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BackgroundTIGIT, an inhibitory immune checkpoint, is a target of interest for immuno-oncology combination therapies. TIGIT is part of a complex molecular network containing four receptors (DNAM1, TIGIT, PVRIG and CD96) and two ligands (PVR and PVRL2). Here we describe Dual Signaling Protein 502 (DSP502), a novel, multi-functional IgG1-Fc-fusion protein targeting this molecular pathway in a unique way. DSP502, comprising the extracellular domains of TIGIT and PD1, is designed to simultaneously bind its two respective ligands, PVR and PD-L1, overexpressed on cancer and myeloid cells in the tumor microenvironment. DSP502 binds PVR preventing inhibitory signaling through TIGIT and CD96 and promoting DNAM1 costimulatory signaling on activated T- and NK-cells. DSP502's PD1 arm binds PD-L1 to unleash effector T-cells through checkpoint inhibition. In parallel, DSP502's IgG1-Fc delivers an immune-activating signal via Fc receptors. The net effect is enhanced anti-tumor immunity (figure 1).MethodsDSP502 heterodimer was successfully produced in a mammalian expression system. DSP502 was evaluated for binding to its cognate ligands on cells and in ELISA-based assays, with and without competing antibodies. NK and PBMC killing activity were evaluated against human K562 CML cells overexpressing PVR. Simultaneous binding of DSP502 to fluorescently-labeled tumor and NK-cells was evaluated by FACS. In vivo activity of DSP502 was evaluated in a humanized NSG A549 NSCLC xenograft mouse model.ResultsBoth DSP502 arms were shown to bind their cognate ligands in ELISA and on cell surface. DSP502 binding was dependent on the presence of both ligands on cells and was abolished by competing antibodies to the respective targets, demonstrating binding specificity and the 'AND-gate' phenomenon. Overexpression of PVR reduced the sensitivity of K562 cells to NK-cell mediated killing, while DSP502 treatment restored it as measured by target cell killing and granzyme-B secretion. Increased, dose-dependent, complexation of NK- and tumor cells was observed following DSP502 treatment and was abolished by both PVR and FcR antibodies. Treatment with DSP502 markedly inhibited tumor growth of A549-NSCLC xenograft in a humanized NSG mouse model, with all mice being tumor-free at the end of the experiment, compared to control PBMC-injected mice.ConclusionsHere we report the design and function of a novel immunotherapeutic fusion protein, DSP502, that offers multiple functionalities that can coordinately and synergistically drive anti-tumor immunity. Beyond targeting PVR and PDL1, DSP502 has the potential to additionally impact the TIGIT pathway through its effects on CD96 and DNAM1. DSP502 is currently in IND-enabling studies and CMC development.Ethics ApprovalThe study was conducted at the Authority of Biological and Preclinical Models, the Hebrew University of Jerusalem, Ein Kerem, Sharet Specific Pathogen-Free (SPF) Unit under the Hebrew university ethic committee board approval (number MD-19-15815-5).Abstract 790 Figure 1

Background: With increased use of continuous-flow left ventricular assist devices (CF-LVAD), development of malignant tumors in this population is not uncommon. We sought to evaluate malignancies in CF-LVAD patients and evaluate the outcomes of treatment strategies. Methods: Overall, 18 articles consisting of 28 patients were identified who developed malignancies after CF-LVAD placement. Patient-level data were extracted for systematic review. Results: Median patient age was 60 years [59–67] and 85.7% (24/28) were male. CF-LVAD was placed as bridge-to-transplant (BTT) in 60.9% (14/23) of patients. The three most common malignancy types were GI in 35.7% (10/28) of patients, lung in 21.4% (6/28) and skin in 10.7% (3/28). Median time from CF-LVAD implant to malignancy diagnosis was 6.9 [2.5–12.8] months. Metastatic disease occurred in 17.9% (5/28) over a median time of 5.0 [1.0–82.0] months from the diagnosis. Surgical resection of the malignancy was performed in 57.1% (16/28) of patients. Our results showed that while there was a significantly higher probability of survival among patients who underwent surgery versus those who did not, when only stage I and II patients were included in the analysis, this difference was no longer statistically significant. Three patients were relisted for heart transplant after surgical treatment, and two received the transplant. Conclusions: Surgical management of malignancies in patients on CF-LVADs may improve survival and transplant eligibility status, therefore, a CF-LVAD should not always preclude surgical treatment.

