scholarly journals Prospects for Development of Induced Pluripotent Stem Cell-Derived CAR-Targeted Immunotherapies

2021 ◽  
Vol 70 (1) ◽  
Author(s):  
Roberta Mazza ◽  
John Maher
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Human Cancer ◽  
Induced Pluripotent Stem Cell ◽  
Solid Tumours ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Drug Products ◽  
Induced Pluripotent ◽  
Near Future

AbstractTechnologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.

scholarly journals Chimeric antigen receptors that trigger phagocytosis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Meghan A Morrissey ◽  
Adam P Williamson ◽  
Adriana M Steinbach ◽  
Edward W Roberts ◽  
Nadja Kern ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cell ◽  
Human Cancer ◽  
Antibody Fragment ◽  
Cell Number ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Cell Therapies ◽  
Human Cancer Cells

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.

scholarly journals An Alternative Cell Therapy for Cancers: Induced Pluripotent Stem Cell (iPSC)-Derived Natural Killer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1323
Author(s):  
Li-Jie Hsu ◽  
Chao-Lin Liu ◽  
Ming-Ling Kuo ◽  
Chia-Ning Shen ◽  
Chia-Rui Shen
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cell ◽  
Ex Vivo ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
The Body ◽  
Cell Therapies ◽  
Induced Pluripotent

Cell therapy is usually defined as the treatment or prevention of human disease by supplementation with cells that have been selected, manipulated, and pharmacologically treated or altered outside the body (ex vivo). Induced pluripotent stem cells (iPSCs), with their unique characteristics of indefinite expansion in cultures and genetic modifications, represent an ideal cell source for differentiation into specialized cell types. Cell therapy has recently become one of the most promising therapeutic approaches for cancers, and different immune cell types are selected as therapeutic platforms. Natural killer (NK) cells are shown to be effective tumor cell killers and do not cause graft-vs-host disease (GVHD), making them excellent candidates for, and facilitating the development of, “off-the-shelf” cell therapies. In this review, we summarize the progress in the past decade in the advent of iPSC technology and review recent developments in gene-modified iPSC-NK cells as readily available “off-the-shelf” cellular therapies.

scholarly journals Induced Pluripotent Stem Cell as a New Source for Cancer Immunotherapy

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Farzaneh Rami ◽  
Halimeh Mollainezhad ◽  
Mansoor Salehi
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Pluripotent Stem Cell ◽  
Ex Vivo ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Protective Function ◽  
Induced Pluripotent

The immune system consists of cells, proteins, and other molecules that beside each other have a protective function for the host against foreign pathogens. One of the most essential features of the immune system is distinguishability between self- and non-self-cells. This function has an important role in limiting development and progression of cancer cells. In this case, the immune system can detect tumor cell as a foreign pathogen; so, it can be effective in elimination of tumors in their early phases of development. This ability of the immune system resulted in the development of a novel therapeutic field for cancer treatment using host immune components which is called cancer immunotherapy. The main purpose of cancer immunotherapy is stimulation of a strong immune response against the tumor cells that can result from expressing either the immune activator cytokines in the tumor area or gene-modified immune cells. Because of the problems of culturing and manipulating immune cells ex vivo, in recent years, embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) have been used as new sources for generation of modified immune stimulatory cells. In this paper, we reviewed some of the progressions in iPSC technology for cancer immunotherapy.

scholarly journals Ex vivo generation of platelet products from human iPS cells

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Sou Nakamura ◽  
Naoshi Sugimoto ◽  
Koji Eto
Keyword(s):  
Turbulent Flow ◽  
Platelet Transfusion ◽  
Blood Donation ◽  
Ex Vivo ◽  
Induced Pluripotent Stem Cell ◽  
Turbulent Energy ◽  
Culture Conditions ◽  
Insulin Growth Factor ◽  
Human Ips Cells ◽  
Induced Pluripotent

