What Triggers the Initiative of Developments in Transfusion Medicine: Advances in Ex Vivo Haematopoietic Cell Therapy and Next Generation Transfusion Products

1996 ◽  
pp. 177-192
Author(s):  
D. E. van Epps
Keyword(s):  
Cell Therapy ◽  
Ex Vivo ◽  
Transfusion Medicine ◽  
Next Generation ◽  
Haematopoietic Cell

Adoptive Cell Therapy for Gastrointestinal Cancers

2020 ◽  
Vol 04 (04) ◽  
pp. 345-350
Author(s):  
Ryan J. Slovak ◽  
Hyun S. Kim
Keyword(s):  
Cell Therapy ◽  
Clinical Research ◽  
Solid Tumors ◽  
Immune Cells ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Hematologic Malignancies ◽  
Gastrointestinal Cancers ◽  
Gastrointestinal Malignancies ◽  
Specific Antigens

AbstractThe reinfusion of autologous or allogeneic immune cells that have been educated and/or engineered ex vivo to respond to tumor-specific antigens is termed “adoptive cell therapy.” While adoptive cell therapy has made tremendous strides in the treatment of hematologic malignancies, its utilization for solid tumors has lagged somewhat behind. The purpose of this article is to concisely review the clinical research that has been done to investigate adoptive cell therapy as a treatment for gastrointestinal malignancies.

Cytotoxic effector cells with antitumor activity can be amplified ex vivo from biopsies or blood of patients with renal cell carcinoma for cell therapy use

2003 ◽  
Vol 52 (11) ◽  
pp. 699-707 ◽  
Author(s):  
Françoise Bouet-Toussaint ◽  
Jean-Jacques Patard ◽  
Alban Gervais ◽  
Noëlle Genetet ◽  
Cécile Thomas de la Pintière ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Antitumor Activity ◽  
Cell Therapy ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Ex Vivo ◽  
Effector Cells ◽  
Cytotoxic Effector

scholarly journals Small Molecule Screening Identifies Rho-Associate Protein Kinase (ROCK) As a Regulator of NK Cell Cytotoxicity Against Cancer

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3607-3607
Author(s):  
Grace Lee ◽  
Sheela Karunanithi ◽  
Zachary Jackson ◽  
David Wald
Keyword(s):  
Cell Therapy ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Akt Activation ◽  
Nk Cell Cytotoxicity ◽  
Rock Inhibition ◽  
Nk Cell Therapy

NK cells are a subset of lymphocytes that directly recognize and lyse tumor cells without the limitation of antigen specific receptor recognition. In addition to behaving as cytotoxic effector cells, NK cells unlike T cells are not thought to elicit graft versus host disease. The combination of these characteristics makes NK cells a powerful tool for adoptive cell therapy. Despite the promise of NK cell therapy, key hurdles in achieving significant clinical efficacy include both generating sufficient numbers of highly tumoricidal NK cells and maintaining the cytotoxic activity of these cells in vivo despite the immunosuppressive tumor microenvironment. Our lab and others have developed several feeder cell line-based expansion modules that robustly stimulate the ex vivo proliferation of NK cells. However, strategies to enhance and sustain the activity of NK cells once administered in vivo are still limited. In order to identify strategies to enhance the cytotoxic activity of NK cells, we developed a high-throughput small molecule screen (Figure 1A) that involved a calcein-based cytotoxicity assay of ex vivo expanded and treated NK cells against ovarian cancer cells (OVCAR-3). 20,000 compounds were screened and the screen was found to be highly robust (Z'>0.59). We identified 29 hits that led to at least a 25% increase in cytotoxicity as compared to DMSO control-treated NK cells. One of the most promising hits was the pan-ROCK inhibitor, Y-27632 that led to an 30% increase in NK killing of the OVCAR-3 cells. We validated that ROCK inhibition leads to enhanced NK cell cytotoxic activity using Y-27632 (Figure 1B) as well as other well-established ROCK inhibitors such as Fasudil using a flow cytometry based killing assay. Y-27632 increased NK cell cytotoxicity in a dose- and time- dependent manner. ROCK inhibition consistently led to ~10-25% increase in NK cell cytotoxic activity directed against a variety of ovarian (Figure 1C) and other solid tumor cell lines (Figure 1D). Interestingly, we found that the NK hyperactivation persists for up to 48hrs after washing off the drug that may enable ex vivo stimulation before NK cell infusion. Our preliminary results showed that ROCK inhibition activates PI3K-dependent Akt activation (Figure 1E). We hypothesize that ROCK inhibition restores Akt activation which may be critical for NK cell activating receptor pathways and our current investigations will test these hypotheses. ROCK inhibitors, such as Y-27632 and Fasudil have been utilized in both preclinical and clinical studies for a variety of diseases such as atherosclerosis, neurodegenerative disorders, and ocular diseases. However, the consequences of ROCK inhibition in NK cells has not been thoroughly investigated. Our work shows a promising novel strategy to significantly enhance NK cell therapy against cancer that has high translational potential. Disclosures No relevant conflicts of interest to declare.

scholarly journals Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Ratchapong Netsrithong ◽  
Methichit Wattanapanitch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Biology ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Basic Knowledge ◽  
Car T Cells ◽  
Car T ◽  
Induced Pluripotent

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term ex vivo expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products.

scholarly journals Differences of Clonogenic Mesenchymal Stem Cells on Immunomodulation of Lymphocyte Subsets

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Pascual Martínez-Peinado ◽  
Sandra Pascual-García ◽  
Enrique Roche ◽  
José Miguel Sempere-Ortells
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Wide Spectrum ◽  
Fold Change ◽  
Heterogeneous Environments ◽  
Peripheral Blood Mononuclear ◽  
Proliferation Assays

Mesenchymal stem cells (MSC) are a widely used population in cell therapy for their ability to differentiate into distinct tissues and more lately, for their immunomodulatory properties. However, the use of heterogeneous populations could be responsible for the nondesired outcomes reflected in the literature. Here, we analyse the different capacities of five one-cell-derived MSC clones to exert their immunomodulation ex vivo. We assessed proliferation assays in cocultures of MSC clones and purified cluster of differentiation (CD)3+, CD4+, or CD8+ lymphocytes; analysed the regulatory T (Treg) cells fold change rate; determined the effects on viability of peripheral blood mononuclear cells (PBMC); and also measured the coculture cytokine profiles (Th1/Th2). Conditioned media (CM) of different clones were also used to perform both proliferation assays and to analyse Treg fold change. The five clones analysed in this work were able to generate heterogeneous environments. Different clones inhibited proliferation of CD3+ and CD4+ lymphocytes, with different intensities. Surprisingly, all clones promoted proliferation of CD8+ lymphocytes. Different MSC clones and their CM were able to increase the number of Treg with different intensities. Finally, different clones also promoted different effects on the viability of PBMC treated with ultraviolet light. Considering all these data together, it seems that different clones, even from the same donor, can promote a wide spectrum of responses from anti-inflammatory to proinflammatory character. This fact may be important to standardise the design of personalized cell therapy protocols, thus diminishing the aforementioned undesired outcomes existing nowadays in this type of therapies.

Abstract 2876: Early Retention and Subsequent Engraftment of Transplanted Progenitor Cells is Improved by Delivery within Collagen Matrix

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yan Zhang ◽  
Marc Lamoureux ◽  
Stephanie Thorn ◽  
Vincent Chan ◽  
Joel Price ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Progenitor Cells ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Collagen Matrix ◽  
Cell Labeling ◽  
Type I ◽  
The Matrix ◽  
Early Retention

Background: To investigate the mechanisms involved in the potentiation of cell therapy by delivery matrices, we evaluated the retention and engraftment of transplanted human circulating progenitor cells (CPCs) injected in a collagen matrix by using in vivo positron emission tomography (PET) imaging, ex vivo biodistribution, and immunohistochemistry. Methods: CPCs were labeled with 18 F-FDG and injected with or without a collagen type I-based matrix in the ischemic hindlimb muscle (IM) of rats (2x10 6 cells; n=15/group). Localization of cells was acquired by PET imaging (15 min) at 150 min post-injection. In addition, radionuclide biodistribution, immunofluorescence, and immunohistochemical examination of transplanted CPCs were performed at up to 14 days. Results: Cell labeling efficiency was CPC-concentration dependent (r=0.61, p <0.001), but not 18 F-FDG-dose dependent. Labeled CPCs exhibited excellent short-term stability and viability. Persistence of 18 F-FDG radioactivity in cells was markedly greater than non-specific retention in the matrix. Wholebody (WB) PET images revealed better CPC retention in the IM and less non-specific leakage to other tissues when CPCs were delivered within the matrix (IM/WB retention ratio of 43.9±8.2%), compared to cells injected alone (22.3±10.4%; p =0.040) and to 18 F-FDG injected with or without the matrix (9.7±5.5% and 11.0±5.5%, respectively; p <0.005). Radioactivity biodistribution confirmed that accumulation was increased (by 92.5%; p =0.024) in the IM and reduced (by 1.1 to 23.8%; p <0.05) in non-specific tissues when cells were injected within the matrix, compared to cells injected alone. Anti-human mitochondria staining showed increased cell retention in the IM with use of matrices (3.0±2.1%) versus cells only (1.9±0.8%; p =0.048). At 14 days the number of CD31 + transplanted human cells was greater (1.6±0.1%) when injected within the matrix than injected alone (0.7±0.1%; p =0.004). Conclusions: Collagen-based delivery matrices improve the early retention of transplanted CPCs, which in turn favors subsequent cell engraftment in the ischemic tissue. This mechanism conferred by the matrix has potential implications for the optimization of cell therapy at the early stages after cell delivery.

scholarly journals Adoptive Cell Therapy in Breast Cancer: A Current Perspective of Next-Generation Medicine

2020 ◽  
Vol 10 ◽  
Author(s):  
Jesús Fuentes-Antrás ◽  
Kissy Guevara-Hoyer ◽  
Mariona Baliu-Piqué ◽  
José Ángel García-Sáenz ◽  
Pedro Pérez-Segura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Next Generation ◽  
Current Perspective ◽  
A Current
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