Understanding the Role of the Immune System in Improving Tissue Regeneration Proceedings of a Workshop (2022) / Chapter Skim
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4 Engineering of Allogeneic Donor Cells for Acceptance by the Host's Immune System
4 Engineering of Allogeneic Donor Cells for Acceptance by the Host's Immune System
Pages 33-52
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From page 33... ...
(Schrepfer) • Hypoimmune cells evade allogeneic immune rejection, do not acti vate a response from natural killer cells and macrophages, can be transplanted into sensitized patients, and do not alter the recipient's immune system.
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From page 34... ...
The objective of the second session of the workshop was to explore recent advances in engineering allogeneic donor cells for acceptance by a host's immune system, including gene editing approaches, universal donor cells, and immune evasion. Rachel Salzman, of the American Society of Gene and Cell Therapy, moderated the session.
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From page 35... ...
Mesenchymal Stromal Cell Therapies The anti-inflammatory properties of MSCs through intravenous infusion and local injection have been evaluated in clinical trials for a number of diseases, Le Blanc said.1 Although clinical experience confirms an exceptional safety profile, the efficacy of MSC therapy has been difficult to establish. This may be due in part to the tendency to generalize and combine results from different types of MSCs and patients with diverse disease characteristics.
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From page 36... ...
The results suggest that there are clear differences between those who respond to MSC treatment and those who do not, Le Blanc remarked. Potential Markers of Responsiveness to Mesenchymal Stromal Cell Therapies Le Blanc commented that she and Mauro Krampera, a collaborator of hers from the University of Verona, were asked to speculate on the markers that could predict responsiveness to MSCs or indicate patient responses after infusions.
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From page 37... ...
Autologous cell products carry the risk that miHA neoantigens will form and allogeneic HLA-matched cell products from HLA banks can also present miHA, leading to immune rejection. Autologous Regenerative Stem Cell Therapy In the autologous cell products approach, somatic cells from a patient hospitalized with organ failure, for example, are isolated and reprogrammed into iPSCs, Schrepfer explained.
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38 FIGURE 4-1 Overview of regenerative stem cell therapy. NOTE: HLA = human leukocyte antigen; iPSC = induced pluripotent stem cells; miHA = minor histocompatibility antigens.
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From page 39... ...
This indicates that the immune system can recognize even a single nucleotide polymorphism, demonstrating that autologous HLA can present neoantigens leading to rejection of autologous iPSCs, Schrepfer explained. Human Leukocyte Antigen Banking for Pluripotent Stem Cells The HLA banking concept aims to achieve matched transplantation that avoids autoimmune recognition, which has been tested by Teruhisa Kawamura and colleagues, said Schrepfer (Kawamura et al., 2016)
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From page 40... ...
A well-characterized master cell line could be developed from one healthy donor, avoiding the need for cumbersome banking of huge numbers of cell lines and enabling easier manufacturing and quality control, Schrepfer explained. Adaptive and Innate Immune Responses to Human Leukocyte Antigen in Allogeneic Cells The field of hypoimmunity started years ago when researchers began studying a naturally occurring allogeneic graft -- the fetus in a pregnant BOX 4-1 Advantages of Hypoimmune Cell Products • No immune rejection ˚ Does Evades allogeneic immune rejection ˚ and macrophages not activate the "missing self" response from natural killer cells • No need to generate individualized cell products • No cumbersome banking of huge amounts of cell lines • One well-characterized master cell line • Easier manufacturing and quality control • Ample availability of cell products • Can be transplanted into sensitized recipients • Do not alter the recipient's immune system SOURCE: Schrepfer presentation, November 2, 2021.
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From page 41... ...
FIGURE 4-2 Adaptive and innate immune responses to allogeneic cells. NOTE: HLA = human leukocyte antigen; NK = natural killer.
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From page 42... ...
With the creation of hypoimmune cells as a genetic endpoint, the engineering approach to off-the-shelf cell therapies involves taking iPSCs from healthy donors, removing HLA class I and II molecules, and then overexpressing CD47 (Deuse et al., 2021a; Deuse et al., 2019; Deuse et al., 2021b; Hu et al., 2021)
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From page 43... ...
Finally, the unmodified iPSCs were rejected in rhesus monkeys after three weeks, whereas the hypoimmune iPSCs survived. When all immune system components are considered -- NK cells as well as T cells -- immune evasion with hypoimmune cells appears to be an achievable goal, Schrepfer said.
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. The uniform composition and fully characterized master cell bank enable a renewable clonal cell line that can be used to create homogenous cell products.
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FIGURE 4-3 Platform for mass production of induced pluripotent stem cell products. NOTE: iPSC = induced pluripotent stem cell; NK = natural killer.
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From page 46... ...
Chimeric Antigen Receptor T-Cell Therapy Fate Therapeutics is focusing their pipeline on CAR-targeting strategies, Valamehr said. The pipeline consists of multifaceted, multi-targeted CAR T and NK cells that can be synergized with current therapeutic agents.
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From page 47... ...
This product not only survives in the host immune system, but it also becomes activated through engagement with the host immune system, Valamehr remarked. Fate Therapeutics is advancing both these novel immune evasion strategies and off-the-shelf T and NK cell products, which may be combined to combat cancer and its process of evolution, he said.
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From page 48... ...
Mesenchymal Stromal Cell Therapy Given that most MSC products are approved for local injection rather than infusion, Salzman asked Le Blanc about the risk–benefit profile of MSCs and how this applies on a translational level. There may be more safety data on infusion delivery than on local delivery, and these safety data are extraordinary, Le Blanc responded.
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From page 49... ...
Immune responses have been detected, but these are minor, and true rejection is therefore unlikely to be the cause of the rapid disappearance of cells, she said. Specifics of Hypoimmunity Salzman asked Schrepfer about the stage of cell development at which the effects of engineered hypoimmunity become apparent in stem cells such as iPSCs, embryonic stem cells (ESCs)
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Distributing cell products into community hospitals is the next goal, he replied. Few people live near a cellular therapy research facility,
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Competition within the body for cytokines limits available space in bone marrow. Conditioning allows for reducing endogenous immune cells, CD8s, CD4s, and NK cells that may reject the product while increasing homeostatic cytokines such as IL15.
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From page 52... ...
Many clinical diagnoses of inflammatory disorders are made based on symptoms rather than on biology, Le Blanc remarked. Including biology in both staging and diagnosing disease will shed light on treatment requirements, she reiterated.
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