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Tumor buster - where will the CAR-T cell therapy 'missile' go?

Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME

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… V H : heavy chain variable domain; V L : light chain variable domain; scFv: single-chain fragment variable; VHH: single variable domain on a heavy chain The fact that tumor recognition is not dependent on the major histocompatibility complex (MHC) constitutes their primary benefit. …

Molecular Inhibitors of Growth Signals

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Эпидемиология, патология и патогенез MS: терапевтические последствия.

Множественный склероз (MS) является хроническим и потенциально деактивирующим воспалительным заболеванием центральной нервной системы (CNS). МS, как правило, характеризуется повторяющимися и самоограниченными эпизодами неврологической дисфункции, которые происходят непредсказуемо и часто приводят к множественным повреждениям тканей в рамках CNS. В настоящее время женщины страдают в два-три раза чаще, чем мужчины, хотя это, возможно, не произошло в предыдущие периоды времени. Известно, что патогенез MS связан как с критическими генетическими, так и с экологическими механизмами. Тем не менее, по

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… The strongest association is with the HLA Class-II haplotype, DRB1∗15:01∼DQB1∗06:02 located at ( 6p21.3 ) within the major histocompatibility complex ( MHC ) on the short arm of chromosome 6 [ 5 , 6 , [84] , [85] , [86] , [87] , [88] , [89] ]. …

Cancer-Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets.

Cancer-associated fibroblasts (CAFs) are functionally diverse stromal regulators that orchestrate tumor progression, metastasis, and therapy resistance through dynamic crosstalk within the tumor microenvironment (TME). Recent advances in single-cell multiomics and spatial transcriptomics have identified conserved CAF subtypes with distinct molecular signatures, spatial distributions, and context-dependent roles, highlighting their dual capacity to promote immunosuppression or restrain tumor growth. However, therapeutic strategies struggle to reconcile this functional duality, hindering clinica

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… A recently identified subset, apCAFs, expresses major histocompatibility complex (MHC) class II molecules and has been implicated in antigen presentation, potentially influencing antitumor immune responses, although their precise role remains under investigation [ 15 ]. …

Breaking Therapy Resistance: An Update on Oncolytic Newcastle Disease Virus for Improvements of Cancer Therapy.

Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian virus combines, upon inoculation into non-permissive hosts such as human, 12 described anti-neoplastic effects with 11 described immune stimulatory properties. Fifty years of clinical application of NDV give witness to the high safety profile of this biological agent. In 2015, an important milestone was achieved, namely the succ

Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review.

Despite rapid advances in treatment approaches of multiple myeloma (MM) over the last two decades via proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), their efficacies are limited. MM still remains incurable, and the majority of patients shortly relapse and eventually become refractory to existing therapies due to the genetic heterogeneity and clonal evolution. Therefore, the development of novel therapeutic strategies with different mechanisms of action represents an unmet need to achieve a deep and highly durable response as well as to improve pa

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… The development of immunotherapeutic modalities for MM has been delayed because of immune evasion by tumor cells through decreased expression of tumor-specific antigens, enhanced expression of inhibitory ligands such as programmed cell death ligand 1 (PD-L1) or major histocompatibility complex (MHC) …

C

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CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges.

Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-rela

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… Thus, CAR-T cells recognize specific surface antigens on tumor cells without antigen processing and presentation, which indicates that antigen recognition by CAR-T cells is independently of major histocompatibility complex (MHC) restriction. …

Application of dendritic cell extracellular vesicles as a valid nanoparticle platform for cancer therapies: a narrative review.

The prevalence of cancers has actually increased during the last few decades, affecting almost all human societies. Despite progress in therapeutic protocols, cancer is still the main cause of global human mortality. Although the advancement of modern immunotherapeutic approaches can increase the survival rate of cancer patients, new modalities are essential for improved therapeutic outcomes. Extracellular vesicles (EVs) are nanosized particles and are used for cell-free approaches instead of direct whole cell-based administration. It has been thought that EVs can reduce the risks and side eff

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… Meanwhile, DC EVs possess comparable immunological features of their parent DCs and harbor major histocompatibility complex (MHC) molecules and co-stimulatory molecules, which are required for the activation of T lymphocytes and natural killer (NK) cells [ 8 ]. …

Different origin-derived exosomes and their clinical advantages in cancer therapy.

