Search

Background: Chemotherapy predisposes people who menstruate to abnormal uterine bleeding that can be life-threatening and may also damage ovaries, resulting in premature menopause. The purpose of this study was to explore the incidence of menstrual history documentation and counseling before, during, and after cancer treatment. Patients and Methods: The medical charts of 137 consecutive females (self-reported) aged 18 to 49 years receiving anticancer treatment at a major tertiary metropolitan hospital in Australia between 2017 and 2020 were reviewed. Data collected included primary diagnosis, stage of cancer, treatment(s) received, rates of remission or progression, documentation of involvement of a specialist gynecologist, reproductive history, menstrual disturbances, menstruation counseling or intervention offered, and diagnosis of early ovarian failure. Results: Only 16.1% of patients had their menstrual history documented at the initial consult, and 49.6% had their menstrual history documented at a subsequent consult with their treating oncologist or hematologist. Most (82.4%) patients with a menstrual history documented experienced menstrual disturbance posttreatment, most commonly amenorrhea (48.0%), followed by menopause or menopause symptoms (20.6%), irregular menstrual bleeding (16.7%), menorrhagia (13.7%), dysmenorrhea (3.9%), and iron deficiency from bleeding (2.9%). Menopause/Menopausal symptoms and iron deficiency were more likely to be treated than other disturbances. Conclusions: Menstruation disturbance is a common side effect of cancer treatment. Menstrual care should be integral to cancer care for people who menstruate, and higher engagement could be achieved through education of medical and allied health staff, information technology systems automating prompts and referral pathways, regular audits to ensure compliance, better alliances between cancer and fertility specialists, and the creation of accessible patient information to promote awareness and facilitate discussion.

Cardiac light chain (AL) amyloidosis is a condition with a very poor prognosis. We report a retrospective analysis comparing the traditional melphalan and dexamethasone protocol with cyclophosphamide, bortezomib and dexamethasone in late-stage cardiac AL amyloidosis. The primary end points were overall survival and haematological response. Both regimens provided meaningful responses in this difficult to treat patient group.

Palliative radiotherapy (RT) is often given to symptomatic sites of multiple myeloma (MM). Three-dimensional conformal radiotherapy (3DCRT) is often the main modality due its efficiency but it may involve irradiation volumes which include organs at risk (OARs). A case of end-stage MM with innumerable skull lesions was treated with volumetric modulated arc therapy (VMAT) which demonstrated superior conformity compared to a 3DCRT plan. VMAT planning yielded an 88% dose reduction to the hippocampi, 60% dose reduction to the brain yet equivalent dose homogeneity to the skull target. Treatment with 15Gy in five fractions gave significant almost complete symptom resolution with no adverse OAR related complications at 4 weeks.As the life expectancy of MM patients and other cancers increases with better systemic therapy, there will be a greater chance of experiencing late effects of RT in OARs. This case supports the notion that perhaps VMAT could be considered in some cases of palliative RT.

Aims Receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP) dephosphorylates Tie-2 as well as CD31, VE-cadherin, and vascular endothelial growth factor receptor 2 (VEGFR2). The latter form a signal transduction complex that mediates the endothelial cell response to shear stress, including the activation of the endothelial nitric oxide (NO) synthase (eNOS). As VE-PTP expression is increased in diabetes, we investigated the consequences of VE-PTP inhibition (using AKB-9778) on blood pressure in diabetic patients and the role of VE-PTP in the regulation of eNOS activity and vascular reactivity. Methods and results In diabetic patients AKB-9778 significantly lowered systolic and diastolic blood pressure. This could be linked to elevated NO production, as AKB increased NO generation by cultured endothelial cells and elicited the NOS inhibitor-sensitive relaxation of endothelium-intact rings of mouse aorta. At the molecular level, VE-PTP inhibition increased the phosphorylation of eNOS on Tyr81 and Ser1177 (human sequence). The PIEZO1 activator Yoda1, which was used to mimic the response to shear stress, also increased eNOS Tyr81 phosphorylation, an effect that was enhanced by VE-PTP inhibition. Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. Finally, phosphorylation of eNOS on Tyr80 (murine sequence) was found to be reduced in diabetic mice and diabetes-induced endothelial dysfunction (isolated aortic rings) was blunted by VE-PTP inhibition. Conclusions VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE-cadherin/VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81. VE-PTP inhibition, therefore, represents an attractive novel therapeutic option for diabetes-induced endothelial dysfunction and hypertension.

Purpose To evaluate the ocular hypotensive efficacy and safety of razuprotafib, a novel Tie2 activator, when used as an adjunct to latanoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods Subjects with OAG or OHT and an unmedicated IOP from ≥22 mm Hg to

Autologous haematopoietic stem cell transplantation (AHSCT) has the potential to induce sustained periods of disease remission in multiple sclerosis (MS), which is an inflammatory disease of the central nervous system (CNS) characterised by demyelination and axonal degeneration. However, the mechanisms associated with durable treatment responses in MS require further elucidation.To characterise the longer term immune reconstitution effects of AHSCT at 24 and 36 months (M) post-transplant, high-dimensional immunophenotyping of peripheral blood mononuclear cells from 22 MS patients was performed using two custom-designed 18-colour flow cytometry panels.The higher baseline frequencies of specific pro-inflammatory immune cells (T-helper-17 (Th17) cells, mucosal-associated invariant T-cells and CNS-homing T-conventional (T-conv) cells observed in MS patients were decreased post-AHSCT by 36M. This was accompanied by a post-AHSCT increase in frequencies and absolute counts of immunoregulatory CD56AHSCT induces substantial recalibration of pro-inflammatory and immunoregulatory components of the immune system of MS patients for up to 36M post-transplant.

Infectious diseases contribute significantly to morbidity and mortality in recipients of allogeneic haematopoietic stem cell transplantation (aHSCT), particularly in the era of highly immunosuppressive transplant regimens and alternate donor transplants. Delayed cellular immune recovery is a major mechanism for the increased risk in these patients. Adoptive cell therapy with ex vivo manipulated pathogen-specific T cells (PSTs) is increasingly taking its place as a treatment strategy using donor-derived or third party–banked cells. The majority of clinical trial data in the form of early-phase studies has been in the prophylaxis or treatment of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus (AdV). Advancements in methods to select and enrich PSTs offer the opportunity to target the less common viral pathogens as well as fungi with this technology. Early clinical studies of PSTs targeting polyomaviruses (BK virus and JC virus), human herpesvirus 6 (HHV6), varicella zoster virus (VZV) and Aspergillus spp. have shown promising results in small numbers of patients. Other potential targets include herpes simplex virus (HSV), respiratory viruses and other invasive fungal species. In this review, we describe the burden of disease of this wider spectrum of pathogens, the progress in the development of manufacturing capability, early clinical results and the opportunities and challenges for implementation in the clinic.

