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Combinatorial CAR design improves target restriction.

Hakan Köksal1, Pierre Dillard1, Asta Juzeniene2

  • 1Department of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.

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|November 25, 2020
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Summary

Chimeric antigen receptor (CAR) T cell therapy shows promise for B cell cancers but causes infections. A new dual-target CAR T cell therapy improves cancer cell targeting while minimizing side effects.

Keywords:
B cell malignanciescell therapychimeric antigen receptor (CAR) T cellsimmunoglobulin kappa light chainimmunotherapy

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Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has shown significant success in treating B cell malignancies.
  • However, CD19 CAR T cells eliminate all B lineage cells, leading to B cell aplasia and increased susceptibility to infections.

Purpose of the Study:

  • To develop a novel CAR T cell strategy with improved target selectivity for B cell malignancies.
  • To overcome the limitations of current CD19-targeted CAR T cells by designing a construct that retains efficacy while reducing off-target B cell depletion.

Main Methods:

  • Designed a second-generation CAR targeting the immunoglobulin kappa (Igκ) light chain, termed IGK CAR, for enhanced specificity.
  • Investigated the efficacy of IGK CAR in the presence of serum immunoglobulin G (IgG), which was found to reduce its effectiveness.
  • Developed and evaluated combinatorial CAR constructs, including the Kz-19BB design, integrating CD19 CAR with IGK CAR components.

Main Results:

  • The IGK CAR demonstrated high target specificity but its efficacy was diminished by serum IgG.
  • The combinatorial Kz-19BB CAR construct, featuring a CD19 CAR with a 4-1BB costimulatory domain and an IGK CAR with a CD3zeta stimulatory domain, maintained Igκ target specificity.
  • This novel construct proved resistant to the inhibitory effects of soluble IgG, preserving its therapeutic potential.

Conclusions:

  • Combinatorial CAR T cell designs offer a promising approach to enhance target selectivity and therapeutic efficacy in B cell malignancies.
  • The Kz-19BB CAR represents a potential advancement in CAR T cell therapy, aiming to improve treatment outcomes for B cell leukemia and lymphoma while mitigating adverse effects.