CELLULAR THERAPIES

OVERVIEW

Chimeric antigen receptor-T (CAR-T) cell therapy is a personalized immunotherapy that uses T cells from a patient’s own blood (autologous) or T cells from a donor (allogeneic) to fight cancer.1 A patient’s T cells are genetically engineered in a lab with a CAR designed to recognize antigens on cancer cells and then returned to the patient via intravenous (IV) infusion.


CAR-T Components:2

CAR-T Proposed Mechanism of Action

CAR-T cells bind antigens on cancer cells through the scFv recognition domain in a major histocompatibility complex-independent manner.1 CAR-T cells then promote tumor cell lysis. The costimulatory domain promotes CAR-T cell cytokine production.3 In addition to cytokine release, tumor cell killing occurs through the perforin and granzyme axis and the Fas and Fas ligand axis.


Therapeutic Potential

CAR-T cell therapy, a personalized immunotherapy, may be an appropriate treatment for hematological cancers.1 While laborious to produce, CAR-Ts may have the benefit of potentially persisting long term in the patient.

 

Other Cell Types

Other immune cells such as natural killer (NK) cells and macrophages can be modified to express CARs.4 In particular, CAR-NKs have innate tumor killing abilities and may have lower toxicity over T cells.5

sCART Cell Therapy

 

Switchable CAR-T (sCAR-T) cell therapy is a two-component infusion system of autologous sCAR-T cells and a targeted antibody switch that turns CAR-T cells on and off.2,6,7 The switch activates the CAR-T cells and induces tumor cell killing. The CAR-T cells (lacking an endogenous antigen target) and switch (lacking intrinsic activity) are individually inactive. The CAR-T cells are regulated through dosage of the switch. 

Traditional CAR-T cell therapy has the following potential limitations that may be overcome by using sCAR-T cell therapy:

  • Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) due to uncontrolled cytokine production from the genetically engineered cells
  • Relapse due to tumor antigen loss
  • B-cell aplasia due to continuous activity of CD19-targeted CAR-T cells

The sCAR-T-cell approach potentially allows for:

  • Controlled cytokine production, reducing the risk of CRS or ICANS
  • Cyclical on/off stimulation of the switchable CAR-T cells, leading to greater memory and persistence of the cells
  • B-cell repopulation, thus avoiding B-cell aplasia
  • Improved durability of the therapy
  • Engineered cells to “rest”

Relevant Targets

  1. Benmebarek M-H, et al.  Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019;20(6):1283.
  2. Young, T. CLBR001+SWI019: A novel switchable CAR-T cell platform enabling functionally reversible on/off control of CAR-T cell activity for B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND04.
  3. Mohanty R, et al. CAR T cell therapy: A new era for cancer treatment (Review). Oncol Rep. 2019;42(6)2183-2195.
  4. Mehrabadi AZ, et al.  Therapeutic potential of CAR T cell in malignancies: A scoping review. Biomed Pharmacother. 2022;146:112512.
  5. Xie G, et al. CAR-NK cells: A promising cellular immunotherapy for cancer. BioMed Pharmacother. 2022;146:112512.
  6. Nikolaenko L, et al. First in human study of an on/off switchable CAR-T cell platform targeting CD19 for B cell malignancies (CLBR001+SWI019). Blood. 2021;138(1):2822.
  7. Laborda E, et al. IND-enabling studies of a switchable chimeric antigen receptor-T cell (CLBR001+SWI019) to support first in human clinical study. Blood. 2021;138(1):1695.