Background: Given the increasing numbers of multiple sclerosis (MS) patients undergoing autologous haematopoietic stem cell transplant (AHSCT) worldwide, and with women of childbearing age overrepresented in the target population, it is increasingly important to review fertility and pregnancy outcomes following AHSCT. Objective: To evaluate the rate of pregnancy and complications post-AHSCT for MS. Method: Retrospective evaluation of the rate of pregnancy and associated complications in a cohort of patients post-AHSCT with BEAM conditioning for MS since 2010 in a tertiary referral centre. Results: In our ongoing Phase 2 trial of AHSCT for MS, 55 patients have undergone AHSCT with 30 females being of childbearing age at time of transplantation. Four pregnancies occurred following AHSCT. Two pregnancies were carried to term. No maternal or neonatal complications were reported in either case. Two pregnancies were not carried to term due to elective terminations. Both of these patients became pregnant unexpectedly 2 years following AHSCT. Of the 21 male patients, one patient has fathered three children since his AHSCT. There were no newborn complications. Conclusions: This is the first report to our knowledge on fertility outcomes in both sexes post-AHSCT for MS. Patients of both sexes should be counselled prior to treatment on infertility and contraceptive use.

Objectives Adoptive immunotherapy using donor‐derived antigen‐specific T‐cells can prevent and treat infection after allogeneic haemopoietic stem cell transplant (HSCT). Methods We treated 11 patients with a prophylactic infusion of 2 × 107 cells per square metre donor‐derived T‐cells targeting seven infections (six viral and one fungal) following HSCT. Targeted pathogens were cytomegalovirus (CMV), Epstein–Barr virus (EBV), adenovirus, varicella zoster virus, influenza, BK virus (BKV) and Aspergillus fumigatus. Results T‐cell products were successfully generated in all patients with 10 products responsive to 6 or 7 infections. T‐cell infusions were associated with increases in antigen‐experienced activated CD8+ T‐cells by day 30. CMV, EBV and BKV reactivation occurred in the majority of patients and was well controlled except where glucocorticoids were administered soon after T‐cell infusion. Three patients in that circumstance developed CMV tissue infection. No patient required treatment for invasive fungal infection. The most common CMV and EBV TCR clonotypes in the infusion product became the most common clonotypes seen at day 30 post‐T‐cell infusion. Donors and their recipients were recruited to the study prior to transplant. Grade III/IV graft‐versus‐host disease developed in four patients. At a median follow‐up of 390 days post‐transplant, six patients had died, 5 of relapse, and 1 of multi‐organ failure. Infection did not contribute to death in any patient. Conclusion Rapid reconstitution of immunity to a broad range of viral and fungal infections can be achieved using a multi‐pathogen‐specific T‐cell product. The development of GVHD after T‐cell infusion suggests that infection‐specific T‐cell therapy after allogeneic stem cell transplant should be combined with other strategies to reduce graft‐versus‐host disease., In this study, 12 patients were treated with ex vivo expanded donor‐derived T‐cells specific for seven virus and fungal pathogens. There was no acute infusion‐related toxicity. CD8 T‐cell numbers in the peripheral blood rose within 30 days of infusion. Graft‐versus‐host disease and corticosteroid use were associated with viral reactivation; no patient developed fungal disease. Relapse (n = 5) and multi‐organ failure (n = 1) were the causes of death. Infection did not contribute to death in any patient.

Purpose Tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) activation in Schlemm's canal (SC) endothelium is required for the maintenance of IOP, making the angiopoietin/Tie2 pathway a target for new and potentially disease modifying glaucoma therapies. The goal of the present study was to examine the effects of a Tie2 activator, AKB-9778, on IOP and outflow function. Methods AKB-9778 effects on IOP was evaluated in humans, rabbits, and mice. Localization studies of vascular endothelial protein tyrosine phosphatase (VE-PTP), the target of AKB-9778 and a negative regulator of Tie2, were performed in human and mouse eyes. Mechanistic studies were carried out in mice, monitoring AKB-9778 effects on outflow facility, Tie2 phosphorylation, and filtration area of SC. Results AKB-9778 lowered IOP in patients treated subcutaneously for diabetic eye disease. In addition to efficacious, dose-dependent IOP lowering in rabbit eyes, topical ocular AKB-9778 increased Tie2 activation in SC endothelium, reduced IOP, and increased outflow facility in mouse eyes. VE-PTP was localized to SC endothelial cells in human and mouse eyes. Mechanistically, AKB-9778 increased the filtration area of SC for aqueous humor efflux in both wild type and in Tie2+/- mice. Conclusions This is the first report of IOP lowering in humans with a Tie2 activator and functional demonstration of its action in remodeling SC to increase outflow facility and lower IOP in fully developed mice. Based on these studies, a phase II clinical trial is in progress to advance topical ocular AKB-9778 as a first in class, Tie2 activator for treatment for ocular hypertension and glaucoma.

Viral infections, principally cytomegalovirus, Epstein Barr virus (EBV) and adenovirus, are a leading cause of morbidity and mortality after allogeneic stem cell transplantation. The use of systemic antivirals is limited by limited efficacy and organ toxicities. Inability to clear infection is exacerbated by transplant-related immunosuppression and prophylaxis or treatment of acute graft versus host disease. We report the first patient to clear three serious viral infections after stem cell transplant using third-party donor partially human leukocyte antigen (HLA) matched virus-specific cytotoxic T cells. The patient, a 53 year old female with transplanted for relapsed leukemia, with severe graft versus host disease received five T cell infusions from three separate donors that ultimately cleared serious systemic infections with cytomegalovirus and adenovirus, and an EBV-driven lymphoma. Systemic antivirals had resulted in failed clinical responses. Use of repeated infusions of partially HLA matched virus-specific T cells from banks containing cryopreserved cells should be strongly considered in transplant recipients with single or multiple refractory viral infections.

