Mesenchymal Stem/Stromal Cells: MESENCURE: A PROFESSIONALIZED CELL THERAPY FOR ARDS REDUCED THE MORTALITY OF SEVERE COVID-19 PATIENTS BY 68% ACCORDING TO A RECENTLY CONCLUDED MULTI-CENTER, CONTROLLED PHASE II STUDY

Background & Aim: The wide gap in severe Covid-19 management is increasingly addressed by mesenchymal cell (MSC) therapies, despite studies that failed to show significant efficacy in ARDS. To improve the therapeutic utility of MSCs in ARDS, Bonus BioGroup developed MesenCure: An allogeneic adipose-derived MSC product professionalized by a combination of culture conditions enhancing the cells’ potency and stability, producing unique transcriptomic, proteomic, and morphological signatures. Up to 100k fresh MesenCure doses with a shelf life sufficient for global supply can be produced from a single donor under 20 PDLs, further preventing potency loss due to cryopreservation and culture aging. Based on preclinical data presented during ISCT2021, demonstrating MesenCure’s advantages over non-professionalized MSCs, and its safety in a Phase I study, Bonus BioGroup initiated a multi-center Phase II trial in severe Covid-19 patients that was recently concluded. Methods, Results & Conclusion: The Phase II trial included 50 severe Covid-19 patients suffering from diffuse pneumonia and oxygen desaturation treated with up to 3 MesenCure doses (1.5x106 cells/kg on days 1, 3, and 5), on top of the Standard of Care (SoC), and 150 similar severe control patients treated by the SoC only and stratified according to gender, age, and comorbidities. A substantial 68% reduction in the mortality rate of the test patients was measured (Fig. 1A, p<0.05), along with a 57% drop in their risk of intubation relative to the control (Fig. 2A, p<0.05). Over 50% of the patients treated with MesenCure were released from the hospital within two days after treatment, and a 38% reduction was measured in the hospital length of stay (LoS) of patients having LoS>7 days (Fig. 1C, p<0.01). Starting from a similar baseline as the control, the median CRP and CK levels of the test patients, after MesenCure treatment, ended 52% (p<0.0001) and 33% (p<0.01) lower than their respective control levels. As shown in Fig. 2 [Figure Presented] Fig. 1 ( 25). (A) Mortality rates among test and control patients at Visit 8 (one month after the first MesenCure dose or the equivalent time points for the control). (B) Test and control patients’ risk of deteriorating to mechanical ventilation. (C) Average hospital length of stay (LoS) of patients having LoS > 7 days. Two-sided p values were calculated using the Fisher Exact test (A and B) or t-test (C). [Figure Presented Fig. 2 ( 25). (A) CRP and (B) CK levels measured at Visit 6, the earliest of two weeks after the first MesenCure dose (Visit 2) or upon hospital release, or the equivalent time points for the control. The test and control groups started from similar median CRP and CK levels. (C) Changes in control and test patients’ LDH levels from Visit 1 (screening) to Visit 6. (D) Area of test patients’ diffuse pneumonia during Visits 1, 6, and 8 (one month after Visit 2). (E) Blood oxygen saturation measured during test patients visits 1, 2-4 (upon or before receiving the first to third MesenCure dose), Visit 5 (the earliest of one week after Visit 2 or upon hospital release), and Visit 6. (F) Test patients’ blood lymphocytes levels (absolute) across Visits 1 and 6. Charts are presented as box-and-whiskers (according to the Tukey method). p values were calculated using the Mann-Whitney test (A, B, and C), Dunn’s multiple comparisons (D and E), or the Wilcoxon test (F). the more profound improvements in inflammatory and tissue damage markers observed in test patients were accompanied by a rapid recovery in pneumonia, respiratory functions, and lymphopenia, emphasizing MesenCure’s powerful effect. In conclusion, we show that MesenCure saves patients’ lives and accelerates their healing, possibly reducing the risk of long-term damages while freeing ICU beds allowing better care for other patients, and reducing the burden associated with hospitalization and additional long-term healthcare costs.

Mesenchymal Stem/Stromal Cells: Late Breaking Abstract: FIRST EVIDENCE FOR THE TRANSLATIONAL POTENTIAL OF MESENCURE™, A PROFESSIONALIZED ALLOGENEIC MESENCHYMAL CELL THERAPY, FOR TREATING IMMUNOTHERAPY-RELATED CYTOKINE RELEASE SYNDROME

Background & Aim: Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) are related side effects of immunotherapies seen in up to 76% of patients treated with CAR-T and 48% of those treated with BiTEs. In up to 27% of the patients, these syndromes may lead to severe consequences. Current treatments for severe CRS are ineffective in >30% of the cases and can worsen ICANS prognosis, calling for novel treatments, especially in light of the expanding use of immunotherapies. Despite their obvious potential, mesenchymal cell (MSC) therapies were seldom investigated in this context. In the present study, Bonus BioGroup has set to assess the potential for treating CRS with MesenCure™, our allogeneic MSC platform, professionalized to enhance the cells’ potency and shown safe and effective in severe COVID patients. Methods, Results & Conclusion: A highly translational and validated CRS model was established in humanized NSG mice bearing human PBMCs, B-cell lymphoma, and CAR-T cells. CAR-T introduction significantly increased the serum levels of proinflammatory cytokines in model animals, indicative of CRS (Fig. 1A). Two IV MesenCure injections were well-tolerated in this model (Fig. 1B) and did not obstruct the CAR-Ts’ ability to inhibit tumor growth by 89% (Fig. 1C, p<0.0001). Remarkably, significant reductions in all proinflammatory cytokines tested (excluding IL-6) were measured in model animals treated with MesenCure, substantiating its potential to treat CRS (Fig. 1A). Interestingly, the magnitudes of these reductions resembled those observed in 50 severe COVID patients treated with MesenCure. MesenCure’s robust immunomodulatory capacity was further demonstrated in vitro by its ability to inhibit the proliferation of activated CD4 T cells with an IC50 of 6k MSC/200k PBMCs, twice more effectively than non-professionalized MSCs. Comparable results were also obtained with CD8 T cells. Similarly, MesenCure inhibited neutrophils’ ROS production by up to 80% within an hour following activation (IC50 19k MSC/200k neutrophils). These effects are likely mediated, in part, by IDO, whose RNA levels were found to be 6.8-fold higher in MesenCure cells than in non-professionalized MSCs (p<0.05), two hours after activation with IFNγ. Moreover, IDO inhibition by 1-MT (1 mM) reduced MesenCure’s (Figure Presented) Fig. 1 (A) The levels of serum proinflammatory cytokines measured in tumor-bearing NSG mice after CRS induction by injection of human PBMCs/CAR-Ts (or saline control) and MesenCure treatment (or saline control). Experimental groups’ designation: Control – not injected with PBMCs/CAR-Ts and not treated by MesenCure;CAR-T – CRS model animals, injected with PBMCs/CAR-Ts but not treated with MesenCure;MesenCure – treated with MesenCure but not injected with PBMCs/CARTs;and CAR-T + MesenCure – CRS model animals treated with MesenCure. (B) Relative change in body weight from the day of tumor induction (Day 0) and (C) IVIS analysis of tumor burden (dorsal aspect) in the above four experimental groups. Statistical significance indicators: ns – not significant, * p<0.05, *** p<0.001, **** p<0.0001. Statistical tests: Holm-Šídák’s multiple comparisons test (A) and two- sided t-test (C). ability to inhibit T cells’ proliferation by 73%. In conclusion, we provide the first evidence for the potential of MSCs and MesenCure, in particular, for treating immunotherapy-related CRS.

Abdominal imaging findings on computed tomography in patients acutely infected with SARS-CoV-2: what are the findings?

OBJECTIVES: To investigate what findings are new on contrast-enhanced abdominopelvic CT in patients infected with SARS-CoV-2. METHODS: Contrast-enhanced CT of the abdomen and pelvis of patients with COVID-19 at a tertiary oncologic center acquired over a 2-month period were reviewed independently by two readers and scored for new imaging abnormalities compared with a prior scan. CT scans were included if the study was performed between - 3 and 45 days from the time of COVID-19 diagnosis. Clinical information was gathered from the medical records. RESULTS: A total of 63 patients (34 male, 29 female; mean age 60.6 years, range 24.4-85.0 years) were included in this retrospective cross-sectional study. Aside from new ground glass opacities seen at the lung bases (29/63, 46.0%), the most common findings were new thickening of the stomach, small bowel or colon or fluid-filled colon (14/63, 22.2%), new small volume ascites (7/63, 14.3%), gallbladder distention in those without prior cholecystectomy (3/43, 7.0%), and single cases each of acute pancreatitis (1/63, 1.6%) as well as new portal vein thrombosis (1/63, 1.6%). CONCLUSION: Aside from lung base ground glass opacities, the most common new imaging abnormality on abdominopelvic CT in patients with COVID-19 finding in our cohort was abnormalities of the gastrointestinal tract, followed by small volume ascites, gallbladder distention, and isolated cases of pancreatitis and portal vein thrombosis. These findings overlap with those previously reported that did not have a prior scan for comparison, and provide supportive evidence that some of these findings may be related to SARS-CoV-2 infection.

Use of a portable computed tomography scanner for chest imaging of COVID-19 patients in the urgent care at a tertiary cancer center.

To present a novel use of a portable computed tomography (CT) for evaluation of COVID-19 patients presenting to an urgent care center (UCC). Infection control is imperative for hospitals treating patients with COVID-19, even more so in cancer centers, where the majority of the patient population is susceptible to adverse outcomes from the infection. Over the past several weeks, our department has worked to repurpose a portable CT scanner from our surgical colleagues that operates with fixed-parameters to perform non-contrast, helical, thin-slice chest imaging to address the known pulmonary complications of COVID-19. Despite the technical limitations of the portable CT unit that was repurposed for the UCC, diagnostic-quality images in an acute care setting were successfully obtained. Repurposing of a portable CT scanner for use in COVID-19 patients offers a feasible option to obtain diagnostic quality images while minimizing the risk of exposing other patients and hospital staff to an infected patient.