Background: The domino-donor operation occurs when a “conditioned” heart from the heart-lung transplant (HLT) recipient is transplanted into a separate heart transplant (HT) recipient. The purpose of this systematic review was to investigate the indications and outcomes associated with the domino procedure. Methods: An electronic search was performed to identify all prospective and retrospective studies on the domino procedure in the English literature. Eight studies reported 183 HLT recipients and 263 HT recipients who were included in the final analysis. Results: HLT indications included cystic fibrosis in 58% (95% CI: 27–84%) of recipients, primary pulmonary hypertension (PPH) in 17% (95% CI: 12–24%), bronchiectasis in 5% (95% CI: 3–10%), emphysema in 5% (95% CI: 0–45%), and Eisenmenger’s syndrome in 4% (95% CI: 2–8%). HT indications included ischemic heart disease in 40% (95% CI: 33–47%), non-ischemic disease in 39% (95% CI: 25–56%), and re-transplantation in 10% (95% CI: 1–59%). The pooled mean pulmonary vascular resistance (PVR) in HT recipients was 3.05 Woods units (95% CI: 0.14–5.95). The overall mortality in the HLT group was 28% (95% CI: 18–41%) at an average follow-up of 15.68 months (95% CI: 0.82–30.54), and 35% (95% CI: 17–58%) in the HT group at an average follow-up of 37.26 months (95% CI: 6.68–67.84). Freedom from rejection in HT was 94% (95% CI: 75–99%) at 1 month, 77% (95% CI: 30–96%) at 6 months, and 41% (95% CI: 33–50%) at 1 year. Conclusions: The domino procedure appears to be a viable option in properly selected patients that can be performed safely with acceptable outcomes.

Background: Left ventricular assist device (LVAD)-associated endocarditis remains poorly studied, especially in newer continuous-flow LVADs (CF-LVADs). The aim of this review was to assess outcomes of patients with LVAD-associated endocarditis, as stratified by CF-LVAD and pulsatile LVAD (P-LVAD) use as well as by different interventions and pathogen types. Methods: An electronic search was performed to identify studies in the English literature on LVAD-associated endocarditis. Results: Overall, 16 articles with 26 patients were included; seven had CF-LVADs and 19 had P-LVADs; time to development of endocarditis was 91 days (152 vs . 65 days, respectively, P=0.05). Eleven of 25 patients were treated with antibiotics only. Remaining 14 patients received antibiotics, however, they also underwent additional surgical intervention. One patient was treated with embolization alone for mycotic aneurysm and was therefore excluded. At a median follow-up time of 344 days post implant, there was no difference in overall mortality between CF-LVAD and P-LVAD-associated endocarditis patients (57.9% vs . 42.9%, P=0.81). Patients who underwent additional surgical intervention had higher overall survival compared to those treated with antibiotics alone (71.4% vs . 27.3%, P=0.07); with no difference in outcomes amongst those who underwent surgical device exchange as compared to heart transplantation (80.0% vs . 66.7%; P=0.23) Conclusions: Compared to patients with P-LVADs, CF-LVAD patients appeared to be resistant to early development of LVAD-associated endocarditis. There was a trend towards high survival observed amongst patients who underwent additional surgical intervention as compared to those treated with antibiotics alone, with no difference amongst surgical device exchange as compared to heart transplantation. Advantages of additional surgical intervention vs . medical therapy alone deserves further exploration to determine its applicability in CF-LVADs.

