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>himeric antigen receptor (CAR) T-cell therapy is a novel approved cancer treatment that has shown remarkable efficacy in the treatment of patients with relapsed leukemia and lymphoma. Implementation of CAR T-cell therapy in a hospital setting requires careful and detailed planning because of the complexities in delivering this specialist service. A multi-disciplinary approach with dedicated funding is required to meet clinical, scientific, logistic and regulatory requirements. Tisagenlecleucel was the first approved CAR T-cell therapy in Australia. The treatment has been made available to Australian patients in specialist public hospitals through federal and state funding. Royal Prince Alfred Hospital (RPAH) is one of Australia's oldest tertiary referral public health care institutions and was approved for the provision of CAR T-cell therapy service in 2019. A multi-disciplinary clinical program has been established for the collection and cryopreservation of donor cells shipped for manufacturing as well as for the receipt, storage and administration of CAR T-cell therapy and patient management. The program encompasses a Therapeutic Goods Administration-accredited apheresis unit and a state-of-the-art facility for cell processing, cryopreservation and storage. The program's clinical expertise extends to hematology, oncology, intensive care, pharmacy, neurology and radiology services with direct experience in managing patients receiving CAR T-cell therapies. The introduction of CAR T-cell therapies at RPAH was a complex undertaking facilitated by the existing infrastructure and clinical expertise. [ABSTRACT FROM AUTHOR]

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 Considering the number of products that have been progressively approved and, in some cases, withdrawn in recent years, the ISCT would like to present a brief annual report on CGTs with marketing authorization (MA) in different regions.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]

The article discusses the challenges associated with generating data on unproven cell therapies, such as selection of a characterized cell type, technical aspects of cell isolation, and the pre-clinical disease models.

A key objective of bioengineering is the development of new scaffolding biomaterials with appropriate mechanical and biological properties such as strength, elasticity and biocompatibility that mimic the native host connective tissue. Here we describe the production and properties of massive synthetic elastin assemblies formed by chemically cross-linking recombinant human tropoelastin with bis(sulfosuccinimidyl) suberate, permitting the construction of elastic sponges, sheets and tubes. The innate characteristics of synthetic elastin constructs are common with those of native elastin. The Young''s Modulus ranged from 220 to 280 kPa with linearity of extension to at least 150%. Synthetic elastin was extensible by 200–370%. The constructs behaved as hydrogels and displayed stimuli-responsive characteristics towards temperature and salt concentrations. Intrinsic fluorescence spectroscopy demonstrated that the elastin fluorophore is a feature of the polypeptide. Scanning electron microscopy allowed us to construct a model of elastin assembly that was driven by the lateral association of small twisted rope-like fibrils. FT–Raman spectra at 100% strain gave amide I and III peaks that correlated with a stretch-dependent increase in α-helical content. Growth and proliferation of cells were supported in vitro while in vivo implants were well tolerated. We conclude that synthetic elastin has potential as a novel biomaterial that can be easily molded into a variety of shaped tissue substrates and has a range of properties that are required for elastic, cell-interacting and compliant applications. Furthermore, its in vitro construction provides a powerful tool to probe the early stages of elastin assembly and the molecular basis for its elasticity. [Copyright &y& Elsevier]

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]

Several anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy. MSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry. In parallel, the cytotoxicity and specificity of two anti-MSLN CAR T cells (m912 and SS1) were compared against these cell lines using a real-time impedance-based assay. The effect of two MSLN 'sheddase' inhibitors (lanabecestat and TMI-1) that increase MSLN surface expression was also tested in combination with CAR T cells. SS1 CAR T cells were more cytotoxic compared with m912 CAR T cells against cell lines that expressed fewer than ∼170 000 MSLN molecules/cell. A comparison of the m912 and amatuximab (humanized SS1) antibodies identified that amatuximab could detect and bind to lower levels of MSLN on pancreatic cancer and mesothelioma cell lines, suggesting that superior antibody/scFv affinity was the reason for the SS1 CAR's superior cytotoxicity. The cytotoxicity of m912 CAR T cells was improved in the presence of sheddase inhibitors, which increased MSLN antigen density. These data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN. [Display omitted] [ABSTRACT FROM AUTHOR]

