies were conducted on immunotherapy for patients with advanced HCC by using OS as the primary outcome measure, and PFS and ORR as the secondary outcome measures to obtain clinico-pathological characteristics of patients which might be preferable responses to programmed death-1 (PD-1) and programmed cell death-Ligand 1 (PD-L1) inhibitors. Toxicity and specific treatment-related adverse events (TRAEs) were also determined.
RESULTS
After screening 1392 relevant studies, 12 studies were included in this systematic review and meta-analysis to include 5948 patients. Based on the analysis of interaction, the difference in OS after first-line immunotherapy between the subgroups of viral hepatitis [hazard ratio (HR)=0.73 vs 0.87, P for interaction=0.02] and macrovascular invasion and/or extrahepatic spread (HR=0.73 vs 0.89, P for interaction=0.02) were significant. The difference in PFS between the subgroups of viral hepatitis was highly significant (pooled HR=0.55 vs 0.81, P for interaction=0.007). After second-line immunotherapy, the difference in ORR between the subgroups of Barcelona Clinic Liver Cancer was significant (pooled ES=0.12 vs 0.23, P for interaction=0.04). Compared with PD-L1 inhibitors, PD-1 inhibitors may have a higher probability to cause TRAEs. Diarrhea, increased aspartate aminotransferase, and hypertension were the top three TRAEs.
CONCLUSIONS
This systematic review and meta-analysis represents the first pilot study aimed at identifying crucial clinico-pathological characteristics of patients with advanced HCC that may predict favorable treatment outcomes in terms of OS, PFS, and ORR to immunotherapy. Findings suggest that patients with viral hepatitis positivity (especially hepatitis B virus) and macrovascular invasion and/or extrahepatic spread may benefit more in OS when treated with PD-1/PD-L1 immune checkpoint inhibitors.
Topics: Humans; Carcinoma, Hepatocellular; B7-H1 Antigen; Immune Checkpoint Inhibitors; Pilot Projects; Programmed Cell Death 1 Receptor; Liver Neoplasms; Treatment Outcome; Immunotherapy; Hepatitis, Viral, Human; Lung Neoplasms
PubMed: 37598406
DOI: 10.1097/JS9.0000000000000652 -
Frontiers in Immunology 2023The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in cancer patients. However, the safety of these combination regimens remains conflicting in former researches. Therefore, in order to address this issue, we performed a systematic review and network meta-analysis (NMA) to evaluate and compare the safety profile.
METHODS
We performed a systematic review by searching randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science up to August 15, 2022. The primary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) immune-related adverse events (irAEs). Secondary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) irAEs of subgroups of ICIs.
RESULTS
There were 22 RCTs included in the NMA, involving a total of 15 963 patients diagnosed with any type of cancer. ICIs+nab-PTX was associated with a noticeably decreased risk of grade 3-5 pneumonitis (odds ratio [OR]=0.28, 95% credible interval [CrI]: 0.09,0.90) compared to ICI monotherapy; ICIs+PTX showed a lower risk of grade 1-5 hyperthyroidism (OR=0.46, 95% CrI: 0.22-0.96) and grade 1-5 hypothyroidism (OR=0.49, 95% CrI: 0.26-0.93) than ICIs. Compared with PD-1, PD-1+PTX was associated with a statistically significantly lower risk of grade 1-5 pneumonitis (OR=0.32, 95% CrI: 0.11-0.92). PD-L1 resulted in a noticeably lower risk of grade 1-5 hypothyroidism (OR=0.34, 95% CrI: 0.12-1.00) than PD-L1+PTX. Nearly all treatment regimens containing ICIs demonstrated significantly higher risks of irAEs compared to the standard chemotherapy groups.
CONCLUSION
Nab-PTX/PTX+ICIs demonstrated an approach leading to decreased risk of irAEs compared with ICI monotherapy. This finding supports that ICIs+nab-PTX/PTX may be a safer treatment strategy. Moreover, we also found that the combination regimens containing ICIs had a higher risk of irAEs than standard chemotherapy. Additionally, ICIs+nab-PTX demonstrated a decreased risk of irAEs compared to ICIs+PTX. PD-1 inhibitors were associated with a higher risk of irAEs than PD-L1 inhibitors.
Topics: Humans; Immune Checkpoint Inhibitors; B7-H1 Antigen; Antineoplastic Agents, Immunological; Programmed Cell Death 1 Receptor; Network Meta-Analysis; Neoplasms; Paclitaxel; Hypothyroidism; Pneumonia
PubMed: 37520574
DOI: 10.3389/fimmu.2023.1175809 -
International Journal of Molecular... Jul 2023In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options... (Review)
Review
In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.