Background: Optimal surgical treatment of infective tricuspid valve endocarditis in patients with intravenous drug use (IVDU) remains controversial. Tricuspid valvectomy has been proposed for infective tricuspid valve endocarditis in this patient population given the inherent social concerns. The aim of this systematic review and meta-analysis was to compare outcomes of valvectomy versus replacement for the surgical treatment of isolated infective tricuspid valve endocarditis. Methods: An electronic search was performed to identify all relevant studies published. After assessment for inclusion and exclusion criteria, 16 original studies were pooled for systematic review and meta-analysis. Results: There were a total of 752 patients with infective tricuspid valve endocarditis, of which 14% underwent valvectomy and 86% underwent replacement (mean follow-up 4.2 years, 95% CI, 1.9–6.4 years). The most common indications for surgical intervention were septic pulmonary embolism in the valvectomy group (74%, 95% CI, 28–95%) and persistent sepsis in the replacement group (62%, 95% CI, 31–86%). There were no differences in rates of stroke [valvectomy 4% (95% CI, 1–11%) vs. replacement 3% (95% CI, 1–16%), P=0.85] but there was increased likelihood of prolonged ventilation in those who underwent valvectomy [valvectomy 40% (95% CI, 30–51%) vs. replacement 26% (95% CI, 23–30%), P

Background: Heparin-induced thrombocytopenia (HIT) is a severe antibody-mediated reaction leading to transient prothrombosis. However, its incidence in patients on extracorporeal life support (ECLS) is not well described. The aim of this systematic review was to report the incidence of HIT in patients on ECLS, as well as compare the characteristics and outcomes of HIT in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and veno-venous ECMO (VV-ECMO). Methods: An electronic search was performed to identify all studies in the English literature examining outcomes of patients with HIT on ECLS. All identified articles were systematically assessed using specific inclusion and exclusion criteria. Random effects meta-analysis as well as univariate analysis was performed. Results: Of 309 patients from six retrospective studies undergoing ECLS, 83% were suspected, and 17% were confirmed to have HIT. Due to the sparsity of relevant retrospective data regarding patients with confirmed HIT on ECLS, patient-based data was subsequently collected on 28 patients from case reports and case series. Out of these 28 patients, 53.6% and 46.4% of them underwent VA-ECMO and VV-ECMO, respectively. Patients on VA-ECMO had a lower median platelet count nadir (VA-ECMO: 26.0 vs . VV-ECMO: 45.0 per µL, P=0.012) and were more likely to experience arterial thromboembolism (VA-ECMO: 53.3% vs . VV-ECMO: 0.0%, P=0.007), though there was a trend towards decreased likelihood of experiencing ECLS circuit oxygenator thromboembolism (VA-ECMO: 0.0% vs . VV-ECMO: 30.8%, P=0.075) and thromboembolism necessitating ECLS device or circuit exchange (VA-ECMO: 13.3% vs . VV-ECMO 53.8%, P=0.060). Kaplan-Meier survival plots including time from ECLS initiation reveal no significant differences in survival in patients supported on VA-ECMO as compared to VV-ECMO (P=0.300). Conclusions: Patients who develop HIT on VA-ECMO are more likely to experience more severe thrombocytopenia and arterial thromboembolism than those on VV-ECMO. Further research in this area and development of standardized protocols for the monitoring, diagnosis and management of HIT in patients on ECLS support are warranted.

Background: Saphenous vein grafts (SVG) are a commonly used conduit for coronary artery bypass graft (CABG) surgery and can be harvested by either an open or endoscopic technique. Our goal was to evaluate long-term angiographic and clinical outcomes of open compared to endoscopic SVG harvest for CABG. Methods: Electronic search was performed to identify all studies in the English literature that compared open and endoscopic SVG harvesting for CABG with at least one year of follow-up. The primary outcome was graft patency. Secondary outcomes included perioperative morbidity and mortality. Results: Of 3,255 articles identified, a total of 11 studies were included for analysis. Of 18,131 patients, 10,873 (60%) patients underwent open SVG harvest and 7,258 (40%) patients underwent endoscopic SVG harvest. The mean age of patients was 65 years and 87% were male. The overall mean follow-up period was 2.6 years. During follow-up, patients who underwent open SVG harvest had superior graft patency per graft [open 82.3% vs. endoscopic 75.1%; OR: 0.61 (95% CI, 0.43–0.87); P=0.01], but higher rates of overall wound complications in the immediate post-operative period [open 3.3% vs. endoscopic 1.1%; OR: 0.02 (95% CI, 0.01–0.06); P

Background Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. Methods IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. Results No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). Conclusions Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication.