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“Off-the-Shelf” Allogeneic CAR Cell Therapy—Neglected HvG Effect

  • Leukemia (PH Wiernik, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Chimeric antigen receptor (CAR) cell therapy offers patients with hematological malignancies a new therapeutic option. Traditionally, autologous T cells are used to generate CAR designed T cells for each patient. However, this method has several drawbacks, the development of allogeneic CAR cell therapy would be a promising breakthrough that could address several of these limitations. From the clinical trials that have published data, the efficacy of allogeneic CAR cell therapy did not meet the expectations. Because of the host-versus-graft (HvG) effect, allogeneic CAR cells are eliminated by the host, resulting in short-term persistence of allogeneic CAR cells and poor efficacy. It is critical to solve the HvG effect of allogeneic CAR cells. The current commonly used methods are suppressing the host’s immune system, using HLA-matched homozygous donors, reducing the expression of HLA, targeting alloreactive lymphocytes and eliminating anti-CAR activities. In this review, we will focus on the HvG effect of the “off-the-shelf” allogeneic CAR cell therapy, especially its mechanism and current methods to solve this problem and summarize relevant clinical trial data.

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Abbreviations

CAR:

Chimeric antigen receptor

HvG:

Host-versus-graft

CR:

Complete remission

GVHD:

Graft-versus-host disease

allo-HSCT:

Allogeneic hematopoietic stem cell transplantation

B-ALL:

B cell acute lymphoblastic leukemia

DLI:

Donor lymphocyte infusion

UCB:

Umbilical cord blood

iPSC:

Induced pluripotent stem cell

DLT:

Dose-limiting toxicity

CRS:

Cytokine release syndrome

ICANS:

Immune effector cell-associated neurotoxicity syndrome\

PR:

Partial remission

ADCC:

Antibody-dependent cell-mediated cytotoxicity

APC:

Antigen-presenting cell

VST:

Virus-specific T cell

iNKT:

Invariant NKT

MAC:

Mesenchymal stem cell

MMP:

Matrix metalloproteinase

ECM:

Extracellular matrix

PTCL:

Peripheral T cell lymphoma

TRAC:

T cell receptor alpha constant

TRBC:

T cell receptor beta constant

PEBL:

Protein expression blocker

shRNA:

Short hairpin RNA

DSA:

Donor-specific anti-HLA antibody

HAMA:

Anti-mouse antibody

scFv:

Single-chain variable fragment

PNA:

Purine nucleotide analogue

ALCL:

Activation-induced C-type lectin

HCMV:

Human cytomegalovirus

ADR:

Alloimmune defense receptor

CHAR:

Chimeric HLA accessory receptor

RRMM:

Recurrent/refractory multiple myeloma

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Acknowledgements

We thank all colleagues at Tianjin First Central Hospital and First Center Clinic College of Tianjin Medical University for related discussions.

Data Availability

The authors declare that data is available.

Funding

This work was supported by grants from the General Project of the National Natural Science Foundation of China (81970180 to MZ), the Science and Technology Project of Tianjin Municipal Health Committee (TJWJ2022QN030 to MZ), Key projects of Tianjin Applied Basic Research and Multi-Investment Fund (21JCZDJC01240), Science and Technology Project of Tianjin Municipal Health Committee (TJWJ2022XK018 to MZ), and the Key Science and Technology Support Project of Tianjin Science and Technology Bureau (20YFZCSY00800 to MZ), as well as Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-056B).

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YXA was a major contributor in writing the manuscript. XJ designed the outline of this manuscript. HKZ, MZ, SM have substantively revised it. MFZ, WYL reviewed and amended the draft. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. First Center Clinical College, Tianjin Medical University, Tianjin, 300192, China

    Yuxin An MMed, Meng Zhang MD & Sadhana Mahara MMed

  2. Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, China

    Xin Jin PhD, Wenyi Lu MD, PhD & Mingfeng Zhao MD, PhD

  3. College of Life Sciences, Nankai University, Tianjin, 300071, China

    Hongkai Zhang PhD

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  1. Yuxin An MMed
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An, Y., Jin, X., Zhang, H. et al. “Off-the-Shelf” Allogeneic CAR Cell Therapy—Neglected HvG Effect. Curr. Treat. Options in Oncol. 24, 409–441 (2023). https://doi.org/10.1007/s11864-023-01061-8

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