Abstract The CD47-SIRPα axis is a critical checkpoint that prevents SIRPα-positive macrophages from phagocytosing CD47-expressing solid tumors. Several agents aiming to block this axis have recently ...entered early clinical trials including anti-CD47 and anti-SIRPα monoclonal antibodies (mAb). These checkpoint inhibitors (CPI) aim to modulate the phagocytotic activity of endogenous tumor associated macrophages (TAMs). However, the adoptive transfer of macrophages resistant to CD47-based inhibition in the tumor microenvironment (TME) could also increase clinical efficacy while avoiding side effects linked to the use of anti-CD47 mAb. Cell therapy based on autologous macrophages have gained increasing attention for cancer treatment due to their ability to infiltrate into the immunosuppressive TME and their unique immunomodulatory characteristics. However, due to required intricate genetic manipulation of autologous macrophage cell product for each patient, optimization and consistency of the cell product remains challenging. In contrast, the use of induced pluripotent stem cell (iPSC)-derived macrophages (iMACs) facilitates the introduction of genetic modifications to further optimize the iMAC cell product and limits the need for combination therapies. The knockout (KO) of the SIRPα gene in iMACs is a promising genetic modification that results in a potent iMAC cell therapy product resistant to phagocytosis inhibition by CD47-expressing tumor cells. A SIRPα KO was introduced in a fully characterized GMP iPSC line that was then differentiated to iMACs using Evotec’s 3D differentiation protocol. The SIRPα KO iMACs were then evaluated for their antibody-dependent cellular phagocytosis (ADCP) capacity in comparison to antibody-loaded wildtype (WT) iMACs when co-cultured with CD47-expressing tumor cells. SIRPα KO iPSCs showed differentiation potential comparable to WT iPSC and resulted in iMACs expressing typical markers of fully differentiated macrophages. SIRPα KO iMACs exhibited increased phagocytic potency and killing capacity compared to WT iMACs when both cell types were exposed to CD47-positive tumor cells and loaded with the same tumor-targeting mAb. This increased phagocytosis of tumor cells by antibody-loaded SIRPα KO iMACs was also comparable to ADCP observed for WT iMACs in the presence of an anti-CD47 blocking antibody. Using Evotec’s gene editing platform we were able to efficiently generate SIRPα-deficient iPSCs that serve as the starting material to manufacture highly pure, genetically modified iMACs that lack SIRPα expression rendering them resistant to CD47-dependent inhibition of phagocytosis. This novel allogeneic off-the-shelf iMAC cell product overcomes the need to combine this cell therapeutic with CD47-SIRPα axis CPIs and provides the basis to develop innovative treatments for solid tumors. Citation Format: Kathrin Haake, Michela Mirenda, Quentin Bernard, Philip Hublitz, Lucie Gouxette, Martin Briscadieu, Philine Scheinpflug, Garima Singh, Alica Hinkelmann, Tanja Schneider, Michael Esquerré, Audrey Holtzinger, Michael Epstein, Daniel Sommermeyer, Michael Paillasse, Andreas Scheel, Markus Dangl, Monika Braun, Nadja Wagner. SIRPα knockout iPSC-derived macrophages (iMACs) are resistant to CD47-dependent inhibition of phagocytosis and efficiently kill tumor cells in pre-clinical models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5244.
Extracorporeal membrane oxygenation (ECMO) is used for severe acute respiratory distress syndrome. However, available ECMO systems are large and not well designed for fast delivery, emergency ...implantation, and interhospital transfer. Therefore, a new miniaturized oxygenator with integrated rotary blood pump (ILIAS) was developed and compared with a standard ECMO system in a large animal model. Acute lung injury was induced with repeated pulmonary saline lavage in 14 pigs until PaO2/FiO2‐ratio was <100 mm Hg with a positive‐end‐expiratory‐pressure of 5 mbar. Pigs were assigned to the following three groups: group 1 (n = 4): control group with conventional ventilation; group 2 (n = 5): standard vv‐ECMO; group 3 (n = 5): vv‐ILIAS. Gas exchange, hemodynamics, hemolysis, and coagulation activation were examined over a period of 8 h. No device failed during the observation period. PaCO2 decreased from 59.40 ± 4.14 mm Hg to 48.62 ± 4.50 mm Hg after 1 h in the ILIAS group compared with an improvement of PaCO2 from 48.86 ± 7.45 to 40.10 ± 6.02 in the conventional ECMO group (P = not significant n.s.). ARDS‐induced respiratory acidosis was controlled promptly with a pH of 7.2 ± 0.1 at baseline increasing to 7.4 ± 0.1 in both study groups after 60 min of ECMO support. Mean carbon dioxide transfer was comparable between the conventional ECMO and ILIAS (211.36 ± 78.39 mL/min vs. 219.99 ± 76.72 mL/min, P = n.s.). PaO2/FiO2 increased from 118.4 ± 15.5 mm Hg to 179.1 ± 72.4 mm Hg in the ILIAS