Cardiac amyloidosis has a very poor prognosis, but it is the nature of the involved precursor protein that ultimately dictates treatment and survival.Definitively characterise the amyloid subtype by mass spectrometry (MS) in an Australian cohort of patients with cardiac amyloidosis.We report the clinical characteristics and survival of 47 cardiac amyloid patients across two Australian centres including 39 patients evaluated for definitive amyloid subtype utilising laser microdissection and tandem mass spectrometry.A quarter (n = 12) of patients were classified as wild-type transthyretin amyloidosis (ATTRwt), 33 patients as light or heavy chain amyloidosis (AL or AH) and two as hereditary mutant transthyretin amyloidosis. Greater left ventricular hypertrophy (interventricular septum 22 vs 15 mm; P = 0.005) and history of cardiac arrhythmia (75% vs 31%; P = 0.016) were significantly associated with ATTRwt patients compared with AL/AH patients. AL patients demonstrated significantly shorter median survival compared with ATTRwt patients (3.5 vs 37 months; P = 0.007). New York Heart Association class III-IV symptoms or plasma cells ≥10% at diagnosis, were the only independent predictors of worse survival in AL patients on multivariate analysis.AL amyloidosis accounted for 68% of our cohort of patients with cardiac amyloidosis while ATTR accounted for 26%. In the era of novel therapies for both AL amyloid and ATTR, identification of the correct amyloid subtype is essential in making therapeutic decisions and providing accurate prognostic information to patients. Laser microdissection and tandem mass spectrometry plays an important role in identifying amyloid subtype, particularly in complex cases.

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n = 147) but not MRD (n = 64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P = .006), and superior 2-year GRFS (35.5% versus 20.0%, P = .003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.

Objectives Cytomegalovirus (CMV) is known to have a significant impact on immune recovery post‐allogeneic haemopoietic stem cell transplant (HSCT). Adoptive therapy with donor‐derived or third‐party virus‐specific T cells (VST) can restore CMV immunity leading to clinical benefit in prevention and treatment of post‐HSCT infection. We developed a mass cytometry approach to study natural immune recovery post‐HSCT and assess the mechanisms underlying the clinical benefits observed in recipients of VST. Methods A mass cytometry panel of 38 antibodies was utilised for global immune assessment (72 canonical innate and adaptive immune subsets) in HSCT recipients undergoing natural post‐HSCT recovery (n = 13) and HSCT recipients who received third‐party donor‐derived CMV‐VST as salvage for unresponsive CMV reactivation (n = 8). Results Mass cytometry identified distinct immune signatures associated with CMV characterised by a predominance of innate cells (monocytes and NK) seen early and an adaptive signature with activated CD8+ T cells seen later. All CMV‐VST recipients had failed standard antiviral pharmacotherapy as a criterion for trial involvement; 5/8 had failed to develop the adaptive immune signature by study enrolment despite significant CMV antigen exposure. Of these, VST administration resulted in development of the adaptive signature in association with CMV control in three patients. Failure to respond to CMV‐VST in one patient was associated with persistent absence of the adaptive immune signature. Conclusion The clinical benefit of CMV‐VST may be mediated by the recovery of an adaptive immune signature characterised by activated CD8+ T cells., In this study, immune profiling with mass cytometry identified immune signatures associated with cytomegalovirus (CMV) reactivation after allogeneic stem cell transplant in patients undergoing natural immune recovery. Failure to control CMV was associated with failure to develop an adaptive immune signature that could be reversed with third‐party CMV virus‐specific T cells in some recipients.

Hematopoietic stem cell transplantation (HSCT) donor–generated virus-specific T cells (VSTs) can provide effective treatment for viral infection post-HSCT but are not readily accessible to all patients. Off-the-shelf cryopreserved VSTs suitable for treatment of multiple patients are an attractive alternative. We generated a bank of 17 cytomegalovirus (CMV)–, 14 Epstein-Barr virus (EBV)–, and 15 adenovirus (AdV)–specific T cell products from 30 third-party donors. Donors were selected for expression of 6 core HLA antigens expressed at high frequency in the local transplant population. T cells were generated by co-culturing venous blood or mobilized hematopoietic stem cell (HSC)–derived mononuclear cells with monocyte-derived dendritic cells pulsed with overlapping peptides covering CMV pp65, AdV5 hexon, or EBV BZLF1/LMP2A/EBNA1 proteins. Addition of a CD14+ selection step instead of plate adherence to isolate monocytes before culture initiation significantly improved expansion in cultures from HSC material. Phenotyping showed the CD8+ subset to have significantly higher numbers of terminal effector T cells (CD45RA+62L−) and lower numbers of effector memory T cells (CD45RA−62L−) when compared with the CD4+ subset. Increased expression of the immunoinhibitory markers PD-1 and TIM-3 was noted on CD4+ but not CD8+ cells when compared with the control group. VST showed antiviral activity restricted through a variety of common HLAs, and modelling suggested a suitably HLA-matched product would be available for >90% of HSCT patients. Only a small number of carefully selected third-party donors are required to generate a VST bank of broad coverage, indicating the feasibility of local banking integrated into existing allogeneic HSCT programs.

Background Patients with secondary acute myeloid leukaemia (sAML), defined as AML that follows a diagnosis of myelodysplastic syndrome or myeloproliferative neoplasm, are known to have a poor prognosis with conventional chemotherapy alone, when compared to de novo AML (dnAML). Allogeneic stem cell transplant offers the best chance of cure due to the often chemo-resistant nature of sAML, although there are limited studies assessing the outcome of allografting in this patient population. The Disease Risk Index (DRI) is a clinical decision tool which assists in determining the balance of transplant risk versus benefit, however validation studies to date have not evaluated the DRI in patients with sAML. Methods A retrospective analysis of 211 patients with dnAML or sAML who underwent allogeneic stem cell transplant between 1 st January 1998 and 31 st July 2015 at St Vincent's Hospital or Royal North Shore Hospital in Sydney Australia, was undertaken. Cases were identified from the Australasian Bone Marrow Transplant Recipient Registry, with additional data collected by medical record review. Overall survival (OS) probability was calculated by the Kaplan-Meier method. Non-relapse mortality (NRM) and relapse incidence (RI) were estimated by cumulative incidence with "death without relapse" and "relapse" as competing risks. A Cox proportional hazards model was used for multivariate regression, with results expressed as hazard ratio (HR) with 95% confidence intervals. Results Of the 211 eligible patients, 63 (30%) had a diagnosis of sAML, compared to 148 with dnAML. Of those with sAML, 74% had antecedent MDS and 26% an MPN. Patients with sAML had an older median age (55 vs 44 years, p3 (p=0.003), and more commonly had at least one cytogenetic abnormality (p=0.026). A myeloablative conditioning regimen was used in 35.3% and 66.0% of s- and dn- AML respectively. Grade II or greater acute graft-versus-host disease (GVHD) occurred in 39.7% of sAML and 29% of dnAML, with chronic GVHD reported in 60.3% and 64.5% respectively. OS at 1 year was 48.5% in sAML and 71.6% in dnAML (HR 1.93 [95%CI 1.32-2.97, p=0.0001]). Multivariate analysis accounting for disease risk index (DRI) as a co-factor identified sAML as an independent adverse risk factor for OS (HR 2.13 [95%CI 1.31-3.45], p=0.002). Compared to dnAML, sAML was associated with higher rates of disease relapse (HR 2.21 [95%CI 1.20-4.05], p=-0.011). Figure 1: Transplant outcomes (A) Overall survival dnAML vs sAML (B) Cumulative incidence of relapse at 1 year dnAML vs sAML Conclusions Patients with sAML experience poorer outcomes following allogeneic stem cell transplant than those with dnAML. Whilst the DRI stratifies AML based on cytogenetic risk and stage, our study identifies sAML as a prognostic marker independent of risk ascribed by the DRI. This has not been reported previously and if replicated, suggests the need for development of an independent prognostic model to capture the adverse risk in the sAML patient cohort. Importantly, despite poor outcomes, the lack of alternate management strategies still makes allogeneic stem cell transplant the only potential curative therapy. Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Pregnant or breastfeeding women are routinely excluded from clinical trials due to fear of teratogenicity and toxicity of therapeutic agents, despite a paucity of evidence to support this practice. In response to the diethylstilbesterol (DES) and thalidomide-induced embryopathy in the mid-20 th century, the US Food and Drug Administration (FDA) released new regulations excluding Women of Child-Bearing Potential (WoCBP) from phase I and II trial participation, followed by an introduction of a new pregnancy category labelling system in 1979. The legacy of these measures is a reliance on accidental exposure pregnancy data rather than rigorous clinical trial efficacy and safety data for medication use in pregnancy and lactation. WoCBP when enrolled in clinical trials are often subjected to prescriptive contraceptive requirements to mitigate the risk of accidental pregnancy, without informed consent for the contraceptive side effects. These barriers to trial participation for WoCBP, particularly in the setting of life-threatening haematological diseases, prevent timely access to therapies only accessible via clinical trial participation. Lymphoma and leukaemia in pregnancy occur with an approximate incidence of 1 in 6000 and 1 in 75,000-100,000 pregnancies respectively. We examined the rates and rationale for exclusion of these patients from clinical trials, as well as contraceptive requirements for WoCBP. Methods: We conducted a cross-sectional observational study of clinical trial protocols recruiting patients with potentially life-threatening haematological malignancies. We searched the clinicaltrials.gov clinical trials database for trial protocols enrolling acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), Hodgkin lymphoma (HL) and/or Diffuse Large B Cell lymphoma (DLBCL) between January 2016 and January 2021. Studies were included if they included WoCBP (15-55 years of age). Studies without complete electronic protocol access were excluded. The following data was collected: target disease, study phase, study location, age of patients, whether pregnant or lactating women were excluded (rationale if provided including evidence of teratogenicity), type of contraception and duration mandated and presence or absence of informed consent for contraception. Results: We identified 68 trials for AML, ALL, DLBCL and HL (40%, 26%, 21% and 13% respectively) (Table 1). Most were phase I-II studies (91%) of novel agents (90%) and of note, the majority were of non-chemotherapy agents (83%). The majority (97%) excluded pregnant women and (69%) without providing rationale. Only 2% cited evidence for embryopathy in either human or animal studies. Most studies (84%) explicitly excluded lactating women, of which 85% did not provide justification. Contraception was mandatory in 90% of the protocols, with 47% of these requiring at least two different forms of contraception for the entire study period. These included hormone-based contraception, barrier methods and abstinence. None of the protocols provided informed consent for the potential side effects of the mandated contraceptive methods in the context of the study. Conclusion: The theoretical harm from anti-cancer therapy to the foetus is typically given greater moral precedence than is a pregnant woman's autonomy. Pregnant and lactating women were almost universally excluded from the trials in this study with limited rationale provided. Study protocols frequently mandated contraception without informed consent of its associated risks in the context of the study. This perpetuates the lack of efficacy and safety data in this patient population, and drives a cycle of systematic exclusion, data shortage, and inequity. Pregnant and lactating women with life threatening haematological malignancies with no alternative treatment options should be eligible for clinical trials where this offers potentially life-saving therapy, with appropriate informed consent around the indefinable and potentially harmful effects on their foetus. We propose obligatory rationale for exclusion of pregnant and breastfeeding women in all clinical trials, using safety data from either human or animal studies and contraception informed consent. Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Chemotherapy is potentially harmful to the developing foetus and there is limited data on the foetal impact of immunotherapy except for rituximab. Therefore determining pregnancy status prior to initiation of chemo- and or immuno-therapy (CIT) should be standard of care. Repeat screening or testing during and after chemotherapy should be considered as women often cannot tell that they are pregnant due to overlapping symptoms of pregnancy, malignancy and treatment. This is of particular importance in women who are not on effective forms of contraception for personal choice or clinical reasons. Clinicians cannot presume that a patient's pregnancy status has been checked, or rely on any assumptions of abstinence, contraception or infertility based on secondary amenorrhoea. While CIT teratogenicity should be part of the informed consent discussion and it is recommended that pregnancy screening occur prior to CIT, there are no specific guidelines on this or on testing during CIT. It is our institutional standard to document consent using a standard tick box form to confirm a discussion of common and uncommon side effects of treatment, long term and life threating complications and impacts on fertility. Teratogenicity, pregnancy implications or contraception are not specified. We performed a retrospective review to evaluate the uptake of pregnancy screening prior to and during first-line CIT as well as an audit of documentation of contraception counselling in haematological and solid-organ malignancies at a large Australian tertiary cancer centre. Methods: We searched our electronic outpatient medical record database for Women of Child Bearing Potential (WoCBP) who were diagnosed with a malignancy and received outpatient based CIT between May 1 2015 and June 12 2020. WoCBP was defined as women 18-55 years of age with no record of menopause or definitive infertility. We captured patient demographics, disease details and CIT regimen. We collected result of any serum or urine b-HCG pregnancy tests done within 90 days prior to or during CIT administration and if positive, the pregnancy outcome. We captured any documentation regarding contraception prior to or during treatment. Results: A total of 415 WoCBP with a median age of 42 years (range 19-51) were included. The majority of women (79.3%) were treated for solid organ malignancies compared to haematological malignancies (20.7%) (Table 1). Only 17.1% were screened for pregnancy prior to its initiation. The average time between screening and CIT initiation was 19.5 days (range 0-90 days). Given the broad range of regimens and taking into consideration teratogenicity potential, CIT was categorised as immunotherapy alone (32.5%), chemotherapy containing an alkylating agent (25.8%) or an antimetabolite (3.9%), combination chemoimmunotherapy (15.2%) and other (22.7%). Rates of pregnancy screening within these categories is represented in Figure 1. One patient with early breast cancer had a positive pregnancy test during her 4 th cycle of adjuvant chemotherapy with paclitaxel, in the emergency department for a presentation of nausea, anorexia, abdominal pain and diarrhoea. The outcome in this case was an early spontaneous miscarriage estimated at 3-4 weeks gestation. This is the only patient who had a pregnancy test beyond the first cycle of CIT. Only 14.8% of patients had documentation of past or present contraception methods. None of the patients had documentation regarding counselling on recommended forms of contraception. Conclusion: A minority of WoCBP received a pregnancy test prior to commencing CIT for haematological or solid organ malignancy, and none intentionally received a test prior to subsequent chemotherapy cycles through the oncology/haematology service. Also none of the women had documented counselling on contraception. These results are concerning because missing a positive pregnancy test puts women at risk of foetal complications, accidental miscarriage, potential bleeding risks and avoidable psychosocial stress. Our results are consistent with the 2 other reports on this topic and are likely generalizable to other cancer centres. This highlights the urgent need for guidelines to increase the rate of pregnancy testing in WoCBP receiving CIT and contraception counselling prior to CIT. Figure 1 Figure 1. Disclosures Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

