Vitaly Chasov

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) characterized by the destruction of the myelin sheath around nerve cells. The prevalence and serious consequences of MS highlight the shortcomings of existing treatments and the importance of developing innovative therapeutic approaches. Based on successful pilot studies in patients and an experimental autoimmune encephalomyelitis (EAE) mouse model, CAR-T cells offer a novel therapeutic mechanism by directly targeting and eliminating B cells, overcoming the shortcomings of antibody-mediated B cell depletion, which is unable to penetrate deep into the CNS. Recent discoveries have also revealed an important role for the gut microbiota in maintaining immune homeostasis. In a state of homeostasis, there is a symbiotic relationship between host factors and the microbiota that helps to maintain a healthy state. However, alterations in the composition and function of the gut microbiota, known as gut dysbiosis, can disrupt this homeostasis. The microbiota, through its metabolites, can influence not only internal processes in the gut but also the CNS in MS. Therapeutic interventions that help restore the balance of the gut microbiota may be a promising additional treatment to existing therapies to alleviate symptoms and promote remission in patients with MS.

Systemic sclerosis (SSc) is a disease in which malfunctioning immune cells lead to the formation of autoantibodies that damage blood vessels and body tissues. Fibrosis then develops in the affected organs. Its complex pathogenesis involves multiple immune and stromal cell types, soluble mediators, and dysregulated tissue repair, resulting in heterogeneous clinical manifestations and poor prognosis. Current disease-modifying therapies provide only modest benefits, often slowing but rarely reversing disease progression, and are associated with considerable adverse effects. These limitations have spurred the development of cell-based therapeutic strategies aimed at restoring immune tolerance and promoting tissue repair. In this review, we summarize recent advances in hematopoietic stem cell transplantation, mesenchymal stem cell therapy, and adoptive regulatory T cell transfer and highlight the emerging role of chimeric antigen receptor (CAR)-T cell therapy as a transformative approach for SSc. Collectively, these evolving strategies hold the potential to improve survival, achieve durable remissions, and significantly enhance quality of life for patients with SSc.

Allogeneic (“off-the-shelf”) CAR-T cells promise faster treatment access, standardized manufacturing, and scalable supply compared with autologous products, but they face a core biological constraint: the recipient immune system recognizes allogeneic CAR-T as a graft and eliminates it, while residual donor T-cell receptor (TCR) activity can cause graft-versus-host disease (GvHD). Clinical progress over the last several years has validated feasibility, with encouraging response rates in B-cell malignancies and generally manageable safety profiles, yet persistence and repeat dosing remain limited by host-versus-graft (HvG) immunity. For example, a peer-reviewed report of allogeneic anti-CD19 CAR-T in LBCL described measurable expansion, persistence up to months, and objective responses in heavily pretreated patients. This mini-review focuses on an increasingly central barrier: humoral rejection (donor-specific antibodies, complement, and Fcγ receptor–dependent effector mechanisms), alongside cellular rejection (host T cells, NK cells, and macrophages) and the “missing-self” problem created by HLA class I ablation. We summarize the current engineering playbook—TCR disruption to prevent GvHD, HLA editing and inhibitory ligand strategies to evade cellular HvG, and emerging concepts to resist antibody-mediated killing—and propose a practical design logic for next-generation allogeneic CAR-T: multi-layer immune evasion without forfeiting antitumor function or manufacturability.

