Current and future immunotherapeutic approaches in pancreatic cancer treatment

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Июнь 4, 2024

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type tumor have remained grim long time. Currently, it extremely challenging to prevent or detect early enough effective treatment because patients rarely exhibit symptoms there are no reliable indicators detection. Most advanced spreading that difficult treat, treatments like chemotherapy radiotherapy can only slightly prolong their life by few months. Immunotherapy has revolutionized pancreatic cancer, yet its effectiveness limited tumor's immunosuppressive hard-to-reach microenvironment. First, article explains microenvironment highlights wide range immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered chimeric antigen [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced cells, immune checkpoint inhibitors, immunomodulators, vaccines, strategies targeting myeloid in context contemporary knowledge future trends. Lastly, discusses main challenges ahead immunotherapy.

Язык: Английский

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Enhancement of anti‐sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2‐targeted CAR

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 1, 2025

Abstract Background Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, represent a group of malignancies that significantly contribute to cancer‐related morbidity mortality in children young adults. These cancers share common challenges, high rates metastasis, recurrence or treatment resistance, leading 5‐year survival rate approximately 20% for patients with advanced disease stages. Despite the critical need, therapeutic advancements have been limited over past three decades. The advent chimeric antigen receptor (CAR)‐based immunotherapies offers promising avenue novel treatments. However, CAR‐T cells faced significant challenges success treating solid tumours due issues such as poor tumour infiltration, immunosuppressive microenvironments off‐target effects. In contrast, adaptation CAR technology natural killer (NK) has demonstrated potential both haematological tumours, suggesting new strategy paediatric sarcomas. Methods This study developed validated CAR‐NK cell therapy targeting ephrin type‐A receptor‐2 (EphA2) antigen, which is highly expressed various Results expression was successfully detected on surface NK post‐electroporation, indicating successful transfection. Significantly, EphA2‐specific enhanced cytotoxic activity against several lines vitro, those compared unmodified cells. Transient messenger RNA (mRNA) transfection safe approach genetic engineering, further chemical modifications mRNA enhancing stability temporal EphA2‐CAR cells, thereby promoting prolonged protein expression. Additionally, vivo EphA2‐CAR‐NK showed anti‐cancer rhabdomyosarcoma osteosarcoma mouse models. Conclusions provides foundational basis clinical evaluation EphA2‐targeted across spectrum anti‐tumour effects observed vitro/vivo suggests improved outcomes hard‐to‐cure Key points Addressing unmet needs Sarcomas. sarcoma, exhibit lack progress decades necessitates innovative approaches. Advancing immunotherapy Natural modified receptors (CARs) overcome limitations particularly tumours. are associated targeting, reduced effects, safety profiles. EphA2 target. EphA2, overexpressed multiple identified viable target CAR‐based its role progression angiogenesis. Innovations mRNA‐based engineering. demonstrates feasibility transient engineer expression, offering non‐integrative safer alternative viral transduction. Enhancements through modifications, can optimise Preclinical efficacy superior cytotoxicity vitro demonstrate models osteosarcoma. Clinical translation potential. findings establish strong preclinical rationale immunotherapeutic option Future research directions: Combining immune checkpoint inhibitors other immunomodulatory agents could enhance durability. Advanced mimicking human needed refine this approach.

Язык: Английский

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CAR-T Cell Therapy: From the Shop to Cancer Therapy

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 15688 - 15688

Опубликована: Окт. 28, 2023

Cancer is a worldwide health problem. Nevertheless, new technologies in the immunotherapy field have emerged. Chimeric antigen receptor (CAR) technology novel biological form to treat cancer; CAR-T cell genetic engineering has positively revolutionized cancer immunotherapy. In this paper, we review latest developments treatment. We present structure of different generations and variants cells including TRUCK (T redirected for universal cytokine killing. explain approaches manufactured ex vivo vivo. Moreover, describe limitations areas opportunity current challenges treating hematological solid using as well its constraints approaches. summarize other immune that been CAR technology, such natural killer (NK), macrophages (M), dendritic (DC). conclude potential not only but chronic diseases.

Язык: Английский

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Advancing Autoimmune Rheumatic Disease Treatment: CAR-T Cell Therapies - Evidence, Safety, and Future Directions

Seminars in Arthritis and Rheumatism, Год журнала: 2024, Номер 67, С. 152479 - 152479

Опубликована: Май 24, 2024

Despite advancements in managing autoimmune rheumatic diseases (ARDs) with existing treatments, many patients still encounter challenges such as inadequate responses, difficulty maintaining remission, and side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has now emerged a promising option cases of refractory ARDs.

Язык: Английский

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Antigen escape in CAR-T cell therapy: Mechanisms and overcoming strategies

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 178, С. 117252 - 117252

Опубликована: Авг. 3, 2024

Chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating hematological malignancies and certain solid tumors. However, its efficacy is often hindered by negative relapses resulting from escape. This review firstly elucidates the mechanisms underlying escape during CAR-T therapy, including enrichment of pre-existing target-negative tumor clones, gene mutations or alternative splicing, deficits processing, redistribution, lineage switch, epitope masking, trogocytosis-mediated loss. Furthermore, we summarize various strategies to overcome escape, evaluate their advantages limitations, propose future research directions. Thus, aim provide valuable insights enhance effectiveness therapy.

Язык: Английский

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Next-Generation Immunotherapy: Advancing Clinical Applications in Cancer Treatment

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(21), С. 6537 - 6537

Опубликована: Окт. 30, 2024

Next-generation immunotherapies have revolutionized cancer treatment, offering hope for patients with hard-to-treat tumors. This review focuses on the clinical applications and advancements of key immune-based therapies, including immune checkpoint inhibitors, CAR-T cell therapy, new vaccines designed to harness system combat malignancies. A prime example is success pembrolizumab in treatment advanced melanoma, underscoring transformative impact these therapies. Combination treatments, integrating immunotherapy chemotherapy, radiation, targeted are demonstrating synergistic benefits improving patient outcomes. also explores evolving role personalized immunotherapy, guided by biomarkers, genomic data, tumor environment, better target individual Although significant progress has been made, challenges such as resistance, side effects, high costs persist. Technological innovations, nanotechnology artificial intelligence, explored future enablers The evaluates trials, breakthroughs, emerging immune-modulating agents delivery systems that hold great promise enhancing efficacy, reducing toxicity, expanding access immunotherapy. In conclusion, this highlights ongoing reshaping care, strategies poised overcome current further extend therapeutic reach.

Язык: Английский

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Targeting refractory diffuse large B cell lymphoma by CAR-WEE1 T-cells: In vitro evaluation

Annals of Hematology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Abstract Refractory Diffuse Large B-cell Lymphoma (DLBCL) presents a major therapeutic challenge due to its resistance standard treatments. Engineered T-cells, especially Chimeric Antigen Receptor (CAR) have shown promise in overcoming drug resistance. This study investigates the effectiveness of WEE1-engineered T-cells targeting and eliminating refractory DLBCL vitro. CAR were created by transducing 5th-generation construct designed recognize WEE1, surface antigen commonly found on cells. The cytotoxic effect engineered was tested against Rituximab-resistant cells (RR-NU-DUL-1). Apoptosis cell cycle evaluated using flow cytometry. Quantitative Real-time PCR (RT-PCR) used measure expression BCL2, CDK2. results showed significant increase target lysis, apoptosis, necrosis, reduction percentage G2M phase cycle, as well decrease gene level, indicating strong anti-tumor activity. These findings suggest that T-cell therapy holds great for treating DLBCL, offering potential path clinical application. vitro evaluation highlights targeted treatment strategy emphasizing their applicability ability overcome mechanisms this aggressive lymphoma subtype.

Язык: Английский

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Basic Concepts and Indications of CAR T Cells

Hämostaseologie, Год журнала: 2025, Номер 45(01), С. 014 - 023

Опубликована: Фев. 1, 2025

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer immunotherapy, particularly for hematological malignancies. This personalized approach is based on genetically engineering cells derived from the patient to target antigens expressed—among others—on malignant cells. Nowadays they offer new hope where conventional therapies, such as chemotherapy and radiation, have often failed. Since first FDA approval in 2017, CAR rapidly expanded, proving highly effective against previously refractory diseases with otherwise a dismal outcome. Despite its promise, continues face significant challenges, including complex manufacturing, management of toxicities, resistance mechanisms that impact long-term efficacy, limited access well high costs, which continue shape ongoing research clinical applications. review aims provide an overview therapy, fundamental concepts, applications, current future directions

Язык: Английский

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A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Апрель 27, 2023

Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been FDA-approved, CAR targeting CD22, as well dual-targeting CD19/CD22 T-cells, currently being evaluated in clinical trials. This systematic review and meta-analysis aimed to evaluate efficacy safety CD22-targeting T-cell therapies. We searched MEDLINE, EMBASE, Web Science, Cochrane Central Register Controlled Trials from inception March 3rd 2022 full-length articles conference abstracts trials employing acute lymphocytic leukemia (ALL) non-Hodgkin’s lymphoma (NHL). The primary outcome was best complete response (bCR). A DerSimonian Laird random-effects model with arcsine transformation used pool proportions. From 1068 references screened, 100 were included, representing 30 early phase studies 637 patients, investigating CD22 or T-cells. had a bCR 68% [95% CI, 53-81%] ALL (n= 116), 64% 46-81%] NHL 28) 74% 96% patients having received anti-CD19 previously respectively. rate 90% 84-95%] 297) 47% 34-61%] 137). estimated incidence total severe (grade ≥3) CRS 87% 80-92%] 6% 3-9%] ICANS 16% 9-25%] 3% 1-5%] Early show high remission rates NHL. Severe (1)rare did not increase toxicity. Variability construct, dose, patient factors amongst limits comparisons, long-term outcomes yet be reported. Systematic registration https://www.crd.york.ac.uk/prospero , identifier CRD42020193027.

Язык: Английский

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Advancements in Personalized CAR-T Therapy: Comprehensive Overview of Biomarkers and Therapeutic Targets in Hematological Malignancies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(14), С. 7743 - 7743

Опубликована: Июль 15, 2024

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel anticancer using autologous or allogeneic T-cells. To date, six CAR-T therapies for specific B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) have been approved by the Food Drug Administration (FDA). Significant barriers to effectiveness of include cytokine release syndrome (CRS), neurotoxicity in case Allogeneic Stem Cell Transplantation (Allo-SCT) graft-versus-host-disease (GVHD), escape, modest antitumor activity, restricted trafficking, limited persistence, immunosuppressive microenvironment, senescence exhaustion CAR-Ts. Furthermore, cancer drug resistance remains major problem clinical practice. therapy, combination with checkpoint blockades bispecific engagers (BiTEs) other drugs, appears be an appealing strategy. Many these agents shown impressive results, combining efficacy tolerability. Biomarkers like extracellular vesicles (EVs), cell-free DNA (cfDNA), circulating tumor (ctDNA) miRNAs may play important role toxicity, relapse assessment, prediction, can implicated applications establishing safe efficacious personalized medicine. However, further research required fully comprehend particular side effects immunomodulation, ascertain best order this medication conventional chemotherapy targeted therapies, find reliable predictive biomarkers.

Язык: Английский

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