INTRODUCTION: The Tie2 pathway is a key regulator of vascular stability. Deactivation of this pathway, caused by hyperglycemia or ischemia, results in pathological vascular inflammation, permeability and neovascularization. AKB-9778 is a small molecule Tie2 activator. The TIME-2 study (NCT02050828) was performed to examine the efficacy of AKB-9778 for the treatment of diabetic retinopathy and nephropathy. METHODS: TIME-2 was a multicenter randomized trial in which 144 diabetic patients with center-involved diabetic macular edema (DME) were randomized (1:1:1) to 3 months of treatment with 15 mg AKB-9778 administered subcutaneously (SC) BID plus monthly intravitreal treatment (IVT) with 0.3 mg ranibizumab (RBZ), 15 mg AKB-9778 plus sham IVT, or RBZ plus placebo SC injections BID. DME was measured by optical coherence tomography (OCT), severity of diabetic retinopathy was measured by grading of 7-field color fundus photos (ETDRS DRSS scale), and kidney function was measured by UACR and eGFR. RESULTS: Reduction of DME was 50% greater after 3 months of combination AKB-9778 + RBZ treatment than with RBZ treatment alone (-164 µm vs -110 µm; P< 0.01). Diabetic retinopathy was improved by ≥ 2 steps in 11.4%, 8.8%, and 10% of patients in study eyes of the combination, RBZ, and AKB-9778 treatment groups, respectively. In fellow eyes (no RBZ) 11.4% showed ≥ 2-step improvement in retinopathy with systemic AKB-9778 compared to 4.2% of untreated eyes in the placebo group. UACR geometric mean was improved by 21% in patients with albuminuria at baseline (UACR ≥ 30 mg/g) in patients treated with AKB-9778 for 3 months. CONCLUSIONS: The TIME-2 study provides evidence that restoration of Tie2 activity by AKB-9778 has beneficial effects on retinal and kidney function in patients with diabetes mellitus. A one-year treatment trial is currently underway. AKB-9778 is a promising therapeutic for the prevention of end-organ damage in diabetic patients.

