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Human Vaccines & Immunotherapeutics Dec 2023To overcome challenges associated with adoptive cell therapy (ACT), we developed a personalized autologous T-cell therapy program. Patients with advanced cancer with... (Review)
Review
To overcome challenges associated with adoptive cell therapy (ACT), we developed a personalized autologous T-cell therapy program. Patients with advanced cancer with HLA-A *02:01 allele and tumor expression of PRAME, MAGEA1, MAGEA4, MAGEA8, NY-ESO-1, COL6A3 exon 6, MXRA5, and/or MMP1 underwent leukapheresis and T-cell product manufacturing. Patients received lymphodepletion, IMA101 infusion and interleukin 2 for 14 days. Of 214 screened patients, 14 were treated (6, IMA101; 8, IMA101 and atezolizumab). The most common adverse events were cytokine release syndrome (G1, = 6; G2, = 4) and cytopenia. At 6 weeks, 12 (85.7%) patients had stable disease. Three patients had prolonged disease stabilization for 12.9, 7.3, and 13.7 months, respectively. The median progression-free survival and overall survival were 3.4 months and 9.4 months, respectively. Target-specific T cells expanded to constitute up to 78.7% of CD8+ cells. In conclusion, IMA101 was feasible and well tolerated, leveraging the potential of multi-targeted ACT that warrants further investigation.
Topics: Humans; Antigens, Neoplasm; Receptors, Antigen, T-Cell; Neoplasms; CD8-Positive T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 38114231
DOI: 10.1080/21645515.2023.2290356 -
Blood Cancer Discovery Sep 2023In this issue, Paiva and colleagues characterize the dynamics of minimal residual disease (MRD) and clinical responses during chimeric antigen receptor (CAR) T-cell...
In this issue, Paiva and colleagues characterize the dynamics of minimal residual disease (MRD) and clinical responses during chimeric antigen receptor (CAR) T-cell therapy of relapsed/refractory multiple myeloma. Although both correlate with prolonged progression-free survival, MRD is reached faster in the bone marrow than complete response in peripheral blood; consequently, the study addresses the need for future guidelines to explore new MRD-negative definitions that are independent of the monoclonal (M) protein to overcome this limitation, particularly in clinical trials using early depth of response as an endpoint. See related article by Paiva et al., p. 365 (1).
Topics: Humans; Receptors, Chimeric Antigen; Multiple Myeloma; Immunotherapy, Adoptive; Plasma Cells; Prognosis; Neoplasm, Residual
PubMed: 37655402
DOI: 10.1158/2643-3230.BCD-23-0134 -
Nature Medicine Apr 2024Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to...
Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 10 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Glioma; T-Lymphocytes; Glioblastoma; Immunotherapy, Adoptive
PubMed: 38454126
DOI: 10.1038/s41591-024-02875-1 -
Transfusion and Apheresis Science :... Dec 2023Chimeric antigen receptor (CAR) T-cell therapy is an effective, individualized immunotherapy, and novel treatment for hematologic malignancies. Six commercial CAR-T cell... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is an effective, individualized immunotherapy, and novel treatment for hematologic malignancies. Six commercial CAR-T cell products are currently approved for lymphatic malignancies and multiple myeloma. In addition, an increasing number of clinical centres produce CAR-T cells on-site, which enable the administration of CAR-T cells on site. The CAR-T cell products are either fresh or cryopreserved. Manufacturing CAR-T cells is a complicated process that begins with leukapheresis to obtain T cells from the patient's peripheral blood. An optimal leukapheresis product is crucial step for a successful CAR-T cell therapy; therefore, it is imperative to understand the factors that may affect the quality or T cells. The leukapheresis for CAR-T cell production is well tolerated and safe for both paediatric and adult patients and CAR-Τ cell therapy presents high clinical response rate in many studies. CAR-T cell therapy is under continuous improvement, and it has transformed into an almost standard procedure in clinical haematology and stem cell transplantation facilities that provide both autologous and allogeneic stem cell transplantations. In patients suffering from advanced haematological malignancies, CAR-T cell therapy shows incredible antitumor efficacy. Even after a single infusion of autologous CD19-targeting CAR-T cells in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL), long lasting remission is observed, and a fraction of the patients are being cured. Future novel constructs are being developed with better T cell persistence and better expansion. New next-generation CAR-T cells are currently designed to avoid toxicities such as cytokine release syndrome and neurotoxicity.
