Explore the vast range of titles available.

Antigen-specific retargeting of cytotoxic lymphocytes against tumorassociated antigens has thus far remained largely dependent on chimeric antigen receptors (CARs) that can be constructed by the fusion of an extracellular targeting domain (classically a single-chain variable fragment from an antibody) fused with intracellular signaling domains to trigger activation of T or natural killer (NK) cells. A major limitation of CAR-based therapies is that this technology only allows for the targeting of antigens that would be located on the surface of target cells while non-surface antigens, which affect approximately three-fourths of all human genes, remain out of reach. The targeting of non-surface antigens is only possible using inherent T cell receptor (TCR) mechanisms. However, introducing a second TCR into T cells via genetic modification is problematic due to the heterodimeric nature of the TCR ligand-binding domain, which is composed of TCR α and β chains. It has been observed that the delivery of a second TCR α/β pair may lead to the mispairing of new TCR chains with the endogenously expressed ones and create mixed TCR dimers, and this has negatively affected the advancement of TCR-based T cell therapies. Recently, NK cells have been put forward as possible effectors for TCR gene therapy. Since NK cells do not endogenously express TCR chains, this seems to be an infallible approach to circumventing the problem of mispairing. Moreover, the similarity of intracellular signaling pathways and mechanisms of cytotoxicity between NK and T cells ensures that the triggering of antigen-specific responses by the TCR/CD3 complex can be used to induce antigen-specific cytotoxicity by TCR-modified NK (TCR-NK) cells. This review provides an overview of the initial studies of TCR-NK cells, identifies open questions in the field, and defines the place of this approach within the spectrum of adoptive immunotherapy techniques that rely on cytotoxic lymphocytes.

HintergrundMolekular zielgerichtete Therapien und zellbasierte Immuntherapie ergänzen zunehmend die klassische zytotoxische Chemotherapie.ZielDer aktuelle Wissensstand und die größten Herausforderungen der molekularen und zellbasierten Krebstherapie werden dargestellt.Material und MethodeDie PubMed-gelisteten Publikationen und Tagungsberichte zu molekularer und zellbasierte Krebstherapie in den letzten 25 Jahren und den zu erwartenden Entwicklungsperspektiven wurden ausgewertet.ErgebnisseDie Indikationen für molekulare und zellbasierte Therapien nehmen stetig zu. Gerade bei den soliden Tumoren stellen Heterogenität und Evolution bisher eine Limitation für molekular zielgerichtete Therapie dar. Die Identifikation tumorassoziierter Antigene und die Überwindung des immunsuppressiven Tumormikromilieus sind wesentliche Herausforderungen für die Entwicklung zellbasierter Therapien. Erfolgversprechende neue Strategien sind genmodifizierte T‑Zellen, NK-Zellen, mesenchymale Stromazellen, dendritische Zellen, Technologien des In-vivo-Targeting und individualisierte RNA-Vakzine. Die genauere molekulare Charakterisierung von Tumoren auf genomischer, transkriptomischer, epigenetischer und proteomischer Ebene ist eine Voraussetzung für die Entwicklung wirksamer personalisierter Therapien. Künstliche Intelligenz wird benötigt, um die Interpretation der großen Datenmengen, die Diagnosestellung und die ärztliche Entscheidungsfindung zu unterstützen.SchlussfolgerungDie biologische Komplexität von Krebserkrankungen erfordert ein multimodales Konzept und eine umfassende genotypische und phänotypische Charakterisierung, auch unter Zuhilfenahme künstlicher Intelligenz, um unwirksame Behandlungen zu vermeiden, mögliche Resistenzentwicklungen gegen molekulare und zellbasierte Therapien zu umgehen und eine Elimination oder langfristige Erkrankungskontrolle zu erreichen.

HintergrundDurch neue Entwicklungen in der Immunonkologie hat die Systemtherapie maligner Erkrankungen in den letzten Jahren erhebliche Fortschritte gemacht.ZielZiel der Arbeit ist die Erstellung einer Übersicht über die wichtigsten aktuellen Entwicklungen im Bereich der Immuntherapie akuter Leukämien.Material und MethodeZusammenstellung und Diskussion publizierter Daten aus klinischen Studien, Diskussion von immunonkologischen Grundlagenarbeiten.ErgebnisseTherapeutische Fortschritte durch neue Immuntherapien sind zurzeit v. a. bei akuten lymphatischen Leukämien der B‑Zellreihe erzielt worden. Neben klassischen monoklonalen Antikörpern und Antikörper-Drug-Konjugaten zeigen zielgerichtete T‑Zell-basierte Therapieansätze mit dem BiTE-Molekül (BiTE Bi-specific T cell Engager) Blinatumomab und CAR-T-Zellen vielversprechende klinische Ergebnisse. Insbesondere die zielgerichtete Behandlung der minimalen Resterkrankung führt zu einer hohen Rate an rezidivfreien Langzeitüberlebern. Der Stellenwert neuer immuntherapeutischer Ansätze bei akuten Leukämien jenseits der B‑Zell-Reihe, wie z. B. der akuten myeloischen Leukämie (AML), ist zurzeit noch unklar und wird in zahlreichen klinischen Studien geprüft.SchlussfolgerungenEs ist davon auszugehen, dass die Kombination neuer Immuntherapeutika sowie deren Integration in die Erstlinienbehandlung zur Entwicklung weniger toxischer Therapien sowie zu einer weiteren Verbesserung der Heilungschancen akuter Leukämien führen werden. Um diese vielversprechenden Entwicklungen so schnell wie möglich voranzutreiben, sollten Patienten mit akuter Leukämie nach Möglichkeit in klinischen Studien behandelt werden.