Introduction The COVID-19 pandemic has had drastic effects on healthcare provision across Australia and the world. Rural hematology patients who may rely on visiting medical officers from larger cities or long distance travel for reviews are particularly vulnerable to having their treatment affected by the recent changes to healthcare delivery given severe travel restrictions. The Griffith Hematology/Oncology Unit is based in Griffith Base Hospital, a regional hospital in New South Wales, Australia. It is serviced by consultant hematologists from St Vincent's Hospital at the capital city of Sydney, Australia, who visit fortnightly to run hematology outreach clinics and supervise chemotherapy delivery. Griffith is located 575km from Sydney and has an estimated population of over 26,000(1). The COVID-19 pandemic imposed significant travel restrictions, such that visiting haematologists have been unable to travel to continue in-person clinics since April 2020. This has led to the exclusive reliance on telemedicine (telehealth and telephone reviews) and remote chemotherapy delivery supervision. Having an electronic health record (EHR) containing all relevant patient information which is remotely accessible to treating physicians has been integral to the continuity of comprehensive specialist cancer care in this rural setting via telemedicine. Methods The previously reported shared EHR between Griffith and St Vincent's Hospital, Sydney was used to review the impact of COVID-19 on service delivery in Griffith(2). All rural patient information was accessible from the metropolitan location including comprehensive documentation of a patient's clinical findings, routine observations, diagnostic pathology and radiology results, and details of treatment at the Griffith site. Remote chemotherapy prescribing and telemedicine notes were documented through the EHR. Results The number of new referrals, follow ups and total patients over the four months prior to the COVID-19 related changes (December 2019 to March 2020) and the four months following (April to July 2020) were compared. From April 2020 onwards, the Griffith clinic patients underwent reviews via telemedicine or telephone with no in-person reviews able to be conducted in Griffith due to the travel restrictions. The number of new referrals, follows up visits and the total number of patients seen following the change to telemedicine had all increased with no reduction in service delivery seen (Table 1). The total number of patient reviews was 167 visits over the four months prior to the change, which increased to 186 reviews after the travel restrictions were applied. Despite the travel restrictions, the hematology outreach services to Griffith were maintained through telemedicine reviews in a similar manner to the metropolitan service. Griffith rural hematology patients continue to undergo regular telemedicine reviews with monitoring of laboratory and imaging results through the EHR, receiving the same level of care as metropolitan patients. Chemotherapy is still able to be prescribed, adjusted and reviewed from the Sydney location for all patients. The total number of chemotherapy treatment cycles delivered in Griffith only slightly decreased despite the changes to service provision, which was attributed to normal variation in patients requiring treatment over 2020 (Table 2). 32 chemotherapy treatment cycles were delivered prior to the change compared to 26 cycles following, for the primary indications of lymphoma and myeloma. Conclusion In recent months, the centralised EHR has proven critical in minimising clinical service disruptions caused by the COVID-19 pandemic by facilitating telemedicine links and remote patient management. We demonstrate how the shared EHR has been integral to the continuation of complex rural patient management during the COVID-19 pandemic due to the availability of remotely accessible patient information and chemotherapy prescribing. No significant change in clinical service activity was seen following the drastic travel restrictions due to the pandemic. Given these travel restrictions are expected to continue, it is encouraging that the shared EHR will allow rural Griffith patients continued access to appropriate specialist hematology care over the coming months. This work demonstrates how an EHR is fundamental to the sustainability of vital cancer services for rural communities. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria.

Background: Rural Australian oncology patients are known to have inferior mortality rates compared to metropolitan patients, possibly related to access to appropriate healthcare services and treatments. Replacement of paper-based chemotherapy charting with electronic systems improves the safety of chemotherapy administration through reduced prescribing and administrative errors. Aims: To integrate the electronic healthcare delivery systems at a metropolitan hospital and a rural outreach haematology clinic to facilitate streamlined and safe rural outpatient care. Method: The MOSAIQ v2.64 [Elekta] system utilized at St Vincent's Hospital, Sydney, was introduced at a linked rural outreach haematology clinic in Griffith, a city in the Riverina region of New South Wales. MOSAIQ is a comprehensive practice management system incorporating all relevant patient results and notes along with administrative capabilities. The two systems were consolidated into one with patient information accessible from both sites. Results: The electronic systems were successfully linked between the two sites in October 2017. As of November 2018 there were 497 patients registered with the service with the breakdown of diagnoses shown in Figure 1, with lymphoma found to be the most common haematological diagnosis. Tracking of service activity over time including clinic appointments and patient numbers is now possible, with increases in both seen since implementation. Nine chemotherapy regimen types encompassing 2174 overall treatments were delivered at the service over the fifteen months since implementation, the most common being R-CHOP [Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] followed by azacitidine. The linked system has improved streamlined care during patient transitions between the two hospitals with enhanced continuity of documentation and management. Chemotherapy prescribing has transitioned to electronic at the Griffith site and is guided by inbuilt, pharmacist-reviewed protocols allowing for safer and flexible prescribing remotely which has standardized management of haematology patients across both hospitals. Conclusion: Our study provides a novel example of the successful implementation of a centralised electronic healthcare record and chemotherapy prescribing system in a haematology setting shared between a metropolitan service and a rural outreach hospital clinic. This has positive implications for the safety and efficiency of healthcare delivery at the rural site applicable to all linked rural clinics, as well as allowing data collection to assist future planning of the service. Disclosures No relevant conflicts of interest to declare.

Introduction: Diffuse large B cell lymphoma is a heterogenous disease with prognosis known to vary based on histological changes including immunohistochemistry and gene rearrangements by florescence in situ hybridisation (FISH). Both immunohistochemical overexpression as well as gene rearrangements in MYC, BCL2 and BCL6 are thought to contribute to poor prognosis. The benefit of high dose chemotherapy is unclear for those with high grade B cell lymphoma with double hit status (DHL) by FISH , double expressor status (DEL) or gain of MYC/BCL2. The purpose of this study was to retrospectively analyse the effect of escalated chemotherapy in this population over a 5 year period. Methods: All patients with DLBCL treated between 2012-2017 were screened retrospectively for inclusion in the study based on immunohistochemistry and FISH at time of initial diagnosis. Immunohistochemistry was assessed on formalin fixed, paraffin embedded specimens with BCL2 and MYC considered positive at over 40% and 50% respectively. FISH was assessed using dual colour break apart probe. Results: 135 patients were diagnosed with DLBCL of which 53 patients had immunohistochemistry and FISH at diagnosis confirming either, DEL or gain of MYC/BCL2 status. The mean age was 65 years and median follow up 21 months. The overall response rate in DH treated with DA-R-EPOCH was 57%. There were insufficient cases treated with R-CHOP for comparison. Overall response rates in DEL were 94% for DA-R-EPOCH and 93% for R-CHOP. Overall survival (OS) and disease free survival (DFS) in DHL was 6 months and 2 months respectively when treated with DA-R-EPOCH. There was no significant difference in OS or DFS in DEL treated with DA-R-EPOCH compared with R-CHOP (OS: 42 months vs 38 months respectively (p=0.962), DFS 36 months vs 30 months (p=0.931)). Gain of MYC/BCL2 did not affect OS (p= 0.539) or DFS (p=0.439) when comparing treatment regimen. Conclusion: DA-R-EPOCH did not improve treatment response rates OS or DFS in patients with double expresser lymphoma or gain of MYC/BCL2. This study also confirms the previously reported poor outcomes associated with DHL Disclosures No relevant conflicts of interest to declare.

