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Abstract Cell and gene therapies (CGTs) are progressively entering into clinical practice in different parts of the world. The International Society for Cell & Gene Therapy (ISCT), a global scientific society, has been committed since 1992 to supporting and developing knowledge on clinical applications of CGTs. Considering the number of products that have been progressively approved and, in some cases, withdrawn in recent years, the ISCT would like to present a brief annual report on CGTs with marketing authorization (MA) in different regions. This article reflects the dynamic momentum around authorized CGTs coinciding with the parallel increase of unproven approaches where cells are delivered without appropriate and rigorous scientific and regulatory assessment and authorization. This is intended to be a living document with a yearly update linked to a dedicated section of the ISCT website for faster adjustments. The aim is to ultimately inform, by periodic snapshots, the scientific community, healthcare stakeholders and patient associations on authorized CGT products as a way to increase communication around the approved therapeutic approaches charged with heightened expectations. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have been widely investigated as a treatment for graft versus host disease (GvHD), but with mixed results. Factors such as MSC donor variability and the effects of prolonged culture expansion may have contributed to disappointing outcomes. The novel Cymerus™ manufacturing process facilitates virtually limitless production of well-defined and consistent MSCs from a single iPSC bank, using proprietary clonogenic progenitor-based technology. This avoids both inter-donor variability and the need for excessive culture expansion once MSCs are formed. This is a multi-center, open label study of Cymerus MSCs (CYP-001) in adults with steroid-resistant acute GvHD, following allogeneic hematopoietic stem cell transplantation (NCT02923375). Prior to enrolment, all subjects had failed to respond to at least three days of steroid treatment (≥1 mg/kg/day), administered in accordance with standard management at each center. Subjects received two intravenous infusions of CYP-001 one week apart, at a dose of 1 × 106 cells/kg (Cohort A) or 2 × 106 cells/kg (Cohort B), in addition to standard of care medications. The study involves follow-up over two years, with primary evaluation at 100 days. GvHD was staged and graded according to the 1994 Consensus Conference on Acute GvHD Grading. An Overall Response (OR) was defined as at least a one-grade improvement in GvHD severity, while a Complete Response (CR) was defined as the absence of any GvHD signs or symptoms. The primary objective was assessment of safety and tolerability, while the secondary objective was efficacy, based on overall survival (OS) and best responses by Day 28/Day 100. Eight subjects were enrolled per cohort, but one subject in Cohort B withdrew prior to the initiation of CYP-001 treatment. All subjects had Grade II or III GvHD at baseline. The treatment was well tolerated in all cases, and there were no treatment-related Serious Adverse Events (SAEs) reported. One patient in Cohort A died after developing pneumonia, which was not considered to be CYP-001 treatment-related. One patient in Cohort B did not show a response to CYP-001 treatment, and withdrew from the trial on Day 22 to commence palliative care. All other patients showed an OR and remained alive at Day 100. Overall, outcomes by Day 100 were similar in both cohorts, but Day 28 data suggest a faster response to the higher dose level used in Cohort B (see Table 1 and Figure 1). In conclusion, CYP-001 infusions were found to be safe and well tolerated in this study, and we believe the encouraging treatment response and overall survival rates support progression to a Phase II trial. [ABSTRACT FROM AUTHOR]

Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials. [Display omitted] [ABSTRACT FROM AUTHOR]