Jane Reese-Koc’s research while affiliated with Case Western Reserve University and other places

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Publications (14)


Trained Mesenchymal Stromal Cell-Based Therapy HXB-319 for Treating Diffuse Alveolar Hemorrhage in a Pristane-induced Murine Model
  • Article

November 2024

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7 Reads

Stem Cells

Hulya Bukulmez

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Adrienne T Dennis

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Jane Reese-Koc

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[...]

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Steven N Emancipator

Introduction Mesenchymal stromal cells (MSCs) can modulate immune responses and suppress inflammation in autoimmune diseases. Although their safety has been established in clinical trials, the efficacy of MSCs is inconsistent due to variability in potency among different preparations and limited specificity in targeting mechanisms driving autoimmune diseases. Methods We utilized High-Dimensional Design of Experiments methodology to identify factor combinations that modulate gene expression by MSCs to mitigate inflammation. This led to a novel MSC-based cell therapy, HXB-319. Its anti-inflammatory properties were validated in vitro by flow cytometry, RT-PCR, and mass spectrophotometry. To evaluate in vivo efficacy, we treated a diffuse alveolar hemorrhage (DAH) mouse model (C57Bl/6). Seven days post-DAH induction with pristane, mice received either MSCs or HXB-319 (2X106 cells, IP). On day 14, peritoneal lavage fluid (PLF) and lung tissue were collected for flow cytometry, histopathological examination and mRNA. Results HXB-319 increased gene expression levels of anti-inflammatory, angiogenic and anti-fibrotic factors (e.g. TSG-6, VEGF and HGF). KEGG pathway analysis confirmed significant activation of relevant anti-inflammatory, angiogenic, and anti-fibrotic proteins, corroborating RT-PCR results. In the DAH model, HXB-319 significantly reduced lung inflammation and alveolar hemorrhage compared to MSC treated and untreated DAH mice. HXB-319 treatment also significantly decreased neutrophils, plasmacytoid dendritic cells and RORγT cells, and increased FoxP3+ cells in PLF, and reversed alterations in mRNA encoding IL-6, IL-10 and TSG-6 in lung tissue compared to DAH mice. Conclusion HXB-319 effectively controls inflammation and prevents tissue damage in pristane induced DAH, highlighting its therapeutic potential for autoimmune inflammatory diseases.


Adjunct Therapy with T Regulatory Cells Decreases Inflammation and Preserves the Anti-Tumor Activity of CAR T Cells
  • Article
  • Full-text available

July 2023

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49 Reads

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4 Citations

Cells

With greater accessibility and an increased number of patients being treated with CAR T cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood-derived (UCB) regulatory T cells (Tregs) can resolve inflammation and treat acute and immune-mediated lung injuries. Allogeneic, cryopreserved UCB Tregs have shown a clinical benefit in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Treg cells include a lack of plasticity under inflammatory micro-environments, no requirement for HLA matching, a long shelf life of cryopreserved cells, and immediate product availability, which makes them attractive for treating acute inflammatory syndromes. Therefore, we hypothesized that adjunct therapy with UCB Tregs may resolve the undesirable inflammation responsible for CAR T cell therapy-associated toxicity. In in vitro analysis, no interference from the addition of UCB Tregs was observed on CD19 CAR T cells’ ability to kill CD19 Raji cells at different CAR T: Raji cell ratios of 8:1 (80.4% vs. 81.5%); 4:1 (62.0% vs. 66.2%); 2:1 (50.1% vs. 54.7%); and 1:1 (35.4% vs. 44.1%). In the xenogeneic B-cell lymphoma model, multiple injections of UCB Tregs were administered 3 days after CD19 CAR T cell injection, and no detrimental effect of add-on Tregs was noted on the circulating CD8+ T effector cells. The distribution of CAR T cells in multiple organs remained unaffected by the addition of the UCB Tregs. Specifically, no difference in the overall tumor burden was detected between the UCB Treg + CAR T vs. CAR T alone recipients. No tumor was detected in the liver or bone marrow in CAR T cells + UCB Tregs recipients, with a notable corresponding decrease in multiple circulating inflammatory cytokines when compared to CART alone recipients. Here we show the proof of concept for adjunct therapy with UCB Tregs to mitigate the hyper-inflammatory state induced by CAR T cells without any interference in their on-target anti-tumor activity. Administration of UCB Tregs after CAR T cells allows sufficient time for their synapse formation with tumor cells and exerts cytotoxicity, such that the UCB Tregs are diverted to interact with the antigen-presenting cells at the site of inflammation. Such a differential distribution of cells would allow for a two-pronged strategy of a UCB Treg “cooling blanket” effect and lay the groundwork for clinical study.

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(A) Cumulative incidence of ANC and platelet engraftment. (B) Overall survival of all the patients. ANC, absolute neutrophil count.
Swimmer plot of all the patients. Patient 1, 2, 3, and 8 received conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation, while Patient 5 and 7 received conditioning regimen of fludarabine, melphalan, and rabbit antithymocyte globulin. ANC, absolute neutrophil count. Plt, platelet.
Patients' characteristics.
Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens

May 2023

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41 Reads

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2 Citations

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.


Figure 1. hMSC Anti-Inflammatory Potency Screen on Murine BMDM. Each of the pre-GMP donor preparations (shown by a different color) were cultured in the absence of antibiotics for 72 h. The supernatants were screened for the ability to suppress the production of TNFα from either murine WT or Cftr tm2Kth BMM stimulated with LPS (10 µg/mL, n = 8) (A). Evaluating each hMSC-CM individually, the Cftr-deficient (B, n = 8) and WT (C, n = 6) were analyzed. Consistent with previous studies, the hMSCs significantly decreased TNFα gene expression by the BMDM stimulated with LPS (star designates p < 0.05) with each hMSC-conditioned medium having a unique anti-inflammatory potency.
Demographics of hMSC Donors.
Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the “First in Cystic Fibrosis” Phase I Clinical Trial (CEASE-CF)

February 2023

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87 Reads

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8 Citations

Pharmaceuticals

Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the “First in CF” Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.


A Phase I study to determine maximum tolerated dose of ex vivo expanded natural killer cells derived from unrelated, HLA-disparate adult donors

February 2022

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53 Reads

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17 Citations

Transplantation and Cellular Therapy

Background . The administration of allogeneic natural killer (NK) cells following a lymphodepleting chemotherapy regimen is emerging as a well-tolerated therapeutic approach in the management of various malignancies. Contrary to the expected complications of allogeneic T-cell therapy, there remains no evidence of graft versus host disease (GvHD) mediated by NK cells in numerous clinical trials. On the contrary, pre-clinical and clinical studies suggest that NK cells do not induce GvHD and may in fact prevent its development following allogeneic hematopoietic cell transplantation (HCT). In this study, we sought to determine the maximum tolerated dose of non-HLA matched donor NK cells derived from peripheral blood and ex vivo expanded using a novel feeder cell platform. Methods . In a single-center Phase I clinical trial using a “3 × 3” design, nine patients each received two infusions of NK cells two weeks apart following a preparative regimen of cyclophosphamide (60mg/kg IV) and fludarabine (25mg/m2/day IV x 5 days). No exogenous cytokines were administered. NK cells were administered at three dose levels: 1 × 10⁷/kg, 2.5 × 10⁷/kg and 5 × 10⁷/kg. Three patients had myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) while the other 6 subjects were colorectal carcinoma patients. Recipients were monitored over a 4-week period for GvHD as well as other adverse events and for persistence of donor NK cells in systemic circulation. Disease assessment started at 28 days following the first NK cell infusion and continued until post-infusion day 100 or disease progression. Results . In all nine study subjects, there was no occurrence of GvHD and no dose-limiting toxicities that would warrant cohort expansion at any of the three planned cell dose levels. Low level donor NK cell persistence was observed up to 4 weeks after the first NK cell infusion at all dose levels. The best observed response was a complete response with incomplete platelet recovery in a MDS patient who experienced disease relapse after prior allogeneic HCT. Other responses were stable disease in one MDS and two colorectal cancer patients up to post-infusion day 100. Conclusion . This off-the-shelf, third-party NK cell product can be administered safely without inducing GvHD and exhibits in vivo persistence promoted by preparative lymphodepletion alone. The observed clinical responses could be enhanced by administration of exogenous cytokine support as well as complementary approaches that promote NK cell function in the tumor microenvironment.


Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients

December 2021

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697 Reads

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56 Citations

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.


Conditioned medium (CM) from human mesenchymal stem cells (MSCs) treated with cytokines suppresses CD4+ T cell proliferation. A, CD4+ T cell proliferation is suppressed by CM from four different human MSC donors preconditioned with interferon γ (IFNγ), Interleukin‐1 β (IL1β), tumor necrosis factor α (TNFα), or a combination of the three cytokines (all‐3) compared with unconditioned control (UC) human MSCs. eFluor 670‐labeled CD4+ T cells were CD2/3/28 activated and cultured in the presence of various human MSC CM. Proliferation was determined under each condition by eFluor 670 dilution assessed by flow cytometry. The yellow peaks represent generation 1 of the CD4+ T cell population, whereas cells in purple have undergone cell division. Percentage suppression is calculated as described in the methods (the percentage of suppression cells are indicated in the top left). B, Aggregated data from four independent experiments demonstrate the mean level of suppression of healthy control CD4+ T cells incubated with the range of human MSC CM. All conditions are compared with reference UC human MSC. Statistical analysis using one‐way ANOVA and Dunnett's Multiple Comparison post‐test demonstrated significance as indicated. *P < 0.05, ***P < 0.001, and ****P < 0.0001.
CD4+ T cell proliferation is suppressed to a greater extent by human mesenchymal stem cells (hMSCs) preconditioned with cytokines for 48 hours than at 24 hours. A, eFluor 670‐labeled healthy CD4+ T cells were CD2/3/28‐activated and cultured in the presence of various hMSC conditioned medium (CM) harvested from hMSCs at 24 and 48 hours. Proliferation was determined under each condition by eFluor 670 dilution assessed by flow cytometry. Representative histograms from three independent experiments are shown (the percentages of suppression cells are indicated in the top left). B, CD4+ T cell suppression in the presence of hMSC CM under each condition, as described in A. Combined data from three hMSC donors. A paired t‐test was used to compare 24 hours with 48 hours. Data are given as mean ± SEM. *P < 0.05. all‐3, a combination of the three cytokines; IFNγ, interferon γ; TNFα, tumor necrosis factor α.
Variability within suppression assays can be seen by varying the human mesenchymal stem cell (hMSC) donors and CD4+ T cells donors. A, Secretomes from hMSC donors A and C effectively suppress healthy control (HC) and rheumatoid arthritis (RA) CD4+ T cell proliferation. CM from hMSC donor B incompletely suppresses RA CD4+ T cells. Proliferating cells are shown in green, and nonproliferating G0 cells are shown in purple. B, Both RA and HC CD4+ T cells were suppressed by CM, but the magnitude varied depending on which of the three distinct hMSC donor cells were used. T cell suppression (mean ± SEM) was calculated by using a one‐way ANOVA followed by Tukey's multiple comparisons test. *P < 0.05, **P < 0.005, ***P < 0.001, and **** P < 0.0001.
Human mesenchymal stem cell (hMSC) indoleamine 2, 3‐dioxygenase (IDO) protein was upregulated by the combination of all three cytokines (all‐3) or interferon γ (IFNγ) alone. A, hMSCs were preconditioned with the combination of IL1β, tumor necrosis factor α (TNFα), and IFNγ or each cytokine alone for 48 hours. Western blot of total protein extracts probed with antibodies for IDO (top) and β‐actin (bottom) in hMSCs. B, Densitometry was used to quantify protein levels and obtained levels were normalized to β‐actin (the normalized values were related to IDO expression for untreated control [UC], which was set to 1). Combined data from three independent experiments are shown. ***P < 0.0001. C, IDO mRNA expression was upregulated as measured by quantitative real‐time polymerase chain reaction at 48 hours after cytokine stimulation. Fold change was normalized to β‐actin (the normalized values were related to IDO expression for UC, which was set to 1). To determine significance, one‐way ANOVA followed by Dunnett's Multiple Comparison post‐test was used. ****P ≤ 0.0001.
Optimization of Human Mesenchymal Stem Cells for Rheumatoid Arthritis: Implications for Improved Therapeutic Outcomes

November 2021

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95 Reads

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4 Citations

Objective Seropositive rheumatoid arthritis (RA) is a chronic autoimmune disease that is rarely “cured.” Human mesenchymal stem cells (hMSCs) are known to reduce inflammation and restore immune homeostasis. However, methods for predicting therapeutic hMSC potency have not been established. The goal of these studies was to use and refine an ex vivo functional assay that determines potency of hMSCs and can then be validated in clinical trials as a potency measure of hMSCs used therapeutically to treat RA. Methods Allogeneic hMSCs were cytokine-stimulated, and a conditioned medium (CM) was harvested. The CM was tested for the potential to attenuate RA CD4+ T cell proliferation using suppression assays. Indoleamine 2, 3-dioxygenase (IDO) mRNA, and protein were quantified in hMSCs as a measure to compare hMSCs across (prior) studies. Results To mimic a proinflammatory environment that resembles that in RA, interleukin-1(IL1β), tumor necrosis factor α (TNFα) , and interferon γ (IFNγ) (alone or in combination) were used to precondition hMSCs. Treating hMSCs with a combination of these cytokines generated a CM “secretome” that suppressed T cell proliferation between 70 and 83%. Forty-eight hours of cytokine preconditioning hMSCs was required to maximize this effect. T cell suppression positively correlated with increases in hMSC cellular IDO mRNA and protein. Conclusion By standardizing assays to measure hMSC effects, their potency on T cell suppression can be quantified. These studies demonstrate that hMSCs can be compared functionally to identify optimal preparation(s) for therapeutic use in RA and that the potency of hMSC-dependent T cell suppression may differ between hMSC donors. Clinical studies are warranted to validate the hypothesis that ex vivo potency in suppressing T cells will positively correlate with a reduction in RA disease activity and increase in immunological quiescence.


Laboratory parameters, tumor burden and CAR-T cell expansion. (A) Baseline laboratory parameters (n = 20): clockwise: absolute lymphocyte count, CD3+ lymphocytes, LDH, total metabolic tumor volume, CRP, ferritin. Comparisons done with Wilcoxon rank sum test. (B) Peak laboratory parameters: Ferritin, CRP, absolute lymphocyte count. Blue boxes, bars, dots and lines represent results of patients without CRS, red boxes, bars, dots and lines those with CRS. CRP: C reactive protein; CRS: cytokine release syndrome; LDH: Lactate dehydrogenase. Comparisons done with Wilcoxon rank sum test. (C) Mean CAR-T transgene expansion, measured by qPCR, 6, 14, 21 and 30 days after infusion. N = 13. Comparisons done with Wilcoxon rank sum test. **p < 0.01. (D) Scatterplot of CAR-T expansion measured by qPCR, trends generated by locally estimated scatterplot smoothing (loess), AUC of CAR-T transgene (copy/pg DNA x days), n = 13, compared with Wilcoxon rank sum test, p = 0.16. Blue boxes, bars, dots and lines represent results of patients without CRS, red boxes, bars, dots and lines those with CRS. AUC, Area under the curve; CRP, C reactive protein; CRS, cytokine release syndrome; LDH, Lactate dehydrogenase qPCR, quantitative polymerase chain reaction.
Cytokine changes in CAR-T cell patients treated with prophylactic tocilizumab, (n = 13). (A) Median fold change from baseline (pre-lymphodepletion) over time in plasma cytokine concentrations in patients with CRS (left panel) and without CRS (right panel). Days are represented on the horizontal axis. Larger increases from baseline are shown in the green – yellow spectrum. Gray tiles represent missing values. (B) Comparisons of mean plasma cytokine concentrations of patients with CRS and without CRS (Wilcoxon test). Red tiles denote p values < 0.05. Not significant values (NS) are noted with black tiles.
Cytokine changes in CAR-T cell patients treated with prophylactic tocilizumab (n = 13). Scatterplots of cytokine concentrations measured by electrochemiluminescence. Trends generated by locally estimated scatterplot smoothing (LOESS). AUC of cytokine concentration (pg/mL x days) compared with Wilcoxon rank sum test. Blue dots and lines represent patients without CRS, red dots and lines represents patients with CRS. AUC, Area under the curve; CRS, cytokine release syndrome; INFγ, interferon gamma; IL, interleukin; MCP, monocyte chemoattractant protein; MIP, Macrophage inflammatory protein; TNFα, tumor necrosis factor alpha. A. Boxplot of time – based changes in cytokine concentrations with statistically significant differences between patients with CRS (red) and without CRS (blue). Comparisons done with Wilcoxon test.
Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

October 2021

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188 Reads

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82 Citations

Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed/refractory lymphomas. Cytokine release syndrome (CRS) and immune effector cell – associated neurotoxicity syndrome (ICANS) are well-known complications. Tocilizumab, a monoclonal antibody targeting the interleukin-6 (IL-6) receptor was administered 1 hour prior to infusion of anti-CD19 CAR-T cells with CD3ζ/4-1BB costimulatory signaling used to treat non-Hodgkin lymphoma patients. Relapsed/refractory lymphoma patients treated with anti-CD19 CAR-T cells were included in this analysis. Cytokine plasma levels were measured by electrochemiluminescence before lymphodepleting chemotherapy, prior to infusion and then on days 2, 4,6, and 14 days after treatment. Twenty patients were treated. Cell products included locally manufactured anti-CD19 CAR-T (n=18) and tisagenlecleucel (n=2). There were no adverse events attributed to tocilizumab. Ten patients had grade 1–2 CRS at a median of 4 (range 3-7) days. There were no cases of grade ≥3 CRS. Five patients had ICANS, grade 1 (n=4) and grade 4 (n=1). Laboratory studies obtained prior to lymphodepleting chemotherapy were comparable between patients with and without CRS, except for interleukin (IL)-15 plasma concentrations. patients with CRS had higher post-infusion ferritin and C reactive protein, with more marked increases in inflammatory cytokines, including IL-6, IL-15, IFN-γ, fractalkine and MCP-1. Fifteen patients (75%) achieved CR and 2 (10%), PR. One-year OS and PFS estimates were 83% and 73%. Prophylactic tocilizumab was associated with low CRS incidence and severity. There were no adverse events associated with tocilizumab, no increase in frequency or severity of ICANS and excellent disease control and overall survival.




Citations (9)


... We have previously shown that Tregs derived from umbilical cord blood (UCB) coexpress CD45RA + CD45RO + (12) that allow for sustained in vivo proliferation of the injected cells; as well as retain their suppressor function in presence of dexamethasone (12,13). Additionally, treatment with multiple injections of UCB Tregs can reduce burden of inflammation without interfering in the anti-tumor activity of CD19 CART cells in a xenogeneic lymphoma model (14). Recently, Kadia et al., showed that a single infusion of CK0801 Tregs can lead to durable independence from blood and platelet transfusion in patients with bone marrow failure (15). ...

Reference:

Cord blood T regulatory cells synergize with ruxolitinib to improve GVHD outcomes
Adjunct Therapy with T Regulatory Cells Decreases Inflammation and Preserves the Anti-Tumor Activity of CAR T Cells

Cells

... Plastic adherent bone marrow cells were found to result in CFTR expression in airway epithelium, improve bacterial clearance, and increase the survival of CFTR − / − recipient mice 12 . These findings are supported by other studies using verified MSCs 13 and warranted investigation for safety and tolerance as a therapy in the phase-I clinical trial CEASE-CF 14 . ...

Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the “First in Cystic Fibrosis” Phase I Clinical Trial (CEASE-CF)

Pharmaceuticals

... Otegbeye et al. [42] observed that HvG KIR-L mismatch was unfavorable for overall mortality and NRM in cord blood and haploidentical HSCT (without PTCy), but only during the first 6 months. This might be explained by the early post-transplant emergence of NKmediated alloimmunity, which is only later complemented by T-cellmediated GVL effects. ...

A Phase I study to determine maximum tolerated dose of ex vivo expanded natural killer cells derived from unrelated, HLA-disparate adult donors
  • Citing Article
  • February 2022

Transplantation and Cellular Therapy

... Further analysis of T cell subsets revealed substantial proportions of T SCM and T CM , which are early memory T cells possessing long-term persistence and antitumor activity in vivo, in the majority of cell products, which is consistent with previous studies using a similar platform and reagents. 14,19,25 Since 2018, CliniMACS Prodigy has been commonly used for POC manufacturing of CAR-T cells in academic medical centers in the United States, 2,26-29 Spain, 19,[30][31][32] Russia, 27 and India 14 for clinical studies and hospital exemption, while other manufacturing A B Figure 6. Functionality of the final cell product (A) Cytotoxicity of the manufactured SiCF-019 (effector) cells against CD19 + and CD19 À tumor (target) cells. ...

Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients

... The clinical arthritis scores and endothelial cells migration assay denoted the efficacy of MSC-derived small EVs [116]. The role of MSC secretome in the suppression of CD4 þ T-cell proliferation signify its role in reducing inflammation [117]. The use of MSC secretome in adjuvant-induced arthritis (AIA) mice suggested the therapeutic role of MSC secretome in the RA model [88]. ...

Optimization of Human Mesenchymal Stem Cells for Rheumatoid Arthritis: Implications for Improved Therapeutic Outcomes

... Therefore, the levels of IL-6 and other CRS-related cytokines, such as IFNγ and IL-2, should be closely monitored in clinical trials. On the other hand, anti-IL-6 receptor antagonists or corticosteroids, which are usually effective in the management of treatment-mediated CRS in TCE or CAR-T-cell clinical trials [43,44], could be considered for use with HK013-G1. ...

Prophylactic Tocilizumab Prior to Anti-CD19 CAR-T Cell Therapy for Non-Hodgkin Lymphoma

... Retrospective analyses have reported the use of stored PBPCs for stem cell boosts is both effective in successfully recovering hematopoiesis and well tolerated [61,62] . It has also been proposed that stored PBPCs can be used as an alternative starting source for CAR-T cell manufacturing in heavily treated patients, which is being actively investigated [63] . ...

Significant costs and low utilization of stored peripheral blood stem cells for salvage autologous transplant in multiple myeloma patients including those meeting mSMART criteria

Bone Marrow Transplantation

... In addition, AHCT2 is likely a cost-effective option compared with other expensive novel combinations available in relapsed setting [10]. However, most centers collect enough stem cells for >1 transplant, and a recent study from a single center reported a high cost of storage of those cells, but with low utilization rate suggesting potential underutilization of AHCT2 [11]. The depth of response prior to AHCT2 was the only significant factor determining the outcomes in our study and is consistent with several other studies [12][13][14]. ...

Value and Cost Effectiveness of Storing Peripheral Blood Progenitor Cells for Salvage Autologous Stem Cell Transplant in Multiple Myeloma

Biology of Blood and Marrow Transplantation

... They reported that 5-year overall survival and progression-free survival rates were 41% and 35%, respectively, with an early procedure-related mortality rate of 7%. Over the years, improvement in patient selection, mobilization techniques, and supportive care has resulted in survival of greater than 70%, and TRM rates less than 2% [16,17]. A retrospective review published by Reid et al. [18] showed a trend toward better 3-year OS and PFS in response to an outpatient BEAM regimen compared to an inpatient BEAM regimen. ...

Comparison of 2 Carmustine-Containing Regimens in the Rituximab Era: Excellent Outcomes Even in Poor-Risk Patients

Biology of Blood and Marrow Transplantation