Cytomegalovirus (CMV) remains a major contributor to morbidity and mortality following allogeneic haemopoietic stem cell transplant (HSCT) despite widespread use of viraemia monitoring and pre-emptive antiviral therapy. Uncontrolled viral replication occurs primarily in the first 100 d post transplant but this high risk period can extend to many months if immune recovery is delayed. The re-establishment of a functional population of cellular effectors is essential for control of virus replication and depends on recipient and donor serostatus, the stem cell source, degree of HLA matching and post-transplant factors such as CMV antigen exposure, presence of GVHD and ongoing use of immune suppression. A number of immune monitoring assays exist but have not yet become widely accessible for routine clinical use. Vaccination, adoptive transfer of CMV specific T cells and a number of graft engineering processes are being evaluated to enhance of CMV specific immune recovery post HSCT.

Purpose AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME). Design Open-label, dose-escalation clinical trial. Participants Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks. Methods Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks. Main Outcome Measures Safety assessments, change from baseline BCVA, and change from baseline CST. Results All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 μm in 5 patients and by 50 to 100 μm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA. Conclusions No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator.

Cytomegalovirus (CMV) is a significant cause of morbidity, mortality and graft loss in solid organ transplantation (SOT). Treatment options for ganciclovir-resistant CMV are limited. We describe a case of ganciclovir-resistant CMV disease in a renal transplant recipient manifested by thrombotic microangiopathy-associated glomerulopathy. Adoptive T cell immunotherapy using CMV-specific T cells from a donor bank was used as salvage therapy. This report is a proof-of-concept of the clinical and logistical feasibility of this therapy in SOT recipients.

The efficacy of adoptive transfer of stem cell donor-derived virus-specific T cells (VST) to prevent or treat viral infection in allogeneic HSCT is well established. However, this approach has some limitations. It is prerequisite on the donor cells being accessible, and virus seropositive. The generation of a product applicable to a single intended recipient is cost- and labour-intensive, and may not be immediately available in urgent clinical scenarios. Creation of a bank of cryopreserved third party donor-derived VST addresses these limitations. We established such a bank of 177 VST, specific for cytomegalovirus (CMV n=77), Epstein Barr virus (EBV n=55), and adenovirus (AdV n = 47). To date, 19 allogeneic HSCT patients have been treated with partially HLA-matched VST for viral reactivation or disease (CMV=17 (2 with CMV colitis), EBV=1, AdV=1); persistent despite at least 14 days of antiviral treatment. Patients were transplanted from unrelated (n=12), sibling (n=4), or haploidentical (n=3) donors. The graft source was PBSC (n= 15), cord (n=1), or bone marrow (n=3), and 12/19 patients underwent in vivo T cell depletion. The 17 patients treated for CMV received a median of 31 (15-113) days of antiviral therapy prior to infusion, and 14/17 were transplanted from a CMV negative donor. Patients were eligible for up to 4 infusions of 2x107/m2 VST if viral persistence was documented 2 weeks after initial infusion. VST were matched at a minimum of one HLA allele between VST and recipient, and chosen on the basis of greatest number of HLA matches with preference for products with viral activity restricted through a shared HLA. A total of 31 VST have been infused; 1 patient received 4 infusions, 1 patient received 3 infusions, 7 patients received 2 infusions, and 10 patients received 1 infusion. VST were matched at 1/6 (n=4) to 4/6 HLA alleles, with 24/31 infusions matched at both a class I and class II HLA allele. The antiviral activity of VST products (determined by MHC tetramer staining or cytokine response to epitope stimulation) generated from 12 third-party donors was predominantly restricted through class I HLA alleles: A1 (n=4), A2 (n=2), A2 + B7 (n=1), A2 + DRB04:01 (n=1), A2 + B35 + DRB01:01 (n=1), A24 (EBV-specific, n=1), B7 (n=1), and DRB01:01 (Adv-specific, n=1). Best viral response post-initial VST was assessed in 18 evaluable patients. A complete response (CR) was documented if virus PCR negativity was achieved at any time, and partial response (PR) for a greater than 50% reduction from the pre-administration titre. At a median follow-up of 6.3 (1-14.8) m, a CR was attained in 14/18 (78%) patients and PR in 4/18 (22%) patients. Both patients with CMV colitis achieved CR and symptoms resolved. Reinitiation of antiviral therapy after cessation was not required in 15/18 patients post-final VST infusion. The median number of months free from antiviral therapy was 5.1 (0-14.6). No immediate infusion-related toxicities have occurred. One patient with skin GVHD prior to enrolment developed grade II acute skin GVHD post-infusion. Chronic GVHD has been documented in 4 patients (2 had preceding acute GVHD pre-infusion, 1 occurred following donor lymphocyte infusion with no preinfusion GVHD, 1 developed mild skin cGVHD with no preceding GVHD). One patient treated with EBV-specific VST was not evaluated for response as he died from relapsed disease 14 days after VST infusion. A further 4 deaths have occurred; 1 due to presumed CMV disease following a PR to VST; 1 bacterial pneumonia; 1 relapsed disease; 1 due to CNS EBV PLTD in a patient with a CR to CMV-specific VST. T cell receptor deep sequencing was performed to investigate the persistence of infused cells in treated patients, but no clones detected in individual VST products were shown to persist beyond 24hrs post-infusion in the 3 patients examined. Overall, third party VST appear to be safe and efficacious with a 100% overall response rate and durable responses demonstrated in the 18 evaluable patients reported. The use of an 'off the shelf' product has allowed prompt treatment of viral infection in a number of of allogeneic HSCT patients in whom the HSCT donor would not have been suitable or available for generation of T cells. It appears that expansion and persistence of infused cells may not be the predominant mechanism for achieving the demonstrated clinical responses, and investigations are underway to examine alternative potential mechanisms of VST mediated immune modulation. Disclosures No relevant conflicts of interest to declare.