AbstractPlatelet products are used in treatments for thrombocytopenia caused by hematopoietic diseases, chemotherapy, massive hemorrhages, extracorporeal circulation, and others. Their manufacturing depends on volunteers who donate blood. However, it is becoming increasingly necessary to reinforce this blood donation system with other blood sources due to the increase in demand and shortage of supply accompanying aging societies. In addition, blood-borne infections and alloimmune platelet transfusion refractoriness are not completely resolved. Since human induced pluripotent stem cell (iPSC)-platelet products can be supplied independently from the donor, it is expected to complement current platelet products. One big hurdle with iPSC-based systems is the production of 10 units, which is equivalent to 200 billion platelets. To overcome this issue, we established immortalized megakaryocyte cell lines (imMKCLs) by introducing three transgenes, c-MYC, BMI1, and BCL-XL, sequentially into hematopoietic and megakaryocytic progenitor stage cells derived from iPSCs. The three transgenes are regulated in a Tet-ON manner, enabling the addition and depletion of doxycycline to expand and maturate the imMKCLs, respectively. In addition, we succeeded in discovering drug combinations that enable feeder-free culture conditions in the imMKCL cultivation. Furthermore, we discovered the importance of turbulence in thrombopoiesis through live bone marrow imaging and developed a bioreactor based on the concept of turbulent flow. Eventually, through the identification of two key fluid physic parameters, turbulent energy and shear stress, we succeeded in scaling up the bioreactor to qualitatively and quantitatively achieve clinically applicable levels. Interestingly, three soluble factors released from imMKCLs in the turbulent flow condition, macrophage migration inhibitory factor (MIF), insulin growth factor binding protein 2 (IGFBP2), and nardilysin (NRDC), enhanced platelet production. Based on these developments, we initiated the first-in-human clinical trial of iPSC-derived platelets to a patient with alloimmune platelet transfusion refractoriness (allo-PTR) using an autologous product. In this review, we detail current research in this field and our study about the ex vivo production of iPSC-derived platelets.

scholarly journals The impact of SBF2 on taxane-induced peripheral neuropathy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1009968
Author(s):  
Geneva M. Cunningham ◽  
Fei Shen ◽  
Xi Wu ◽  
Erica L. Cantor ◽  
Laura Gardner ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Neuronal Damage ◽  
Ex Vivo ◽  
Sodium Current ◽  
Induced Pluripotent Stem Cell ◽  
Binding Factor ◽  
Induced Pluripotent ◽  
The Impact

Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients. In addition to its impact on quality of life, this toxicity may lead to dose reductions or treatment discontinuation, adversely impacting survival outcomes and leading to health disparities in African Americans (AA). Our lab has previously identified deleterious mutations in SET-Binding Factor 2 (SBF2) that significantly associated with severe TIPN in AA patients. Here, we demonstrate the impact of SBF2 on taxane-induced neuronal damage using an ex vivo model of SBF2 knockdown of induced pluripotent stem cell-derived sensory neurons. Knockdown of SBF2 exacerbated paclitaxel changes to cell viability and neurite outgrowth while attenuating paclitaxel-induced sodium current inhibition. Our studies identified paclitaxel-induced expression changes specific to mature sensory neurons and revealed candidate genes involved in the exacerbation of paclitaxel-induced phenotypes accompanying SBF2 knockdown. Overall, these findings provide ex vivo support for the impact of SBF2 on the development of TIPN and shed light on the potential pathways involved.

scholarly journals Developing T-cell therapies for lymphoma without receptor engineering

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 622-631 ◽  
Author(s):  
Melanie Grant ◽  
Catherine M. Bollard
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Disease Stage ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Cell Therapeutics ◽  
Clinical Responses

AbstractT-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient’s immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival. In this review, we summarize the available T-cell therapeutics beyond receptor engineering for the treatment of patients with lymphoma.

scholarly journals Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma

2021 ◽  
Vol 22 (4) ◽  
pp. 1958
Author(s):  
Haruka Kuriyama ◽  
Satoshi Fukushima ◽  
Toshihiro Kimura ◽  
Hisashi Kanemaru ◽  
Azusa Miyashita ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Immune Cell ◽  
Induced Pluripotent Stem Cell ◽  
Epitope Peptide ◽  
Ips Cell ◽  
Surface Molecules ◽  
T Cell Infiltration ◽  
Tumor Tissues ◽  
Induced Pluripotent

We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor”.

scholarly journals Chimeric antigen receptors that trigger phagocytosis

2018 ◽  
Author(s):  
Meghan A. Morrissey ◽  
Adam P. Williamson ◽  
Adriana M. Steinbach ◽  
Edward W. Roberts ◽  
Nadja Kern ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cell ◽  
Antibody Fragment ◽  
Cell Number ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Cell Therapies ◽  
Car T ◽  
Cytosolic Domains

AbstractChimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity, and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRγ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing macrophages reduce cancer cell number in co-culture by over 40%.SummaryWe report the first Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that promote engulfment of antigen-coated particles and cancer cells.

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