Tumor evolution under immune pressure follows the logic of cancer immunoediting—elimination, equilibrium, and escape—in which immune surveillance removes highly immunogenic clones while selecting for variants capable of persistence and progression. Clinically, this evolutionary outcome is often operationalized as an immune-phenotype continuum, frequently simplified into “hot” (immune-inflamed) and “cold” (immune-excluded or immune-desert) tumors. This mini-review uses the provided schematic of elimination–equilibrium–escape (Figure 1) to organize tumor defense strategies into two archetypes: (i) immune hiding (“cold” tumors)—minimizing immune recognition through impaired priming, trafficking, and antigen presentation; and (ii) active immune resistance (“hot” tumors)—withstanding immune attack through adaptive checkpoint induction (e.g., PD-L1), immunosuppressive stromal/myeloid circuits, and genetic/epigenetic escape from interferon and antigen presentation pathways. We highlight mechanistic nodes that repeatedly govern the cold↔hot state and propose a practical framework to match intervention strategy to dominant failure mode: initiate immunity (convert cold to inflamed) versus release brakes (overcome adaptive resistance in hot tumors). We also briefly situate innate-like stress surveillance (e.g., NKG2D-mediated recognition) within immunoediting, emphasizing how tumors can evade both T cell– and NK cell–mediated control by altering ligand availability and microenvironmental context.

NKG2D is an activating immunoreceptor expressed by natural killer (NK) cells and subsets of T cells that recognizes multiple stress-induced ligands (e.g., MICA/MICB and ULBP1–6) frequently upregulated in malignant transformation. NKG2D signaling in humans is mediated by the DAP10 adaptor and associated downstream nodes (e.g., PI3K and Grb2–Vav1), which collectively control cytotoxic synapse formation and effector function. NKG2D-based CAR-T cells leverage this multi-ligand recognition to broaden tumor coverage and mitigate single-antigen escape, positioning the approach as a potentially “pan-tumor” CAR strategy. Early clinical experience with autologous NKG2D-CAR products has established feasibility and a manageable safety profile in selected settings; however, objective responses have been inconsistent and durability remains limited. A major set of barriers is intrinsic to the NKG2D axis itself: tumors can downregulate ligand expression, shed MICA/MICB via metalloproteases, and accumulate soluble/vesicular ligands that blunt NKG2D function and promote receptor internalization. These mechanisms synergize with tumor microenvironment (TME) suppression, particularly TGF-β–mediated inhibition of NKG2D pathways. This review synthesizes the mechanistic rationale for NKG2D-CAR designs, summarizes representative clinical programs, and focuses on current challenges and practical mitigation strategies: (i) selectivity and safety when stress ligands are inducible in inflamed normal tissues; (ii) ligand shedding and soluble ligand decoy effects; (iii) TGF-β dominance; (iv) persistence/exhaustion constraints; and (v) manufacturing and development considerations.

CAR receptor engineering has progressed from “add a costimulatory domain” to a disciplined, multi-parameter design problem spanning extracellular geometry, intracellular network wiring, and safety control layers. Using the provided schematic of CAR generations (Figure 1) as a conceptual anchor, this mini-review summarizes the current state of CAR design from first-generation ITAM-only receptors to armored/TRUCK concepts and cytokine-receptor/JAK–STAT–coupled “fifth-generation” constructs. TRUCK designs formalized the principle of antigen-triggered payload delivery to reshape the tumor microenvironment. Fifth-generation architectures exemplified by IL-2Rβ/STAT-recruiting CARs attempt to integrate activation, costimulation, and STAT transcriptional programming in an antigen-dependent manner. We highlight design variables that often dominate in vivo behavior yet are underappreciated in “generation” shorthand: hinge/spacer and transmembrane selection, Fc receptor interactions, receptor clustering/tonic signaling, and exhaustion dynamics influenced by CD28 versus 4-1BB signaling. Finally, we frame NKG2D-based CAR approaches as a case study where target biology forces architectural choices (multi-ligand recognition, endogenous adaptor signaling, fratricide risk and ligand dynamics), illustrating how modern CAR design must be co-developed with biomarker strategy and control mechanisms to achieve a favorable therapeutic index.