group compared with an improvement of oxygenation from 107.1 ± 24.9 mm Hg to 179.0 ± 45.7 mm Hg in the standard ECMO group (P = n.s.). Mean oxygen transfer was calculated with 136.09 ± 30.25 mL/min for the ILIAS and 129.05 ± 36.28 mL/min for the standard ECMO. Hemodynamic instability or significant activation of the plasmatic coagulation was not observed. However, hemolysis was significantly higher in the ILIAS group compared with the conventional ECMO. As the ILIAS prototype provided excellent gas exchange with hemodynamic stability comparable with a standard ECMO system, we believe this study serves as a proof of concept. Further development and design modifications (optimized rotation speed and surface coating of rotor) are already done and another experiment is projected to reduce hemolysis and platelet consumption for clinical application.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The first measurement of the coherent photoproduction of ρ 0 vector mesons in ultra-peripheral Xe–Xe collisions at s NN = 5.44 TeV is presented. This result, together with previous HERA γp data and ...γ–Pb measurements from ALICE, describes the atomic number (A) dependence of this process, which is particularly sensitive to nuclear shadowing effects and to the approach to the black-disc limit of QCD at a semi-hard scale. The cross section of the Xe + Xe → ρ 0 + Xe + Xe process, measured at midrapidity through the decay channel ρ 0 → π + π – , is found to be d σ / d y = 131.5 ± 5.6 ( stat . ) – 16.9 + 17.5 ( syst . ) mb. The ratio of the continuum to resonant contributions for the production of pion pairs is also measured. In addition, the fraction of events accompanied by electromagnetic dissociation of either one or both colliding nuclei is reported. The dependence on A of cross section for the coherent ρ 0 photoproduction at a centre-of-mass energy per nucleon of the γA system of W γ A , n = 65 GeV is found to be consistent with a power-law behaviour σ ( γ A → ρ 0 A ) ∝ A α with a slope α = 0.96 ± 0.02 ( syst . ) . This slope signals important shadowing effects, but it is still far from the behaviour expected in the black-disc limit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The coherent photoproduction of J/ψ and ψ' mesons was measured in ultra-peripheral Pb–Pb collisions at a center-of-mass energy $\sqrt{s_{\mathrm {NN}}}~=~5.02$ TeV with the ALICE detector. Charmonia ...are detected in the central rapidity region for events where the hadronic interactions are strongly suppressed. The J/ψ is reconstructed using the dilepton (l+l-) and proton–antiproton decay channels, while for the ψ' the dilepton and the l+l-π+π- decay channels are studied. The analysis is based on an event sample corresponding to an integrated luminosity of about 233 μb-1. The results are compared with theoretical models for coherent J/ψ and ψ' photoproduction. The coherent cross section is found to be in a good agreement with models incorporating moderate nuclear gluon shadowing of about 0.64 at a Bjorken-x of around 6×10-4, such as the EPS09 parametrization, however none of the models is able to fully describe the rapidity dependence of the coherent J/ψ cross section including ALICE measurements at forward rapidity. The ratio of ψ' to J/ψ coherent photoproduction cross sections was also measured and found to be consistent with the one for photoproduction off protons.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The acute respiratory distress syndrome (ARDS) is a life-threatening condition. In special situations, these critically ill patients must be transferred to specialized centers for ...escalating treatment. The aim of this study was to evaluate the quality of inter-hospital transport (IHT) of ARDS patients.
Methods
We evaluated medical and organizational aspects of structural and procedural quality relating to IHT of patients with ARDS in a prospective nationwide ARDS study. The qualification of emergency staff, the organizational aspects and the occurrence of critical events during transport were analyzed.
Results
Out of 1234 ARDS patients, 431 (34.9%) were transported, and 52 of these (12.1%) treated with extracorporeal membrane oxygenation. 63.1% of transferred patients were male, median age was 54 years, and 26.8% of patients were obese. All patients were mechanically ventilated during IHT. Pressure-controlled ventilation was the preferred mode (92.1%). Median duration to organize the IHT was 165 min. Median distance for IHT was 58 km, and median duration of IHT 60 min. Forty-two patient-related and 8 technology-related critical events (11.6%, 50 of 431 patients) were observed. When a critical event occurred, the PaO
2
/FiO
2
ratio before transport was significant lower (68 vs. 80 mmHg,
p
= 0.017). 69.8% of physicians and 86.7% of paramedics confirmed all transfer qualifications according to requirements of the German faculty guidelines (DIVI).