Topics: Adult; Humans; Child; T-Lymphocytes; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Leukapheresis; Immunotherapy, Adoptive; Hematologic Neoplasms
PubMed: 37838564
DOI: 10.1016/j.transci.2023.103828 -
Cell Reports. Medicine Sep 2023Anti-CD19 chimeric antigen receptor (CAR) T cell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events,...
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events, including cytokine release syndrome (CRS), which may require urgent clinical management. Whether interpatient variability in CAR T cell subsets contributes to CRS is unclear. Here, we show that CD4 CAR T cells are the main drivers of CRS. Using an immunocompetent model of anti-CD19 CAR T cell therapy, we report that CD4, but not CD8, CAR T cells elicit physiological CRS-like manifestations associated with the release of inflammatory cytokines. In CAR T cell-treated patients, CRS occurrence and severity are significantly associated with high absolute values of CD4 CAR T cells in the blood. CRS in mice occurs independently of CAR T cell-derived interferon γ (IFN-γ) but requires elevated tumor burden. Thus, adjusting the CD4:CD8 CAR T cell ratio to patient tumor load may help mitigate CAR T cell-associated toxicities.
Topics: Humans; Animals; Mice; Cytokine Release Syndrome; Immunotherapy, Adoptive; CD8-Positive T-Lymphocytes; Antigens, CD19; CD4-Positive T-Lymphocytes
PubMed: 37595589
DOI: 10.1016/j.xcrm.2023.101161 -
Journal of Leukocyte Biology Oct 2023Natural killer cells are a promising platform for cancer immunotherapy. Natural killer cells have high intrinsic killing capability, and the insertion of a chimeric... (Review)
Review
Natural killer cells are a promising platform for cancer immunotherapy. Natural killer cells have high intrinsic killing capability, and the insertion of a chimeric antigen receptor can further enhance their antitumor potential. In first-in-human trials, chimeric antigen receptor-natural killer cells demonstrated strong clinical activity without therapy-induced side effects. The applicability of natural killer cells as an "off-the-shelf" product makes them highly attractive for gene-engineered cell therapies. Traditionally, viral transduction has been used for gene editing; however, the use of viral vectors remains a safety concern and is associated with high costs and regulatory requirements. Here, we review the current landscape of nonviral approaches for chimeric antigen receptor-natural killer cell generation. This includes transfection of vector particles and electroporation of mRNA and DNA vectors, resulting in transient modification and chimeric antigen receptor expression. In addition, using nonviral transposon technologies, natural killer cells can be stably modified ensuring long-lasting chimeric antigen receptor expression. Finally, we discuss CRISPR/Cas9 tools to edit key genes for natural killer cell functionality.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Killer Cells, Natural; Immunotherapy; Cell- and Tissue-Based Therapy; Neoplasms
PubMed: 37403203
DOI: 10.1093/jleuko/qiad074 -
Frontiers in Immunology 2023The tumor microenvironment, particularly the immune microenvironment, plays an indispensable role in the malignant progression and metastasis of gastric cancer (GC). As... (Review)
Review
The tumor microenvironment, particularly the immune microenvironment, plays an indispensable role in the malignant progression and metastasis of gastric cancer (GC). As our understanding of the GC microenvironment continues to evolve, we are gaining deeper insights into the biological mechanisms at the single-cell level. This, in turn, has offered fresh perspectives on GC therapy. Encouragingly, there are various monotherapy and combination therapies in use, such as immune checkpoint inhibitors, adoptive cell transfer therapy, chimeric antigen receptor T cell therapy, antibody-drug conjugates, and cancer vaccines. In this paper, we review the current research progress regarding the GC microenvironment and summarize promising immunotherapy research and targeted therapies.
Topics: Humans; Stomach Neoplasms; Immunotherapy; Immunotherapy, Adoptive; Immunoconjugates; Tumor Microenvironment
PubMed: 38077373
DOI: 10.3389/fimmu.2023.1291117 -
Cancer Treatment Reviews Dec 2023Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies,... (Review)
Review
Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies, including anti-angiogenic agents and poly (ADP-ribose) polymerase inhibitors (PARPi), the majority of patients will relapse and develop treatment resistance, implying that novel therapeutic strategies are required. Adoptive cell therapy (ACT) refers to the process by which autologous immune cells are used to eliminate cancer. Examples include tumour infiltrating lymphocytes (TILs), T cells genetically engineered with T cell receptors (TCR), or chimeric antigen receptor (CAR)-T cells. Recently, ACT has revealed promising results in the treatment of haematological malignancies, however, its application to solid tumours is still limited due to lack of functionality and persistence of T cells, prevalence of an exhausted phenotype and impaired trafficking towards the tumour microenvironment (TME). In this review we explore the potential of ACT for the treatment of ovarian cancer and strategies to overcome its principal limitations.