Topics: Humans; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Immunotherapy; Lung Neoplasms; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Interleukin-1beta
PubMed: 37511306
DOI: 10.3390/ijms241411547 -
Blood Advances Oct 2023Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell... (Meta-Analysis)
Meta-Analysis
Bispecific antibodies, a novel immunotherapy with promising efficacy against multiple myeloma, form immune synapses between T-cell surface marker CD3 and malignant cell markers, including B-cell maturation antigen (BCMA), FcRH5, and G protein-coupled receptor GPRC5D. These bispecific antibodies so effectively deplete plasma cells (and to some extent T-cells) that patients are at increased risk of developing infections. A systematic review and meta-analysis of infections in published studies of patients with myeloma treated with bispecific antibodies was conducted to better characterize the infection risks. A literature search used MEDLINE, EMBASE, and Cochrane to identify relevant studies between inception and February 10, 2023, including major conference presentations. Phase 1b-3 clinical trials and observational studies were included. Sixteen clinical trials comprising 1666 patients were included. Median follow-up was 7.6 months and 38% of the cohort had penta-drug refractory disease. Pooled prevalence of all-grade infections was 56%, whereas the prevalence of grade ≥3 infections was 24%. Patients who were treated with BCMA-targeted bispecifics had significantly higher rates of grade ≥3 infections than non-BCMA bispecifics (25% vs 20%). Similarly, patients treated with bispecifics in combination with other agents had significantly higher rate of all-grade infection than those receiving monotherapy (71% vs 52%). In observational studies (n = 293), excluded from the primary analysis to ensure no overlap with patients in clinical trials, several infections classically associated with T-cell depletion were identified. This systematic review identifies BCMA-targeted bispecifics and bispecific combination therapy as having higher infection risk, requiring vigilant infection screening and prophylaxis strategies.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; B-Cell Maturation Antigen; Immunotherapy; T-Lymphocytes; CD3 Complex
PubMed: 37467036
DOI: 10.1182/bloodadvances.2023010539 -
Frontiers in Pharmacology 2023Chimeric antigen receptor T cells treatment targeting B cell maturation antigen (BCMA) is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM)...
Effectiveness and safety of anti-BCMA chimeric antigen receptor T-cell treatment in relapsed/refractory multiple myeloma: a comprehensive review and meta-analysis of prospective clinical trials.
Chimeric antigen receptor T cells treatment targeting B cell maturation antigen (BCMA) is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) and has demonstrated outstanding outcomes in clinical studies. The aim of this comprehensive review and meta-analysis was to summarize the effectiveness and safety of anti-BCMA CAR-T treatment for patients with relapsed/refractory multiple myeloma (RRMM). Our research identifies variables influencing outcome measures to provide additional evidence for CAR-T product updates, clinical trial design, and clinical treatment guidance. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard was followed for conducting this comprehensive review and meta-analysis, which was submitted to PROSPERO (CRD42023390037). From the inception of the study until 10 September 2022, PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and WanFang databases were searched for eligible studies. Stata software (version 16.0) was used to assess effectiveness and safety outcomes. Out of 875 papers, we found 21 relevant trials with 761 patients diagnosed as RRMM and were given anti-BCMA CAR-T treatment. The overall response rate (ORR) for the entire sample was 87% (95% CI: 80-93%) complete response rate (CRR) was 44% (95% CI: 34-54%). The minimal residual disease (MRD) negativity rate within responders was 78% (95% CI: 65-89%). The combined incidence of cytokine release syndrome was 82% (95% CI: 72-91%) and neurotoxicity was 10% (95% CI: 5%-17%). The median progression-free survival (PFS) was 8.77 months (95% CI: 7.48-10.06), the median overall survival (OS) was 18.87 months (95% CI: 17.20-20.54) and the median duration of response (DOR) was 10.32 months (95% CI: 9.34-11.31). According to this meta-analysis, RRMM patients who received anti-BCMA CAR-T treatment have demonstrated both effectiveness and safety. Subgroup analysis confirmed the anticipated inter-study heterogeneity and pinpointed potential factors contributing to safety and efficacy, which may help with the development of CAR-T cell studies and lead to optimized BCMA CAR-T-cell products. Clinicaltrials.gov, PROSPERO, CRD42023390037.
PubMed: 37408760
DOI: 10.3389/fphar.2023.1149138 -
Translational Psychiatry Jul 2023Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are available, treatment resistance rates are...
Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are available, treatment resistance rates are high. Emerging evidence suggests that biological components, especially autoimmune processes, may be associated with some cases of OCD and treatment resistance. Therefore, this systematic literature review summarizing all case reports/case series as well as uncontrolled and controlled cross-sectional studies investigating autoantibodies in patients with OCD and obsessive-compulsive symptoms (OCS) was performed. The following search strategy was used to search PubMed: "(OCD OR obsessive-compulsive OR obsessive OR compulsive) AND (antib* OR autoantib* OR auto-antib* OR immunoglob* OR IgG OR IgM OR IgA)". Nine case reports with autoantibody-associated OCD/OCS were identified: five patients with anti-neuronal autoantibodies (against N-methyl-D-aspartate-receptor [NMDA-R], collapsin response mediator protein [CV2], paraneoplastic antigen Ma2 [Ma2], voltage gated potassium channel complex [VGKC], and "anti-brain" structures) and four with autoantibodies associated with systemic autoimmune diseases (two with Sjögren syndrome, one with neuropsychiatric lupus, and one with anti-phospholipid autoantibodies). Six patients (67%) benefited from immunotherapy. In addition, eleven cross-sectional studies (six with healthy controls, three with neurological/psychiatric patient controls, and two uncontrolled) were identified with inconsistent results, but in six studies an association between autoantibodies and OCD was suggested. In summary, the available case reports suggest an association between OCD and autoantibodies in rare cases, which has been supported by initial cross-sectional studies. However, scientific data is still very limited. Thus, further studies on autoantibodies investigated in patients with OCD compared with healthy controls are needed.
Topics: Humans; Autoantibodies; Cross-Sectional Studies; Obsessive-Compulsive Disorder; Receptors, N-Methyl-D-Aspartate; Brain
PubMed: 37400462
DOI: 10.1038/s41398-023-02545-9 -
Frontiers in Immunology 2023PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have been controversial in the treatment of metastatic triple negative breast cancer (mTNBC). We collected randomized... (Meta-Analysis)
Meta-Analysis
BACKGROUND
PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have been controversial in the treatment of metastatic triple negative breast cancer (mTNBC). We collected randomized controlled trials in accordance with the study and carried out meta-analysis to comprehensively evaluate the efficacy and safety of immune checkpoint inhibitors in mTNBC.
AIM
To systematically evaluate the efficacy and safety of PD-1/PD-L1 ICIs (hereinafter referred to as ICIs) in the treatment of mTNBC.
METHODS
As of 2023.2.5, Medline, PubMed, Embase, Cochrane library database and Web of Science were searched to determine the study in accordance with the trial of ICIs in the treatment of mTNBC. The assessment endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Meta-analysis of the included studies was performed using Revman 5.4.
RESULTS
A total of six trials with 3172 patients were included in this meta-analysis. The ORR of ICIs combined with chemotherapy was significantly improved compared with chemotherapy (HR=0.88, 95%CI: 0.81-0.94, I= 0%). For PFS, the experimental group were better than the control group in both intention-to-treat (ITT) population and PD-L1 positive population, showing statistical significance (ITT: HR=0.81, 95%CI: 0.74-0.89, P<0.05, I= 0%; PD-L1 positive: HR=0.72, 95%CI: 0.63-0.82, P<0.05, I= 18%); For OS, in the ITT population, no statistical difference was observed in either ICIs combined with chemotherapy(HR=0.92, 95%CI: 0.83-1.02, P=0.10)or immune monotherapy(HR=0.78, 95%CI: 0.44-1.36, P=0.37), in the PD-L1 positive population, ICIs group had better OS than chemotherapy group (HR=0.83, 95%CI: 0.74-0.93, P < 0.05); In safety, serious adverse event (SAE) was no statistically significant difference between the ICIs group and the chemotherapy group; however, the incidence of immune-related adverse event (irAE) was significantly higher in the ICIs group than in the chemotherapy group (HR=2.15, 95%CI: 1.45-3.19, P < 0.05).
CONCLUSION
ICIs combined with chemotherapy significantly improved the PFS of mTNBC, however, ICIs only improved the OS in PD-L1 positive people, and no statistical difference was observed in ITT population; while benefiting from ICIs, we found that irAE in ICIs group increased significantly, and its high rate of adverse events still needs to be taken seriously.
