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Review
. 2021 Jan 8:11:618427.
doi: 10.3389/fimmu.2020.618427. eCollection 2020.

Allogeneic CAR Cell Therapy-More Than a Pipe Dream

Kenneth J Caldwell  1 , Stephen Gottschalk  1 , Aimee C Talleur  1
Affiliations
Review

Allogeneic CAR Cell Therapy-More Than a Pipe Dream

Kenneth J Caldwell et al. Front Immunol. .

Abstract

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.

Keywords: CAR; allogeneic; cancer; cell therapy; immunotherapy.

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Conflict of interest statement

SG has patent applications in the field of immunotherapy, is a DSMB member of Immatics, and on the scientific advisory board of Tidal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
“Off the Shelf” allogeneic cellular therapy production. The production process for an allogeneic cellular therapy starts with collection of peripheral blood mononuclear cells (PBMCs) via leukapheresis from a health donor. Cells can then be sorted and selected for depending on the desired starting cellular material. CAR-encoding genes can be either inserted by non-viral or viral transduction or gene editing into immune cells. Additional gene editing can be performed to knock out genes of interest to mitigate risks such as immunogenicity and/or graft-versus-host-disease. The final product created from a single donor can be expanded, stored and used to treat multiple patients.
Figure 2
Figure 2
Comparison between autologous and allogeneic cells for use in CAR cell therapies. For details see text.
Figure 3
Figure 3
Strategies to improve allogeneic CAR T cells. (A) Elimination of the αβ TCR by knockout of TRAC or retaining TCRs within the Golgi apparatus reduces the risk of allogeneic T cell recognition of healthy host tissues, thereby decreasing risk of graft-versus-host-disease (GVHD). (B) Elimination of MHC I on allogeneic T cells by knockout of β-2 microglobulin (B2M) reduces the risk of host T cell recognition and elimination CAR T cells, increasing likelihood of allogeneic CAR T cell persistence. (C) Knockout of CD52, a T cell marker, allows for the use of CD52 antibody (anti-CD52) for enhanced lymphodepletion of host T cells without affecting infused allogeneic CAR T cells. (D) Expression of alloimmune defense receptor (ADR) destroys alloreactive host T cells targeting 4-1BB, decreasing the risk of rejection.
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