The clinical success of chimeric antigen receptor (CAR) T cell immunotherapy in the treatment of haematological cancers has encouraged the extensive development of CAR design to improve their function and increase their applicability. Advancements in protein engineering have seen modifications to both the ecto- and endo-domains of the CAR, with recent designs targeting multiple antigens and including inducible elements. These developments are likely to play an important role in inducing effective CAR T cell responses in a solid tumour context, where clinical responses have not been effective to date. This review highlights the spectrum of novel strategies being employed in CAR design, including for example variations in targeting tumour antigens by utilising different ectodomain designs such as dual chain CARs, natural receptor or ligand-based CARs, and T cell receptor fusion constructs, and also reviews some of the innovative approaches to a “universal” CAR and various multi-antigen targeting CAR strategies. We also explore how choices in the endodomain impact CAR function and how these need to be considered in the overall CAR design.

Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy with poor prognosis despite multiple available therapies. While chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell malignancies, its application in AML has been limited by early relapses and severe toxicities. Unlike B-cell antigens, most AML-associated surface antigens are also expressed on healthy hematopoietic stem and progenitor cells, creating significant risks of on-target/off-tumor toxicity and prolonged myeloablation. To address the scarcity of AML-specific targets, several innovative CAR strategies have been developed to enhance precision, safety, and efficacy. Logic-gated CARs improve selectivity through dual-antigen recognition or conditional activation. Drug-inducible and transient expression systems, as well as pharmacologic or suicide switches, enable controlled modulation or elimination of CAR cells to reduce toxicity. Adapter CAR platforms allow real-time, flexible targeting, while engineered modulation of gene expression or cytokine secretion enhances persistence and antitumor activity. Finally, alternative immune cells, including natural killer (NK) cells and macrophages, provide versatile platforms that may overcome limitations of conventional T-cell therapies, such as fratricide or challenges in allogeneic use. This review provides a comprehensive overview of these emerging CAR approaches, highlighting their advantages, limitations, and potential to expand immunotherapeutic strategies for AML.

CAR-T cells (CAR-Ts) are genetically engineered T lymphocytes to express a receptor construct bearing an extracellular recognition domain that guides the killing specificity, a transmembrane domain, and an intracellular domain that elicits effector signaling. Upon encountering the target cell, CAR-Ts accomplish their cytolytic effector function directly via engagement of pro-apoptotic pathways and exocytosis of perforin and granzymes, or indirectly via secretion of cytokines that activate NK cells. Autologous CAR-Ts, bearing an extracellular recognition domain specific for the B-cell surface markers CD19 or BCMA, were initially approved for the treatment of late-stage hematologic malignancies. The last five years, mounting evidence from small studies in humans, employing autologous CAR-Ts targeting CD19 to selectively eliminate CD19 + cell subsets from the pool of the B-cell lineage, have revealed acceptable safety profile and encouraging efficacy in treatment-resistant systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myositis. Herein, we focus on a series of groundbreaking reports published within 2025 that enlighten the arising transformational potential and the emerging challenges of the CAR-based therapies regarding the management of life-threatening endotypes of autoimmune diseases.

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient’s age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR’s hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

Chimeric antigen receptor (CAR)-T cell therapy is an emerging staple in the treatment of certain hematological malignancies. While CAR-T cells have produced robust responses in certain hematological malignancies, toxicities associated with the therapy have limited their use. Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening neurotoxicity that commonly occurs with CAR-T cell therapy. Here we will discuss ICANS, its treatment, possible mechanisms, and potential solutions to this critical limitation of CAR-T cell therapy. As the field of CAR-T cell therapy evolves, improved treatments and methods to circumvent or overcome ICANS are necessary to improve morbidity, mortality, and decrease the cost of CAR-T cell therapy. This serious, life-threatening side effect needs to be studied to better understand its mechanisms and develop treatments and alternative strategies.

Chimeric antigen receptor-expressing T cells (CAR T cells) have revolutionized cancer treatment, particularly in B cell malignancies. However, the use of autologous T cells for CAR T therapy presents several limitations, including high costs, variable efficacy, and adverse effects linked to cell phenotype. To overcome these challenges, we developed a strategy to generate universal and safe anti-CD19 CAR T cells with a defined memory phenotype. Our approach utilizes CRISPR/Cas9 technology to target and eliminate the and genes, reducing graft-versus-host and host-versus-graft responses. Additionally, we selected less differentiated T cells to improve the stability and persistence of the universal CAR T cells. The safety of this method was assessed using our CRISPRroots transcriptome analysis pipeline, which ensures successful gene knockout and the absence of unintended off-target effects on gene expression or transcriptome sequence. experiments demonstrated the successful generation of functional universal CAR T cells. These cells exhibited potent lytic activity against tumor cells and a reduced cytokine secretion profile. The CRISPRroots analysis confirmed effective gene knockout and no unintended off-target effects, validating it as a pioneering tool for on/off-target and transcriptome analysis in genome editing experiments. Our findings establish a robust pipeline for manufacturing safe, universal CAR T cells with a favorable memory phenotype. This approach has the potential to address the current limitations of autologous CAR T cell therapy, offering a more stable and persistent treatment option with reduced adverse effects. The use of CRISPRroots enhances the reliability and safety of gene editing in the development of CAR T cell therapies. We have developed a potent and reliable method for producing universal CAR T cells with a defined memory phenotype, demonstrating both efficacy and safety . This innovative approach could significantly improve the therapeutic landscape for patients with B cell malignancies.