A First-in-Human Phase I Clinical Study with MVX-ONCO-1, a Personalized Active Immunotherapy, in Patients with Advanced Solid Tumors.

Over two decades, most cancer vaccines failed clinical development. Key factors may be the lack of efficient priming with tumor-specific antigens and strong immunostimulatory signals. MVX-ONCO-1, a personalized cell-based cancer immunotherapy, addresses these critical steps utilizing clinical-grade material to replicate a successful combination seen in experimental models: inactivated patient's own tumor cells, providing the widest cancer-specific antigen repertoire and a standardized, sustained, local delivery over days of a potent adjuvant achieved by encapsulated cell technology. We conducted an open-label, single-arm, first-in-human phase I study with MVX-ONCO-1 in patients with advanced refractory solid cancer. MVX-ONCO-1 comprises irradiated autologous tumor cells coimplanted with two macrocapsules containing genetically engineered cells producing granulocyte-macrophage colony-stimulating factor. Patients received six immunizations over 9 weeks without maintenance therapy. Primary objectives were safety, tolerability, and feasibility, whereas secondary objectives focused on efficacy and immune monitoring. Data from 34 patients demonstrated safety and feasibility with minor issues. Adverse events included one serious adverse event possibly related to investigational medicinal product and two moderate-related adverse events. More than 50% of the patients with advanced and mainly nonimmunogenic tumors showed clinical benefits, including partial responses, stable diseases, and prolonged survival. In recurrent/metastatic head and neck squamous cell carcinoma, one patient achieved a partial response, whereas another survived for more than 7 years without anticancer therapy for over 5 years. MVX-ONCO-1 is safe, well tolerated, and beneficial across several tumor types. Ongoing phase IIa trials target patients with advanced recurrent/metastatic head and neck squamous cell carcinoma after initial systemic therapy. SIGNIFICANCE: This first-in-human phase I study introduces a groundbreaking approach to personalized cancer immunotherapy, addressing limitations of traditional strategies. By combining autologous irradiated tumor cells as a source of patient-specific antigens and utilizing encapsulated cell technology for localized, sustained delivery of granulocyte-macrophage colony-stimulating factor as an adjuvant, the study shows a very good safety and feasibility profile. This innovative approach holds the promise of addressing tumor heterogeneity by taking advantage of each patient's antigenic repertoire.

Engineering a versatile and retrievable cell macroencapsulation device for the delivery of therapeutic proteins.

Encapsulated cell therapy holds a great potential to deliver sustained levels of highly potent therapeutic proteins to patients and improve chronic disease management. A versatile encapsulation device that is biocompatible, scalable, and easy to administer, retrieve, or replace has yet to be validated for clinical applications. Here, we report on a cargo-agnostic, macroencapsulation device with optimized features for protein delivery. It is compatible with adherent and suspension cells, and can be administered and retrieved without burdensome surgical procedures. We characterized its biocompatibility and showed that different cell lines producing different therapeutic proteins can be combined in the device. We demonstrated the ability of cytokine-secreting cells encapsulated in our device and implanted in human skin to mobilize and activate antigen-presenting cells, which could potentially serve as an effective adjuvant strategy in cancer immunization therapies. We believe that our device may contribute to cell therapies for cancer, metabolic disorders, and protein-deficient diseases.

The polysemous concepts of psychomotricity and catatonia: A European multi-consensus perspective.

Current classification systems use the terms "catatonia" and "psychomotor phenomena" as mere a-theoretical descriptors, forgetting about their theoretical embedment. This was the source of misunderstandings among clinicians and researchers of the European collaboration on movement and sensorimotor/psychomotor functioning in schizophrenia and other psychoses or ECSP. Here, we review the different perspectives, their historical roots and highlight discrepancies. In 1844, Wilhelm Griesinger coined the term "psychic-motor" to name the physiological process accounting for volition. While deriving from this idea, the term "psychomotor" actually refers to systems that receive miscellaneous intrapsychic inputs, convert them into coherent behavioral outputs send to the motor systems. More recently, the sensorimotor approach has drawn on neuroscience to redefine the motor signs and symptoms observed in psychoses. In 1874, Karl Kahlbaum conceived catatonia as a brain disease emphasizing its somatic - particularly motor - features. In conceptualizing dementia praecox Emil Kraepelin rephrased catatonic phenomena in purely mental terms, putting aside motor signs which could not be explained in this way. Conversely, the Wernicke-Kleist-Leonhard school pursued Kahlbaum's neuropsychiatric approach and described many new psychomotor signs, e.g. parakinesias, Gegenhalten. They distinguished 8 psychomotor phenotypes of which only 7 are catatonias. These barely overlap with consensus classifications, raising the risk of misunderstanding. Although coming from different traditions, the authors agreed that their differences could be a source of mutual enrichment, but that an important effort of conceptual clarification remained to be made. This narrative review is a first step in this direction.

First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies.

Chordoma is a rare tumor of notochordal origin, currently principally treated by surgery and/or irradiation. Here, we describe the clinical outcome of 3 consecutive patients with metastatic and locally advanced chordoma, treated with different immunotherapeutic approaches. All patients presented fast growing tumors and failure of standard therapies. One was treated with a tumor-based vaccine, the 2 others with anti-PD1 antibodies, all with impressive clinical and radiological responses. We therefore propose that chordoma is an immunogenic tumor and thus that translational and clinical research is necessary to develop rationally designed immunotherapy approaches.

Integration-deficient lentivectors: an effective strategy to purify and differentiate human embryonic stem cell-derived hepatic progenitors.

BACKGROUND: Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine. However, the safety of cell therapy using differentiated hPSC derivatives must be improved through methods that will permit the transplantation of homogenous populations of a specific cell type. To date, purification of progenitors and mature cells generated from either embryonic or induced pluripotent stem cells remains challenging with use of conventional methods. RESULTS: We used lentivectors encoding green fluorescent protein (GFP) driven by the liver-specific apoliprotein A-II (APOA-II) promoter to purify human hepatic progenitors. We evaluated both integrating and integration-defective lentivectors in combination with an HIV integrase inhibitor. A human embryonic stem cell line was differentiated into hepatic progenitors using a chemically defined protocol. Subsequently, cells were transduced and sorted at day 16 of differentiation to obtain a cell population enriched in hepatic progenitor cells. After sorting, more than 99% of these APOA-II-GFP-positive cells expressed hepatoblast markers such as α-fetoprotein and cytokeratin 19. When further cultured for 16 days, these cells underwent differentiation into more mature cells and exhibited hepatocyte properties such as albumin secretion. Moreover, they were devoid of vector DNA integration. CONCLUSIONS: We have developed an effective strategy to purify human hepatic cells from cultures of differentiating hPSCs, producing a novel tool that could be used not only for cell therapy but also for in vitro applications such as drug screening. The present strategy should also be suitable for the purification of a broad range of cell types derived from either pluripotent or adult stem cells.