As adeno-associated virus (AAV)-based gene therapies are being increasingly approved for use in humans, it is important that we understand vector–host interactions in detail. With the advances in genome-wide genetic screening tools, a clear picture of AAV–host interactions is beginning to emerge. Understanding these interactions can provide insights into the viral life cycle. Accordingly, novel strategies to circumvent the current limitations of AAV-based vectors may be explored. Here, we summarize our current understanding of the various stages in the journey of the vector from the cell surface to the nucleus and contextualize the roles of recently identified host factors. Despite being the 'vector of choice' for in vivo gene transfer, the process of cellular transduction of adeno-associated virus (AAV)-based vectors is not fully understood. The AAV transduction process can be dissected and studied in a stepwise manner, each step requiring the vector to interact with cellular host factors. The interaction of AAV-based vectors with specific host factors is critical for efficient transduction. The expression profiles of these host factors in different cell types determine vector tropism. Modulation of specific steps in cellular transduction may offer a valuable strategy to enhance gene therapy. [ABSTRACT FROM AUTHOR]

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles. [ABSTRACT FROM AUTHOR]

• This article broadly examines cell therapy manufacturing capacity in Australia and New Zealand. • We examined funding and support for cell and gene therapy. • The article covers regulatory aspects. • We surveyed cellular therapy product manufacturing facilities. • The article highlights 26 diverse facilities (23 in Australia and 3 in New Zealand). Cell and gene therapy products are rapidly being integrated into mainstream medicine. Developing global capability will facilitate broad access to these novel therapeutics. An initial step toward achieving this goal is to understand cell and gene therapy manufacturing capability in each region. We conducted an academic survey in 2018 to assess cell and gene therapy manufacturing capacity in Australia and New Zealand. We examined the following: the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and the manufacturing and quality staffing levels. It was found that Australia and New Zealand provide diverse facilities for cell therapy manufacturing, infrastructure and capability. Further investment and development will enable both countries to make important decisions to meet the growing need for cell and gene therapy and regenerative medicine in the region. [ABSTRACT FROM AUTHOR]

Introduction Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease characterized by anemia, iron overload and serious comorbidities for which gene therapy may be an effective treatment option. LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution. Objective Evaluate the efficacy and safety of LentiGlobin in patients with TDT in the phase 1/2 Northstar (HGB-204; NCT01745120) and phase 3 Northstar-2 (HGB-207; NCT02906202) studies. Methods Patients with TDT (≥100 mL/kg/yr of red blood cells [RBCs] or ≥8 RBC transfusions/yr) received G-CSF and plerixafor for mobilization and HSCs were transduced with the BB305 LVV. Patients underwent single agent busulfan myeloablative conditioning, were infused with transduced cells, and were followed for engraftment, safety, and efficacy. Statistics are presented as median (min – max). Results As of March 7, 2018, 18 patients (12 – 35 yrs) were treated in Northstar (follow-up 32.1 [23.1 – 41.9] months) and as of May 15, 2018, 11 patients (12 – 24 yrs) were treated in Northstar-2 (follow-up 8.5 [0.3 – 16.2] months). Patients received a median cell dose of 8.0 (5.0 – 19.4) CD34+ cells × 106/kg in both studies. The median time to neutrophil and platelet engraftment in both studies was 19 (14 – 30) days and 44 (19 – 191) days, respectively; 1 patient in Northstar-2 (0.3 months follow-up) had not engrafted at time of analysis. Of 6 patients with platelet engraftment ≥ Day 60, 4 had non-serious bleeding events prior to engraftment. All 6 had intact spleens and 3/6 received G-CSF between Days 0 – 21. Both factors appeared associated with time to platelet engraftment. In Northstar, 8/10 patients with non-β0/β0 genotypes and 2/8 patients with β0/β0 genotypes achieved transfusion independence (TI; weighted average hemoglobin [Hb] ≥ 9 g/dL without RBC transfusions for ≥ 12 months). Median Hb during TI was 10.0 (9.3 – 13.1) g/dL. In Northstar-2, 7/8 patients with non-β0/β0 genotypes and ≥ 6 months follow-up stopped RBC transfusions with Hb of 11.1 – 13.3 g/dL at last visit; the first patient treated achieved TI. Non-hematologic grade ≥ 3 adverse events post-infusion in ≥ 5/29 (15%) patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Veno-occlusive liver disease attributed to busulfan occurred in 4/29 patients (Table 1). There was no transplant-related mortality, vector-mediated replication competent lentivirus, or clonal dominance. Conclusion In Northstar, 80% of patients with non-β0/β0 genotypes achieved TI and early Northstar-2 data suggest that patients can achieve near-normal Hb without transfusions. The safety profile of LentiGlobin is consistent with myeloablative busulfan conditioning. Longer time to platelet engraftment was observed in few patients, but no graft failure or deaths were reported. [ABSTRACT FROM AUTHOR]