Chimeric Antigen Receptor (CAR)-T cell therapy has transformed the treatment landscape of cancer, yet major challenges remain in enhancing efficacy, reducing adverse effects, and expanding accessibility. Autologous CAR-T cells, derived from individual patients, have achieved remarkable clinical success in hematologic malignancies; however, their highly personalized nature limits scalability, increases costs, and delays timely treatment. Allogeneic CAR-T cells generated from healthy donors provide an “off-the-shelf” alternative but face two critical immune barriers: graft-versus-host disease (GvHD), caused by donor T-cell receptor (TCR) recognition of host tissues, and host-versus-graft rejection, mediated by recipient immune responses against donor HLA molecules. Recent advances in genome engineering, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9, allow precise modification of donor T cells to overcome these limitations. For example, TRAC gene knockout eliminates TCR expression, preventing GvHD, while disruption of HLA molecules reduces immunogenicity without impairing cytotoxicity. Beyond hematologic cancers, CRISPR-edited allogeneic CAR-T cells targeting the NKG2D receptor have shown promise in preclinical studies and early-phase trials. NKG2D CAR-T cells recognize stress ligands (MICA/B, ULBP1–6) expressed on over 80% of diverse solid tumors, including pancreatic and ovarian cancers, thereby broadening therapeutic applicability. Nevertheless, the genomic editing process carries risks of off-target effects, including potential disruption of tumor suppressor genes and oncogenes, underscoring the need for stringent safety and quality control. This review examines the distinguishing features of allogeneic versus autologous CAR-T therapy, with a particular focus on NKG2D-based allogeneic CAR-T approaches for solid tumors. We summarize current strategies to mitigate immune barriers, discuss practical manufacturing challenges, and analyze available clinical data on NKG2D CAR-T trials. Collectively, these insights underscore both the promise and the hurdles of developing safe, universal, and scalable allogeneic CAR-T therapies for solid malignancies.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint inflammation, progressive tissue damage and significant disability, severely impacting patients’ quality of life. While the exact mechanisms underlying RA remain elusive, growing evidence suggests a strong link between intestinal microbiota dysbiosis and the disease’s development and progression. Differences in microbial composition between healthy individuals and RA patients point to the role of gut microbiota in modulating immune responses and promoting inflammation. Therapies targeting microbiota restoration have demonstrated promise in improving treatment efficacy, enhancing patient outcomes and slowing disease progression. However, the complex interplay between gut microbiota and autoimmune pathways in RA requires further investigation to establish causative relationships and mechanisms. Here, we review the current understanding of the gut microbiota’s role in RA pathogenesis and its potential as a therapeutic target.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Although much remains unknown about the pathogenesis of RA, there is evidence that impaired immune tolerance and the development of RA are related. And it is precisely the restoration of immune tolerance at the site of the inflammation that is the ultimate goal of the treatment of RA. Over the past few decades, significant progress has been made in the treatment of RA, with higher rates of disease remission and improved long-term outcomes. Unfortunately, despite these successes, the proportion of patients with persistent, difficult-to-treat disease remains high, and the task of improving our understanding of the basic mechanisms of disease development and developing new ways to treat RA remains relevant. This review focuses on describing new treatments for RA, including cell therapies and gene editing technologies that have shown potential in preclinical and early clinical trials. In addition, we discuss the opportunities and limitations associated with the use of these new approaches in the treatment of RA.

Systemic autoimmune diseases (SAIDs), such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and rheumatoid arthritis (RA), are fully related to the unregulated innate and adaptive immune systems involved in their pathogenesis. They have similar pathogenic characteristics, including the interferon signature, loss of tolerance to self-nuclear antigens, and enhanced tissue damage like necrosis and fibrosis. Glucocorticoids and immunosuppressants, which have limited specificity and are prone to tolerance, are used as the first-line therapy. A plethora of novel immunotherapies have been developed, including monoclonal and bispecific antibodies, and other biological agents to target cellular and soluble factors involved in disease pathogenesis, such as B cells, co-stimulatory molecules, cytokines or their receptors, and signaling molecules. Many of these have shown encouraging results in clinical trials. CAR-T cell therapy is considered the most promising technique for curing autoimmune diseases, with recent successes in the treatment of SLE and SSc. Here, we overview novel therapeutic approaches based on CAR-T cells and antibodies for targeting systemic autoimmune diseases.