Engineered off-the-shelf therapeutic T cells resist host immune rejection

Mo, Feiyan; Watanabe, Norihiro; McKenna, Mary K.; Hicks, M. John; Srinivasan, Madhuwanti; Gomes-Silva, Diogo; Atilla, Erden; Smith, Tyler S.; Atilla, Pinar Ataca; Ma, Royce; Quach, David H.; Heslop, Helen E.; Brenner, Malcolm K.; Mamonkin, Maksim

doi:10.1038/s41587-020-0601-5

Cited by 97 publications

(52 citation statements)

References 45 publications

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“…More recently, a receptor recognizing 4-1BB (CD137)-temporarily upregulated on both activated T and NK cells-and signaling through CD3ζ was developed. 4-1BBζ ADR-engineered T cells were protected from T and NK cell mediated rejection in vitro and in vivo in a mouse xenograft model, and CARs retained their antitumor function when co-expressed with the 4-1BBζ ADR (44). Thus, ADRs have the potential to further enhance the persistence, efficacy, universality and safety of third-party engineered VSTs, and can be co-engineered with CARs.…”

Section: Virus-specific T Cells (Vsts) Adoptive Transfer Of Vsts To Pmentioning

confidence: 97%

Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring “Universal” Donor T Cells

2020

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Chimeric antigen receptor (CAR) engineered T cell therapies individually prepared for each patient with autologous T cells have recently changed clinical practice in the management of B cell malignancies. Even though CARs used to redirect polyclonal T cells to the tumor are not HLA restricted, CAR T cells are also characterized by their endogenous T cell receptor (TCR) repertoire. Tumor-antigen targeted TCR-based T cell therapies in clinical trials are thus far using “conventional” αβ-TCRs that recognize antigens presented as peptides in the context of the major histocompatibility complex. Thus, both CAR- and TCR-based adoptive T cell therapies (ACTs) are dictated by compatibility of the highly polymorphic HLA molecules between donors and recipients in order to avoid graft-versus-host disease and rejection. The development of third-party healthy donor derived well-characterized off-the-shelf cell therapy products that are readily available and broadly applicable is an intensive area of research. While genome engineering provides the tools to generate “universal” donor cells that can be redirected to cancers, we will focus our attention on third-party off-the-shelf strategies with T cells that are characterized by unique natural features and do not require genome editing for safe administration. Specifically, we will discuss the use of virus-specific T cells, lipid-restricted (CD1) T cells, MR1-restricted T cells, and γδ-TCR T cells. CD1- and MR1-restricted T cells are not HLA-restricted and have the potential to serve as a unique source of universal TCR sequences to be broadly applicable in TCR-based ACT as their targets are presented by the monomorphic CD1 or MR1 molecules on a wide variety of tumor types. For each cell type, we will summarize the stage of preclinical and clinical development and discuss opportunities and challenges to deliver off-the-shelf targeted cellular therapies against cancer.

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Section: Virus-specific T Cells (Vsts) Adoptive Transfer Of Vsts To Pmentioning

confidence: 97%

Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring “Universal” Donor T Cells

2020

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“…cytomegalovirus, adenovirus) after allogeneic HCT ( 86 , 87 ), close monitoring of recipients of alemtuzumab and CAR T cells is warranted for now since the risk of viral reactivation/infection in the setting of CAR T cell therapy is currently unknown. Lastly, active depletion of alloreactive host T cells is being explored including the expression of so called alloimmune defense receptors (ADRs) on infused allogeneic T cells that selectively recognizes 4-1BB, a cell surface receptor that is temporarily upregulated by activated host T cells ( 88 ).…”

Section: Allogeneic Car Strategies By Effector Cell Typementioning

confidence: 99%

Allogeneic CAR Cell Therapy—More Than a Pipe Dream

2021

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Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) has shown promise, particularly for the treatment of hematological malignancies. To date, the majority of clinically evaluated CAR cell products have been derived from autologous immune cells. While this strategy can be effective it also imposes several constraints regarding logistics. This includes i) availability of center to perform leukapheresis, ii) necessity for shipment to and from processing centers, and iii) time requirements for product manufacture and clinical release testing. In addition, previous cytotoxic therapies can negatively impact the effector function of autologous immune cells, which may then affect efficacy and/or durability of resultant CAR products. The use of allogeneic CAR cell products generated using cells from healthy donors has the potential to overcome many of these limitations, including through generation of “off the shelf” products. However, allogeneic CAR cell products come with their own challenges, including potential to induce graft-versus-host-disease, as well as risk of immune-mediated rejection by the host. Here we will review promises and challenges of allogeneic CAR immunotherapies, including those being investigated in preclinical models and/or early phase clinical studies.

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“…Expression or overexpression of inhibitory ligands could be a possible solution to prevent NK cell-mediated allorejection, with HLA-E or G (107)(108)(109) or Siglec 7/9 ligands (110,111) being among most promising options. Finally, new alternatives are being developed to avoid CAR T cell rejection, one promising strategy being the recent generation of a CAR that mediates deletion of activated host T and NK cells through expression of an extracellular 4-1BB ligand combined with the intracellular CD3ζ signaling molecule (112).…”

Section: Limiting Allorejectionmentioning

confidence: 99%

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

2021

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Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy in the last decade. Outstanding results in hematological malignancies and encouraging pre-clinical anti-tumor activity against a wide range of solid tumors have made CAR T cells one of the most promising fields for cancer therapies. CAR T cell therapy is currently being investigated in solid tumors including glioblastoma (GBM), a tumor for which survival has only modestly improved over the past decades. CAR T cells targeting EGFRvIII, Her2, or IL-13Rα2 have been tested in GBM, but the first clinical trials have shown modest results, potentially due to GBM heterogeneity and to the presence of an immunosuppressive microenvironment. Until now, the use of autologous T cells to manufacture CAR products has been the norm, but this approach has several disadvantages regarding production time, cost, manufacturing delay and dependence on functional fitness of patient T cells, often reduced by the disease or previous therapies. Universal “off-the-shelf,” or allogeneic, CAR T cells is an alternative that can potentially overcome these issues, and allow for multiple modifications and CAR combinations to target multiple tumor antigens and avoid tumor escape. Advances in genome editing tools, especially via CRISPR/Cas9, might allow overcoming the two main limitations of allogeneic CAR T cells product, i.e., graft-vs.-host disease and host allorejection. Here, we will discuss how allogeneic CAR T cells could allow for multivalent approaches and alteration of the tumor microenvironment, potentially allowing the development of next generation therapies for the treatment of patients with GBM.

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Engineered off-the-shelf therapeutic T cells resist host immune rejection

Cited by 97 publications

References 45 publications

Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring “Universal” Donor T Cells

Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring “Universal” Donor T Cells

Allogeneic CAR Cell Therapy—More Than a Pipe Dream

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

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