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Vitamin D (cholecalciferol) has demonstrated potential anticancer properties, but its clinical application is limited by associated toxicity at effective doses. This study investigated the use of liposomal encapsulation to increase the therapeutic efficacy of vitamin D while mitigating its toxicity. Liposomal vitamin D (VD-LP) was prepared via the film-hydration method and characterized for particle size, polydispersity index, encapsulation efficiency, and long-term stability. gene expression modulation was evaluated in monocytic THP-1 cells, and antiproliferative effects were assessed in HT29 (colorectal), BT474 (breast), and TRAMP-C1 (prostate) cancer cell lines. antitumor efficacy and toxicity were tested in a mouse model with subcutaneously implanted MC38 tumors. Tumor growth, survival rates, and serum calcium and phosphate levels were analyzed. VD-LP demonstrated high encapsulation efficiency and stability over 90 days, with a consistent particle size of approximately 83 nm. VD-LP modulated immune-related and metabolic gene expression in THP-1 cells, including upregulation of antimicrobial peptides and vitamin D receptor genes. VD-LP showed superior antiproliferative effects compared to free vitamin D in all tested cancer cell lines. , VD-LP delayed tumor growth and improved survival without causing hypercalcemia, highlighting its favorable toxicity profile. Liposomal encapsulation of vitamin D significantly improves its anticancer efficacy while mitigating toxicity, making it a promising strategy for future cancer therapies. VD-LP shows potential for enhanced therapeutic applications with reduced adverse effects, warranting further clinical exploration.

Cancer remains the leading cause of death worldwide, with increasing incidence rates. Natural compounds have gained attention as potential therapeutic agents due to their bioactive properties. Anthocyanins, particularly delphinidin-3-sambubioside (Dp-3-sam) and cyanidin-3-sambubioside (Cn-3-sam), are flavonoids with antioxidant and potential antitumor properties. This study investigates the antitumor effects of anthocyanins extracted from L. ( ), administered intratumorally, and their potential as adjuvants to chemotherapy. Anthocyanins were extracted from and characterized using high-performance liquid chromatography (HPLC). The total phenolic content was determined using the Folin-Ciocalteu method. Antioxidant activity was assessed through DPPH, ABTS, and FRAP assays. The antiproliferative effects of Dp-3-sam and Cn-3-sam were evaluated in vitro using MCA-205 fibrosarcoma and CT26 colon carcinoma cell lines. In vivo studies were conducted on mouse tumor models to assess tumor growth inhibition following intratumoral administration of anthocyanins alone or in combination with doxorubicin. The impact on angiogenesis, immune cell recruitment, and long-term immune memory was also analyzed. HPLC analysis confirmed the presence of Dp-3-sam and Cn-3-sam in the extract. The anthocyanins exhibited significant antioxidant activity in all assays. In vitro studies demonstrated dose-dependent inhibition of cancer cell proliferation. In vivo, intratumoral administration of anthocyanins led to a significant reduction in tumor growth. The combination of anthocyanins with doxorubicin further enhanced tumor suppression. Mechanistically, Dp-3-sam and Cn-3-sam reduced angiogenesis and promoted immune cell recruitment but did not elicit an effective antitumor immune response alone. However, co-administration with doxorubicin reversed this limitation, leading to increased immune activation and resistance to tumor rechallenge, suggesting the induction of long-term immune memory. These findings highlight the potential of -derived anthocyanins as adjuvants in cancer therapy. When administered intratumorally, they enhance chemotherapy efficacy and immunogenicity. However, further studies are needed to optimize dosing strategies, evaluate long-term safety, and assess clinical applicability.