Conclusions
The transport of critically ill patients is associated with potential risks. In our study the rate of patient- and technology-related critical events was relatively low. A severe ARDS with a PaO
2
/FiO
2
ratio < 70 mmHg seems to be a risk factor for the appearance of critical events during IHT. The majority of transport staff was well qualified. Time span for organization of IHT was relatively short. ECMO is an option to transport patients with a severe ARDS safely to specialized centers.
Trial registration
NCT02637011 (ClinicalTrials.gov, Registered 15 December 2015, retrospectively registered)
Abstract
Current autologous cell therapies, with blockbuster products on the market, have been leading for a decade to unprecedented clinical successes in patients with hematological malignancies. ...However, these patient-derived T-cell therapies are facing many challenges. The use of GMP iPSC lines to produce immune effector cells will reduce the complexity of the manufacturing process and will provide an unlimited source of starting material. The goal of the EVOcells Oncology platform is to offer a truly allogeneic cell therapy platform to treat a broad number of cancer patients with consistent quality and scalability of the final product. Besides, the versatility of our platform to produce different immune cell types combined to customized genetic engineering strategies will bring cell therapy to the level of personalized medicine. Our “off-the-shelf” cell therapy platform has already validated two pillars: iPSC-derived NK cells (iNK) and iPSC-derived Macrophages (iMACs). Through multiple genetic engineering strategies specific to each immune cell type, we are developing a comprehensive portfolio of cell therapy products to address specific tumor escape mechanism in liquid and solid tumors. Our initial effort aimed to develop these two innate immune cell types to propose efficacious cell therapies with an increased safety profile as they have low risk of graft-versus-host disease (GvHD) or CRS (Cytokine Release Syndrome). Thanks to the expression of a broad pattern of activatory receptors, iNK cells form Immunological Synapses with tumor cells leading in turn to efficient killing with and without addition of a CAR construct. Besides, we demonstrated the possibility to combine “naked” iNK cells with marketed therapeutic monoclonal antibodies (mAb) to further improve their efficacy. At the end of the differentiation process, iMACs are showing a M0 like phenotype with high plasticity allowing the in vitro differentiation of the cells towards either a M1 or a M2 polarization in response to the appropriate stimulations. iMACs produce key macrophages cytokines and are able to kill tumor cells via ADCP (Antibody-Dependent-Cell-Phagocytosis) mechanism when combined to a therapeutic mAb. Thanks to our collaboration with clinicians at the IUCT-Oncopole (Toulouse Cancer Hospital), we were able to identify appropriate cancer indications and further demonstrate in a translational fashion that both iNK and iMACs are able to kill primary resistant tumor cells which were isolated from patient’ samples. Taken together, these results are showing the versatility and the breadth of our EVOcells Oncology platform to produce a true arsenal of cell therapies and its potential for future clinical development.
Citation Format: Michael Esquerré, Audrey Holtzinger, Nadja Wagner, Monika Braun, Mélanie Pichery, Stefanie Pfaender, Stephanie Sontag, Kathrin Haake, Michela Mirenda, Michael Paillasse, Davide Grandolfo, Chloé Beuraud, Mandy Richter, Philip Hublitz, Julien Bousquet, Marion Fabre, Mylène Gador, Daniel Sommermeyer, Tanja Schneider, Oriane Bombarde, Camille Esquerré, Loic Ysebaert, Fabien Despas, Matthias Austen, Andreas Scheel, Markus Dangl. EVOcells Oncology: Tailored genetic engineering of iPSC-derived immune effector cells and combination with the right biologic therapeutics result in optimal killing of primary tumor cells from patients abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3203.
Right heart failure (RHF) because of pulmonary hypertension (PH) is a frequently encountered clinical problem with high mortality. The last resort, if pharmacological therapy fails, is mechanical ...circulatory support. There is a lack of percutaneous systems to support the right ventricle (RV). Venoarterial extracorporeal membrane oxygenation is widely used as a bailout in acute RHF in non-left ventricular assist device patients. Venoarterial extracorporeal membrane oxygenation does not unload the left ventricle and may cause failure of the left ventricle if used for a longer period of time. We report the long-term use of an ECMO-based percutaneous right ventricular assist system (oxyRVAD) capable to deliver up to 6 L/min of blood flow with a returning cannula placed in the main pulmonary artery used in RHF originating from PH with poor oxygenation. We present a series of four patients on oxyRVAD (mean treatment duration 15 ± 7.6 days). Patients benefited from the system clinically; however, two patients eventually died while on oxyRVAD. Nevertheless, we provide a proof-of-concept of this system in PH patients, which is feasible and might provide a useful “bridge-to-recovery” or “bridge-to-transplant” option in the management of patients with severe RHF because of PH.
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