Exosomes, as a class of small extracellular vesicles closely related to the biological behavior of various types of tumors, are currently attracting research attention in cancer diagnosis and treatment. Regarding cancer diagnosis, the stability of their membrane structure and their wide distribution in body fluids render exosomes promising biomarkers. It is expected that exosome-based liquid biopsy will become an important tool for tumor diagnosis in the future. For cancer treatment, exosomes, as the "golden communicators" between cells, can be designed to deliver different drugs, aiming to ac

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… The composition of IM-Exo consists of specific proteins, particularly tetrastransmembrane proteins (e.g., CD9, CD63, CD81, CD82), interacting with other proteins expressed on target cells (e.g., major histocompatibility complex [MHC] molecules, integrins) ( 250 ). …

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm.

Pediatric solid organ and hematopoietic stem cell transplant recipients paradoxically experience accelerated immune aging despite chronological youth, establishing a paradigm with profound implications for cancer risk and long-term outcomes. This comprehensive review synthesizes current evidence demonstrating how transplantation-related factors, anti-thymocyte globulin-mediated T cell depletion, cytomegalovirus reactivation, chronic immunosuppression, and thymic dysfunction, induce premature immunosenescent phenotypes. These processes converge to generate T cell populations exhibiting CD28 los

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… These viral mechanisms include interference with major histocompatibility complex (MHC) class I antigen presentation through multiple viral proteins (US2, US3, US6, US11), inhibition of natural killer (NK) cell function via MHC class I homologs (UL18), modulation of cytokine responses, and induction …

WT1 gene: a potential therapeutic target for multiple cancer treatment strategies.

The Wilms' Tumor 1 (WT1) gene has attracted significant attention in oncological research owing to its involvement in the pathogenesis of a variety of malignancies. Initially identified in association with Wilms' tumor, a pediatric renal carcinoma, WT1 is now recognized for its broader implications in the etiology of multiple cancers, including leukemia, ovarian cancer, and lung cancer. This review offers a comprehensive analysis of the historical development of WT1 research, explores its mechanisms in cancer progression, and assesses its potential as a therapeutic target, with an emphasis on

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… These vaccines deliver WT1-derived peptides, which antigen-presenting cells present via major histocompatibility complex (MHC) molecules, thereby stimulating WT1-specific cytotoxic T lymphocytes (CTLs) to target and destroy tumor cells expressing WT1 (Fig. 4 ). …

Targeted therapies in pediatric oncology: A start.

The treatment of cancers was revolutionized by the use of combination "conventional" chemotherapy, first in children, during the 20th century. That foundation of therapy, while having achieved significant advances in survival, has reached its limits. Innovations in targeted therapies are now building upon that foundation to further improve outcomes in pediatric oncology. These targeted agents are designed to narrowly utilize specific biologic processes for greater efficacy and optimally fewer generalized toxicities. I will provide an overview of the current spectrum of targeted therapies avail

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… Endogenous T cells are activated primarily through their αβ T cell receptors (TCRs) that bind antigens presented as peptides through major histocompatibility complex (MHC) presentation on antigen-presenting cells. …

Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cance

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… Neoantigen presentation provided by antigen-presenting cells (APCs), including dendritic cells (DCs), monocytes/macrophages and B lymphocytes, in the context of major histocompatibility complex class I (MHC I) molecules, is required to stimulate the cytotoxic response of CD8+ T cells. …

Hematology and Immune-Related Disorders

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Guidelines for treatment of renal injury during cancer chemotherapy 2016.

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… d) β2 microglobulin β2 microglobulin is a polypeptide comprising 99 amino acids with a molecular weight of 11,800; it is distributed on the surface of nucleated cells throughout the body as the L chain of the major histocompatibility complex HLA class I antigen. β2 microglobulin passes freely through …

Decoding the epitranscriptome: a new frontier for cancer therapy and drug resistance.

As the role of RNA modification in gene expression regulation and human diseases, the "epitranscriptome" has been shown to be an important player in regulating many physiological and pathological processes. Meanwhile, the phenomenon of cancer drug resistance is becoming more and more frequent, especially in the case of cancer chemotherapy resistance. In recent years, research on relationship between post-transcriptional modification and cancer including drug resistance has become a hot topic, especially the methylation of the sixth nitrogen site of RNA adenosine-m6A (N6-methyladenosine). m6A m

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… Mechanistically, reducing YTHDF1 inhibits translation of lysosomal genes and limits major histocompatibility complex class I (MHC-I) and lysosomal proteolysis of antigens [ 115 ]. …

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research-practice gaps, challenges, and insights.

To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune-based therapeutic modalities of anticancer

Adeno-associated virus as a delivery vector for gene therapy of human diseases.

Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dos