Introduction Hemophilia A (HA) is managed with factor (F)VIII replacement, or non-factor replacement therapy such as emicizumab. More recently, gene therapies have been under investigation for HA. These use a modified viral vector to deliver a functional FVIII gene to liver cells, aiming to safely provide long-term, stable FVIII expression to prevent bleeding. Dirloctocogene samoparvovec (SPK-8011), an investigational gene therapy, uses a modified adeno-associated viral vector designed to achieve clinically meaningful and sustained FVIII expression at the lowest possible dose. The ongoing Phase I/II trial (NCT03003533/NCT03432520) is evaluating the safety and efficacy of dirloctocogene samoparvovec, assessed by FVIII activity levels and patient-reported bleeding events.

Glioblastoma (GBM) is an aggressive primary brain tumor with a dismal prognosis. Given the paucity of tumor infiltrating lymphocytes (TILs), an immune suppressive tumor microenvironment and a low tumor mutation burden, the potential benefits of immune checkpoint inhibition (ICI) for GBM patients are considered low1,2. Anti-PD-1 ICI monotherapy administered post-primary resection or after recurrence has not improved GBM outcomes3,4. Here, we present the first case of newly diagnosed IDH-wildtype, MGMT-unmethylated GBM treated with upfront neoadjuvant triplet ICI (anti-PD-1/anti-CTLA4/anti-LAG3). Twelve days post-therapy, the primary resected GBM showed anti-PD-1-bound TILs and marked TIL infiltration and activation, compared with baseline biopsy. After 10 months, there is no recurrence.

Abstract Intron retention (IR) in cancer was for a long time overlooked by the scientific community, as it was previously considered to be an artifact of a dysfunctional spliceosome. Technological advancements made in the last decade offer unique opportunities to explore the role of IR as a widespread phenomenon that contributes to the transcriptional diversity of many cancers. Numerous studies in cancer have shed light on dysregulation of cellular mechanisms that lead to aberrant and pathologic IR. IR is not merely a mechanism of gene regulation, but rather it can mediate cancer pathogenesis and therapeutic resistance in various human diseases. The burden of IR in cancer is governed by perturbations to mechanisms known to regulate this phenomenon and include epigenetic variation, mutations within the gene body, and splicing factor dysregulation. This review summarizes possible causes for aberrant IR and discusses the role of IR in therapy or as a consequence of disease treatment. As neoepitopes originating from retained introns can be presented on the cancer cell surface, the development of personalized cancer vaccines based on IR-derived neoepitopes should be considered. Ultimately, a deeper comprehension about the origins and consequences of aberrant IR may aid in the development of such personalized cancer vaccines.

