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We describe in this review the historical evidence leading up to the concept and design of Vigil and subsequent clinical applications including safety and efficacy in a randomized, controlled Phase IIB trial. Vigil (gemogenovatucel-T) is a unique triple function targeted immunotherapy that demonstrates preclinical and clinical systemic anticancer activity. Construction of Vigil involves harvest of autologous malignant tissue for neoantigen targeting (ideally containing clonal neoantigens) followed by a two-day process involving transfection with a plasmid to provide a permissive 'training environment' for the patient's immune system. Transfected plasmid components contain an expressive human GMCSF DNA segment to enhance anticancer immune functional response and a second component expressing bi-shRNAfurin which reduces TGFβ isomers (TGFβ1 and TGFβ2) thereby reducing cancer inhibition of the targeted immune response. Results generated to date justify advancement to confirmatory clinical trials supporting product regulatory approval. Plain Language Summary Vigil is an anticancer treatment that employs three methods of enhancing the body's immune system to identify and kill cancer cells. The construction of Vigil involves cancer cells from the same person being treated (personalized therapy) in combination with added anticancer genetic signals to enhance the number and function anti-anticancer immune cells and to guide the immune cells to the cancer and not to normal organs of the body. In this manner, an army of immune cells are created that can move to attacking the cancer using blood vessels to get to the cancer anywhere it tries to grow in the body. One study (Phase I) performed with this product to determine safety and dose range demonstrated an optimal dose and schedule. Another study (Phase IIA) showed initial clinical benefit. A third more complex study (Phase IIB) in patients treated with Vigil compared with standard of care without Vigil demonstrated the ability to prolong the patients life and time without their cancer getting worse without any significant side effects associated with the treatment in a unique subset of ovarian cancer patients, those with the ability to repair their DNA. Based on the composite of these results, Vigil is an attractive targeted immunotherapy justified for late-stage clinical testing. Article highlights Vigil is a novel triple function immunotherapy designed to deliver personalized clonal neoantigens. Historical background Expression of GMCSF has been extensively studied and demonstrates safety, efficacy and immune activation in various solid tumor malignancies. Modulation of both GMCSF and TGFβ impact anticancer immune response specifically related to clinical benefit in association with GMCSF up regulation and TGFβ down regulation. bi-shRNA mechanism bi-shRNA is designed to take advantage of both cleave-dependent and cleavage independent RISC loading thus decreasing mRNA and subsequent protein expression to block signals associated with cancer progression. Vigil: mechanism Vigil is constructed from autologous tumor cells transfected with a plasmid encoding a GMCSF expressive unit, bi-shRNA directed to furin and clonal neoantigens. Clonal neoantigens are associated with increased clinical benefit to immune therapies. Vigil plasmid Vigil plasmid is produced using GMP manufacturing. Vigil construction & product delivery Vigil is constructed via a 2 day manufacturing process consisting of tissue dissociation, electroporation and irradiation. Preparation of the drug product The drug substance is formulated to appropriate concentration using freeze media. Every Vigil batch/lot is tested for product release criteria which has been verified for regulatory suitability. Vigil clinical experience 230 patients have received 1433 doses over various clinical trials in solid tumors. Vigil Phase I testing in solid tumor cancer Phase I testing of Vigil demonstrated manufacturing optimization, appropriate dose, safety and immune response in advanced solid tumor patients. Vigil Phase I/II testing in Ewing's sarcoma Vigil has been tested as monotherapy and in combination with temozolomide/irinotecan in Ewings sarcoma and demonstrated safety and evidence of efficacy. Vigil Phase IIA/IIB evaluation in ovarian cancer In Phase IIA trial in newly diagnosed Stage IIIB/IV ovarian cancer patients, Vigil demonstrated immune activation via ELISpot assay which correlated with clinical benefit. In Phase IIB trial also in newly diagnosed Stage IIIB/IV ovarian cancer patients, Vigil demonstrated improved RFS and OS in BRCA-wt patients. This benefit was further enhanced in patients with HRP molecular profile. In both trials, Vigil demonstrated no ≥ Grade 3 adverse events. Vigil-related biomarkers Several biomarkers have been identified retrospectively including TP53 mutation, and high ENTPD1 expression. Conclusion Vigil demonstrates a strong safety profile combined with durable clinical benefit. [ABSTRACT FROM AUTHOR]

The demand for high-throughput and scalable cell expansion platforms that can accommodate diverse cell types remains a critical requirement across various biomedical fields. Fibronectin (Fn), an essential component of the extracellular matrix (ECM), has been used as a conformal surface coating for two-dimensional (2D) cell culture systems. However, the soluble, globular Fn used for 2D coatings differs structurally from the native Fn, which possesses a three-dimensional (3D) fibrillar structure. Herein, a large-scale engineered ECM (EECM) cell expansion platform based on a 3D fibrillar Fn network spanning over centimeters is presented. Extended fibrillar networks are formed by shearing dilute Fn solutions over tessellated polymeric scaffolds, which are conveniently prepared by 3D printing. The structure and size of the Fn-based 3D EECM scaffold are optimized by evaluating the proliferation of a colorectal tumor cell line, CT26, commonly used in the in vivo tumor immunotherapy models. The 3D EECM scaffolds support a fourfold more efficient tumor cell expansion than a conventional 2D culture system, demonstrating the potential efficacy in supporting the robust expansion of cancer cells ex vivo with an eye on cancer immunotherapy. [ABSTRACT FROM AUTHOR]