: Peritoneal carcinomatosis (PC) remains a major clinical challenge with limited therapeutic options across tumor types. Adoptive cell therapy (ACT) with tumor-specific T cells offers promise, but its efficacy is often impaired by the immunosuppressive tumor microenvironment (TME). Intraperitoneal ACT is under investigation to improve its effectiveness against metastases within the peritoneal cavity. IL-33, a cytokine of the IL-1 family, plays dual roles in immunity and inflammation and may enhance antitumor responses. We evaluated whether IL-33 mRNA-engineered T cells improve ACT efficacy in murine PC models and assessed potential synergy with IL-12 mRNA. : OT.I, PMEL-1, and CEA-specific CAR T cells were electroporated with mRNA encoding IL-33, IL-12, or an IL-33 mutein. assays measured cytokine production and cytotoxicity. RNA-seq was performed to analyze transcriptomic changes following IL-33 mRNA electroporation. ST2 T cells were used to evaluate the role of IL-33 receptor expression on transferred T cells versus host cells. studies in murine PC models assessed survival and immune responses using ELISA, ELISpot, and flow cytometry. : IL-33 mRNA-electroporated OT.I T cells exhibited enhanced IFN-γ expression in a ST2-dependent, T cell-intrinsic manner. , IL-33-engineered T cells significantly improved survival in PC models. IL-33 reshaped the TME by increasing infiltration of innate lymphoid cells and eosinophils while reducing neutrophils. Engineering T cells with a stabilized IL-33 mutein further enhanced antitumor activity. Co-electroporation of IL-33 mutein and IL-12 mRNA in PMEL-1 T cells led to synergistic increases in IFN-γ production, cytotoxicity, and long-term memory, resulting in superior tumor control and protection upon rechallenge. These findings were confirmed using IL-33 mutein/IL-12 mRNA-electroporated CEA CAR T cells in peritoneal tumor models. : IL-33 enhances ACT efficacy by promoting IFN-γ expression via autocrine ST2 signaling and by modulating the TME. The IL-33 mutein improves cytokine stability and antitumor activity, while combination with IL-12 yields synergistic effects. This strategy holds promise for enhancing ACT in peritoneal carcinomatosis.

BackgroundIntravenous dosing of the anti-CD137 (4-1BB) agonist monoclonal antibody urelumab is limited to 8 mg flat doses due to liver toxicity, thus reducing bioavailability. Here we explored intratumoral delivery of urelumab to increase bioavailability at the tumor site while reducing systemic exposure, in combination with systemic nivolumab (clinical trial INTRUST, NCT03792724).MethodsWe delivered three intratumoral injections of urelumab 8 mg, alternating with intravenous nivolumab 240 mg every two weeks, followed by nivolumab maintenance at 480 mg every 4 weeks (figure 1). Patients presenting solid tumors with known sensitivity to PD-1/PD-L1 blockade were treated in two cohorts (Cohort A: PD-1/PD-L1 blockade naive; Cohort B: progression following PD-1/PD-L1 blockade). The first six patients were treated in a safety dose-escalation cohort. We collected fresh tumor biopsies with each intratumoral injection and performed multiplex tissue immunofluorescence and bulk RNA-seq of these specimens. Additionally, a comprehensive series of cytokines in sequential plasma samples was analyzed.ResultsAmong 31 treated patients, we observed two objective responses and a 67.7% disease control rate. Treatment was well tolerated, and no dose-limiting liver toxicity was observed (figure 1). Serial biopsies revealed urelumab-induced increases in T lymphocyte density and CD137 expression. The increase in tumor-infiltrating CD8 T cells was associated with durable clinical benefit (figure 2). RNA-seq results were consistent with such pharmacodynamic changes. Finally, we observed a significant plasmatic elevation of T-cell activation cytokines, denoting immune activation by intratumoral urelumab.ConclusionsIntratumoral delivery of urelumab is feasible, safe, and induces favorable immunopharmacodynamic effects in serial biopsies and in peripheral blood. Our results support the development of next-generation CD137 (4-1BB) agonists in Phase-2/3 clinical trials, especially considering those with concomitant PD(L)-1 blockade.Abstract 531 Figure 1Treatment, safety and clinical outcomes. (A) Schematic time course representation of treatment and collection of samples. (B) Swimmer plot of the patients in the trial, specifying cohort, baseline PD-L1 status, and tumor type. (C) Summary of the main treatment-related and -unrelated side effects[Image Omitted. See PDF.]Abstract 531 Figure 2Treatment-associated changes in the tumor microenvironment. A) mIF images with the indicated markers. B) Quantitative PD-L1 expression. C-D) Percentages of indicated markers over time. E-F) Microphotographs of CD8 and CD137 expression, and changes over time. G) Comparison of disease control and CD8 increases[Image Omitted. See PDF.]