Abstract Introduction Mesenchymal stem cells (MSCs) isolated from donated tissue have been widely investigated as a treatment for acute graft versus host disease (GvHD), but with mixed results. Factors including MSC donor variability and the effects of prolonged MSC culture expansion may have contributed to inadequate outcomes. Induced pluripotent stem cells (iPSCs) can proliferate indefinitely without loss of pluripotency. The novel Cymerus™ manufacturing process facilitates a virtually limitless supply of well-defined and consistent MSCs from a single donation. Production is achieved by differentiating iPSCs into MSCs using proprietary clonogenic progenitor-based technology. This avoids both donor to donor variability and the need for excessive culture expansion once MSCs are formed. We are undertaking a Phase I clinical trial of Cymerus iPSC-derived MSCs (CYP-001) in steroid-resistant acute GvHD (NCT02923375). We believe this will be the first completed clinical trial involving iPSC-derived cells. Methods This is a multi-center, open label, dose escalation study to assess the safety, tolerability and efficacy of CYP-001 in adults with grade II-IV steroid-resistant acute GvHD, following allogeneic hematopoietic stem cell transplantation. 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. The first eight subjects enrolled in Cohort A received two intravenous (IV) infusions of CYP-001 one week apart, at a dose of 1 x 106 cells/kg, in addition to standard of care medications. After an independent data and safety monitoring board review, the next eight subjects entered Cohort B, in which the MSC cell dose was doubled. Primary evaluation was performed over eight study visits to day 100. Subjects then entered a follow-up phase of up to two years. Data for subjects in Cohort A with a minimum of six months follow-up are presented here. GvHD was staged and graded according to the 1994 Consensus Conference on Acute GvHD Grading. A Partial Response (PR) was defined as improvement in the severity of GvHD by at least one grade compared to baseline, while a Complete Response (CR) was defined as the absence of any GvHD signs or symptoms. The Overall Response (OR) rate was defined as the proportion of subjects showing either a PR or CR. The primary objective was assessment of the safety and tolerability of two infusions of CYP-001. The secondary objective was efficacy, assessed by best response to treatment, by Day 28 and Day 100 and overall survival at Day 28 and Day 100. Results Four males and four females, with an average age of 57 years (range: 45-66) were enrolled in Cohort A during 2017. At baseline, subjects had Grade II (n=3) or Grade III (n=5) steroid-resistant acute GvHD. One subject had skin, gastrointestinal (GI) and liver involvement; four subjects had skin and GI involvement; two subjects had GI involvement only; and one subject had skin involvement only. The treatment was well tolerated in all cases, and there were no treatment-related Serious Adverse Events (SAEs) reported. Three subjects experienced SAEs that were not considered to be study drug related: (i) febrile neutropenia, hypokalemia and parainfluenza, each of which resolved; (ii) a lower respiratory tract infection, which resolved; (iii) pneumonia, which was fatal. All eight subjects showed at least a PR. Four subjects achieved a CR by Day 100. In all four cases where a CR was achieved, it was then sustained until Day 100. The median GvHD grade at Day 100 was 0 (range: 0-II), compared to a median grade of III (range: II-III) at baseline. Disease progression (an increase in the severity of GvHD by at least one grade compared to baseline) was not observed in any subject at any study visit. Overall survival was 7/8 (87.5%) six months after the first infusion of CYP-001. The best response rates by Day 28 and Day 100 are summarized in Table 1, while the maximal response by individual subject is illustrated in Figure 1. Conclusion Infusion of CYP-001 at 1 x 106 iPSC-derived MSCs/kg was safe and well tolerated in this patient cohort. Treatment response and overall survival rates are encouraging compared to previously published outcomes. The Cohort B primary evaluation period is expected to be completed by September 2018, and progression to a Phase II trial in this clinically challenging disease will then be considered. Disclosures Bloor: AbbVie: Research Funding; Janssen: Research Funding. Radia:Mallinckrodt: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Specialised Therapeutics Australia: Honoraria. Slukvin:Cynata Therapeutics Limited: Consultancy, Equity Ownership. Kelly:Cynata Therapeutics Limited: Employment, Equity Ownership. Rasko:Gilead: Honoraria; Abbvie: Speakers Bureau; Takeda: Speakers Bureau; International Society for Cellular Therapy: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Speakers Bureau; Cynata: Consultancy, Honoraria; bluebird bio: Honoraria, Other: Clinical trials ; Spark: Consultancy; FSHD Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Current Cure The Future Foundation: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Pfizer: Honoraria; GSK: Honoraria; Genea: Equity Ownership; IMAGO Biosciences: Consultancy; Rarecyte: Consultancy, Equity Ownership; Gene Technology Technical Advisory, OGTR, Australian Government: Other: Chair; Advisory Committee on Biologics, Therapeutics Goods Administration, Australian Government: Other: Past Chair.