Since 2003 we have treated 101 patients with antigen specific T cells for treatment or prevention of opportunistic infections in the context of haemopoietic progenitor cell (HPC) and solid organ transplant. Over this time, we have modified laboratory procedures to progressively incorporate T cell therapy into standard transplant practice. We have increased the number of pathogen targets, utilised HPC products and streamlined culture techniques. We are now able to produce a multipathogen product within 3 weeks of HPC harvest in a manner consistent with good manufacturing practice and within the scope of systems established for HPC processing. Our approach could be used by most accredited transplant laboratories.We have developed robust, simple and inexpensive methods that use marrow or G-CSF mobilised HPC products as starting material for T cell expansion. This has major practical importance in minimising repeated donor screening, blood draws and apheresis. Our current procedure uses monocyte derived dendritic cells (mo-DC) isolated using a modified CD14 selection method that requires minimal quantities of CD14 selection reagent. Maturation of mo-DCs utilises GM-CSF, IL-4, PG-E2, IL-6 and IL-1β. Multiple antigens are presented to T cells by mo-DCs including peptide mixes for cytomegalovirus (CMV), Epstein Barr virus (EBV), BK virus and adenovirus, vaccines (Varicella Zoster and Influenza virus) and mycelial lysate (Aspergillus). Activated antigen specific T cells are expanded using IL-2. We use no T cell selection/depletion procedures, feeder layers, cytokine, tetramer capture or clinical grade sorting methodologies. The overall cost of manufacture of each product, including reagents, staffing and ongoing infrastructure costs is approximately AU$2400 per dose.The phenotypic composition of multipathogen products is mainly CD3 (mean 97%, range 90-97), with variable CD4:8 ratio, minimal contaminating B cells (mean 0.1%), monocytes (mean 0.3%) and NK cells (mean 3%). We have demonstrated antigen specificity using intracellular cytokine staining, MHC multimer analysis (CMV and EBV), interferon-γ Elispot and chromium (Cr51) release cytotoxicity assay. Products do not show alloreactivity by Cr51 release assay (Mean 0.8% specific lysis at E:T ratio of 20:1, range 0-5.3).Clinical results of the first 50 patients treated with CMV specific T cells have previously been reported and showed infusion to be safe and to reduce the need for CMV-directed antiviral therapy. Clinical outcomes of the remaining patients treated with multi-pathogen T cells specific for up to 8 pathogens will be reported when data is mature.Future areas of development will involve extension of the range of infectious pathogens targeted, addition of cells targeting malignant antigens and combination of these therapies with CD34+ stem cell selection. Developing progressively greater selectivity through graft engineering and immunotherapy will improve outcomes of transplantation in the future.

Introduction Adoptive transfer of donor derived virus specific T cells (VST) can be effective therapy for infections in allogeneic HSCT recipients. However, this is not a practical strategy to treat acute infections due to the time required to prepare products and potential unavailability of transplant donors. To overcome this, treatment with cryopreserved partially HLA-matched T cells from third-party donors is being investigated. A recent report described disease resolution using cells matched at only one or two HLA alleles (Leen et al., (2013) Blood 121(26):5113-23). This less stringent requirement for matching would allow a small bank of cells to provide most patients with a therapeutic product. We describe the establishment of a virus specific T cell bank in Australia with centralized manufacturing by the Westmead Hospital BMT laboratory. The bank has been used to treat patients in multiple states in a Phase I clinical trial to treat patients who have failed antiviral pharmacotherapy. Aim To assess the safety and feasibility of treatment with partially HLA-matched VSTs derived from third-party donors for refractory cytomegalovirus (CMV), Epstein-Barr Virus (EBV), or adenoviral (AdV) infection in allogeneic HSCT patients. Methods We generated a bank of cryopreserved VSTs from peripheral blood or G-CSF mobilized stem cell product of healthy donors. Products were generated by co-culturing PBMC with dendritic cells loaded with overlapping peptides covering CMV pp65, AdV hexon or EBV BZLF1, LMP2A and EBNA1 proteins. Cultures were re-stimulated once with peptide loaded DC and cultured for 14 days with IL-2. Products were assessed for phenotype, sterility and specificity by MHC multimer staining where applicable or production of interferon-gamma in response to peptides by flow cytometry. Patients with persistent viral reactivation/infection after 2 weeks of standard therapy were eligible to receive up to 4 fortnightly infusions of 2x107 cells/m2partially HLA matched (minimum 1/6) CMV, EBV, or AdV specific T cells, and were followed for up to 12 months. Results T cell products were expanded from 25 donors to create a bank of 177 bags of VSTs (75 CMV, 47 AdV and 55 EBV). CMV specific products were predominantly T cells (mean 95.8±3%) with a higher proportion of CD8+ compared to CD4+ T cells (mean 66.6±23.9% versus 20.1±6.2%). Specificity was mapped by MHC multimer staining to epitopes restricted to common HLA types including HLA-A*0101, HLA-A*0201, HLA-A*2402, HLA-B*0702 and HLA-B*3501. AdV specific T cells had a higher proportion of CD4+ T cells (mean 64.6±23.8% versus 34.2±20.1% CD8 T cells). Specificity was mapped to CD8 epitopes restricted to HLA-A*0101 and HLA-A*2402 as well as 10 CD4 T cell epitopes restricted to three HLA-DRB1 alleles (DRB1*0301, DRB1*0701, DRB1*1501). EBV specific products contained a mix of CD8+ and CD4+T cells (mean 38.9%±18% AND 42.5±23.1% respectively). The antigen specificity of EBV products showed high variability between donors. Dominant responses to known MHC class I restricted epitopes were infrequent though responses were mapped to HLA-A*0201 and HLA-A*2402 restricted LMP2A epitopes, a HLA-B*0801 restricted BZLF1 epitope and a HLA-B*0702 restricted EBNA1 epitope. Based on HLA frequency analysis in the Australian recipient population we estimate 94%, 89% and 74% of patients would have access to a CMV, AdV and EBV specific product respectively with the current bank. To date nine patients have received VSTs, with median follow-up of 5.5 months (0-12 months). All patients had treatment resistant CMV after a median of 26 days (19-116 days) prior therapy. Six patients received a single infusion and 3 patients received 2, 3 and 4 infusions respectively. HLA matching ranged from 2-4/6 HLA match. There were no instances of 24hr infusion related toxicity. Follow-up data is available for 7 patients. One patient with chronic hepatitis C developed abnormal liver function tests 3 months post-infusion. One patient died from presumed progressive CMV disease 6 months post-enrolment. Five patients achieved a best response of CMV PCR negativity (2 with complete resolution of CMV-colitis). One patient has shown >50% reduction in CMV copy number over 3 weeks. Conclusion The infusion of third party CMV specific T cells is a promising therapy that offers the advantage of rapid availability, centralized manufacturing and relatively low cost per dose when produced on a large scale. Disclosures No relevant conflicts of interest to declare.