Topics: Humans; Female; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Ovarian Neoplasms; Neoplasms; T-Lymphocytes; Receptors, Antigen, T-Cell; Tumor Microenvironment
PubMed: 37837788
DOI: 10.1016/j.ctrv.2023.102632 -
World Journal of Gastroenterology Oct 2023Gastric cancer (GC) is the sixth most common cancer and third leading cause of cancer-related deaths worldwide. Current treatments mainly rely on surgery- and... (Review)
Review
BACKGROUND
Gastric cancer (GC) is the sixth most common cancer and third leading cause of cancer-related deaths worldwide. Current treatments mainly rely on surgery- and chemotherapy-based systemic; however, the prognosis remains poor for advanced disease. Recent studies have suggested that immunotherapy has significant potential in cancer therapy; thus, GC immunotherapy may improve quality of life and survival for patients with this disease.
AIM
To provide a comprehensive overview of the knowledge structure and research hotspots of GC immunotherapy.
METHODS
We conducted a bibliometric analysis of publications on immunotherapy related to GC in the Web of Science Core Collection database. We analyzed 2013 pub-lications from 1999 to February 1, 2023, using the VOSviewer and CiteSpace software. We assessed publication and citation distributions using the WoS platform and explored research countries, institutions, journals, authors, references, and keywords (co-occurrence, timeline view, and burst analysis). In addition, we examined 228 trials on immunotherapy, 137 on adoptive cell therapy, 274 on immune checkpoint inhibitors (ICIs), and 23 on vaccines from ClinicalTrials.gov and the International Clinical Trials Registry Platform. The Impact Index Per Article for the top ten high-cited papers collected from () are presented.
RESULTS
Our bibliometric analysis revealed that the study of immunotherapy in GC has developed rapidly in recent years. China accounted for almost half the publications, followed by the United States. The number of publications in recent years has been growing continuously, and most institutions and authors with the most publications are from China. The main keywords or clusters identified were "tumor microenvironment", "adoptive immunotherapy", "dendritic therapy", and "microsatellite instability".
CONCLUSION
Our analysis of 2013 publications indicated that immunotherapy for GC has led to several new developments in recent years. Considerable progress has been made in vaccinations, immune checkpoint therapy, and adoptive cellular therapy. In particular, ICIs and chimeric antigen receptor T-cells are novel options for the treatment of GC. We suggest that the combination of ICIs, chemotherapy, targeted therapy, and other immunotherapies should be the primary research direction in the future.
Topics: Humans; Clinical Trials as Topic; Immunotherapy; Immunotherapy, Adoptive; Quality of Life; Stomach Neoplasms; Tumor Microenvironment
PubMed: 37970478
DOI: 10.3748/wjg.v29.i40.5593 -
BMJ (Clinical Research Ed.) May 2024In addition to conventional chemoradiation and targeted cancer therapy, the use of immune based therapies, specifically immune checkpoint inhibitors (ICIs) and chimeric... (Review)
Review
In addition to conventional chemoradiation and targeted cancer therapy, the use of immune based therapies, specifically immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T cell therapy (CAR-T), has increased exponentially across a wide spectrum of cancers. This has been paralleled by recognition of off-target immune related adverse events that can affect almost any organ system including the cardiovascular system. The use of ICIs has been associated with myocarditis, a less common but highly fatal adverse effect, pericarditis and pericardial effusions, vasculitis, thromboembolism, and potentially accelerated atherosclerosis. CAR-T resulting in a systemic cytokine release syndrome has been associated with myriad cardiovascular consequences including arrhythmias, myocardial infarction, and heart failure. This review summarizes the current state of knowledge regarding adverse cardiovascular effects associated with ICIs and CAR-T.
Topics: Humans; Neoplasms; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Cardiovascular Diseases; Cardiotoxicity; Myocarditis; Cytokine Release Syndrome; Pericarditis
PubMed: 38749554
DOI: 10.1136/bmj-2023-075859