Background & Aim In Australia clinical trials of viral vector gene therapies or gene modified (GM) viruses are required to be licenced by the Office of the Gene Technology Regulator (OGTR). Institutional Biosafety Committees (IBCs) play a crucial role by reviewing applications before they go to the OGTR for decision. IBCs also advise on cell therapy trials that do not require a licence and on laboratory research. Their advice covers safety, compliance and governance to meet the objective of the Australian Gene Technology Act 2000, which 'is to protect the health and safety of people, and to protect the environment, by identifying risks posed by or as a result of gene technology, and by managing those risks through regulating certain dealings with GMOs [Genetically Modified Organisms]'. Methods, Results & Conclusion Royal Prince Alfred Hospital (RPAH) IBC contributes to cell and gene therapy capacity building within Sydney Local Health District. Since 2008 it has advised on over 22 clinical trials; 14 of which required an OGTR licence. It has reviewed 6 licence applications and local risk management for 7 licences obtained via other IBCs. The number of trials advised on is increasing (5 in 2008-2015, 9 in 2016-2019 and 4 as at March 2020). They cover adeno-associated viral vectors for haemophilia, adenoviral vectors for mesothelioma, oncolytic GM human HSV-1 for melanoma and squamous cell carcinoma, oncolytic GM vaccinia virus vaccine strain for liver and kidney cancer, autologous cells transduced ex vivo with lentiviral vectors for beta-thalassemia (CD34+ cells) and adult diffuse large B-cell lymphoma (chimeric antigen receptor T cells targeting CD19) and allogeneic CRISPR Cas-9 engineered T-cells for B cell malignancies. The IBC conducts science-based risk assessments, facility inspections, assists organisations to prepare for cell and gene therapy clinical trials and contributes to policy and national reviews. It assists applicants and liaises with the OGTR. It has answered infection control queries, educated sponsors, developed a GMO-waste management training program with environmental services; ensured eye-wash, autoclave maintenance and spills management training are provided; assisted with corrective actions; and provided risk prevention advice. The members are scientists, researchers, health professionals, engineers and lay persons. The committee has processes for managing confidential information and dualities of interest and assesses new technologies, policies and regulations as they emerge. In Australia clinical trials of viral vector gene therapies or gene modified (GM) viruses are required to be licenced by the Office of the Gene Technology Regulator (OGTR). Institutional Biosafety Committees (IBCs) play a crucial role by reviewing applications before they go to the OGTR for decision. IBCs also advise on cell therapy trials that do not require a licence and on laboratory research. Their advice covers safety, compliance and governance to meet the objective of the Australian Gene Technology Act 2000, which 'is to protect the health and safety of people, and to protect the environment, by identifying risks posed by or as a result of gene technology, and by managing those risks through regulating certain dealings with GMOs [Genetically Modified Organisms]'. Royal Prince Alfred Hospital (RPAH) IBC contributes to cell and gene therapy capacity building within Sydney Local Health District. Since 2008 it has advised on over 22 clinical trials; 14 of which required an OGTR licence. It has reviewed 6 licence applications and local risk management for 7 licences obtained via other IBCs. The number of trials advised on is increasing (5 in 2008-2015, 9 in 2016-2019 and 4 as at March 2020). They cover adeno-associated viral vectors for haemophilia, adenoviral vectors for mesothelioma, oncolytic GM human HSV-1 for melanoma and squamous cell carcinoma, oncolytic GM vaccinia virus vaccine strain for liver and kidney cancer, autologous cells transduced ex vivo with lentiviral vectors for beta-thalassemia (CD34+ cells) and adult diffuse large B-cell lymphoma (chimeric antigen receptor T cells targeting CD19) and allogeneic CRISPR Cas-9 engineered T-cells for B cell malignancies. The IBC conducts science-based risk assessments, facility inspections, assists organisations to prepare for cell and gene therapy clinical trials and contributes to policy and national reviews. It assists applicants and liaises with the OGTR. It has answered infection control queries, educated sponsors, developed a GMO-waste management training program with environmental services; ensured eye-wash, autoclave maintenance and spills management training are provided; assisted with corrective actions; and provided risk prevention advice. The members are scientists, researchers, health professionals, engineers and lay persons. The committee has processes for managing confidential information and dualities of interest and assesses new technologies, policies and regulations as they emerge.

•In contrast to the prior voluntary system, since 2001, gene technology in Australia has been regulated under a legislated national Gene Technology Regulatory Scheme which is administered by the Gene Technology Regulator.•The Scheme provides science-based assessment of the potential risks of gene technology to the health and safety of people and the environment.•It complements the role of the Australian Therapeutic Goods Administration which regulates all therapeutic products in Australia to ensure they are safe and effective.•Recent reforms to the Scheme contribute to, and anticipate, the continued safe development and delivery of gene-based human therapeutics in Australia as a successful model for other jurisdictions.

CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of 5 CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. Molecular docking and molecular dynamics confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding. However, R339Q and G420D were stabilised by the formation of new primary DNA bonds, contributing to gain-of-function. Our data confirm a spectrum of loss-, change- and gain-of-function impacts in CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. We have established that these diverse cellular phenotypes in CTCF are explained by examining structure-function relationships.

There is a stem cell revolution on the way, but it isn't the one people are pushing, say John E. J. Rasko and Carl Power