Topics: Humans; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Triple Negative Breast Neoplasms; B7-H1 Antigen; Control Groups
PubMed: 37377959
DOI: 10.3389/fimmu.2023.1206689 -
Antibodies (Basel, Switzerland) May 2023Multiple myeloma is a heterogeneous clonal malignant plasma cell disorder, which remains incurable despite the therapeutic armamentarium's evolution. Bispecific... (Review)
Review
Multiple myeloma is a heterogeneous clonal malignant plasma cell disorder, which remains incurable despite the therapeutic armamentarium's evolution. Bispecific antibodies (BsAbs) can bind simultaneously to the CD3 T-cell receptor and tumor antigen of myeloma cells, causing cell lysis. This systematic review of phase I/II/III clinical trials aimed to analyze the efficacy and safety of BsAbs in relapsed refractory multiple myeloma (RRMM). A thorough literature search was performed using PubMed, Cochrane Library, EMBASE, and major conference abstracts. A total of 18 phase I/II/III studies, including 1283 patients, met the inclusion criteria. Among the B-cell maturation antigen (BCMA)-targeting agents across 13 studies, the overall response rate (ORR) ranged between 25% and 100%, with complete response/stringent complete response (CR/sCR) between 7 and 38%, very good partial response (VGPR) between 5 and 92%, and partial response (PR) between 5 and 14%. Among the non-BCMA-targeting agents across five studies, the ORR ranged between 60 and 100%, with CR/sCR seen in 19-63%, and VGPR in 21-65%. The common adverse events were cytokine release syndrome (17-82%), anemia (5-52%), neutropenia (12-75%), and thrombocytopenia (14-42%). BsAbs have shown promising efficacy against RRMM cohorts with a good safety profile. Upcoming phase II/III trials are much awaited, along with the study of other agents in concert with BsAbs to gauge response.
PubMed: 37366654
DOI: 10.3390/antib12020038 -
European Urology Open Science Aug 2023Identifying malignant tissue and leaving adjacent structures undisturbed constitute an ongoing challenge in prostate cancer (PCa) surgery. Image and radioguided surgical... (Review)
Review
CONTEXT
Identifying malignant tissue and leaving adjacent structures undisturbed constitute an ongoing challenge in prostate cancer (PCa) surgery. Image and radioguided surgical technologies targeting the prostate-specific membrane antigen (PSMA) receptor may facilitate identification and removal of diseased tissue.
OBJECTIVE
To perform a systematic review of the clinical studies on PSMA-targeted surgery.
EVIDENCE ACQUISITION
The MEDLINE (OvidSP), Embase.com, and Cochrane Library databases were searched. Identified reports were critically appraised according to the Idea, Development, Exploration, Assessment, Long-term framework criteria. The risk of bias (RoB) was assessed as per the Risk Of Bias In Non-randomized Studies-of Interventions tool. The strengths and limitations of the techniques and corresponding oncological outcomes were extracted as areas of interest. Data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
EVIDENCE SYNTHESIS
In total, 29 reports were selected, including eight prospective studies, 12 retrospective analyses, and nine case reports, all with a high or an unclear RoB. In 72.4% of studies, PSMA targeting was achieved via radioguided surgery (RGS), predominantly using Tc-PSMA-I&S (66.7%). Hybrid approaches that complement RGS with optical guidance are emerging. The majority of studies retrieved were pilot studies with a short follow-up. In 13 reports, salvage lymph node surgery was discussed (44.8%). In 12 more recent reports (41.4%), PSMA targeting was studied in primary PCa surgery (50.0% lymph nodes and 50.0% surgical margins), and four studied both primary and salvage surgery (13.8%). Overall, specificity was higher than sensitivity (median 98.9% and 84.8%, respectively). Oncological outcomes were discussed only in reports on the use of Tc-PSMA-I&S in salvage surgery (median follow-up of 17.2 mo). A decline in prostate-specific antigen level of >90% ranged from 22.0% to 100.0%, and biochemical recurrence ranged from 50.0% to 61.8% of patients.
CONCLUSIONS
In PSMA-targeted surgery, most studies address salvage PSMA-RGS using Tc-PSMA-I&S. Available evidence suggests that the specificity of intraoperative PSMA targeting is higher than the sensitivity. The studies that included follow-up did not yet objectify a clear oncological benefit. Lacking solid outcome data, PSMA-targeted surgery remains investigational.
PATIENT SUMMARY
In this paper, we review recent advances in prostate-specific membrane antigen (PSMA)-targeted surgery, which is used to help identify and remove prostate cancer. We found good evidence to suggest that PSMA targeting helps identify prostate cancer during surgery. The oncological benefits have yet to be investigated further.
PubMed: 37361200
DOI: 10.1016/j.euros.2023.05.014