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

  1. Antigen recognition domain: single chain variable fragment (scFv) made up of heavy (VH) and light chain variable domains (VL)
  2. Hinge/Spacer: flexible connector
  3. Transmembrain domain: anchors the CAR to the T cell
  4. Costimulatory domain: promotes CAR-T cell survival and proliferation
  5. Signaling domain: signal to activate T cells

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.4 In addition to cytokine release, tumor cell killing occurs through


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 NK cells and macrophages can be modified to express CARs.5 In particular, CARNKs may have lower toxicity over T cells and have innate tumor killing abilities.6

sCART Cell Therapy

Switchable chimeric antigen receptor T (sCAR-T) cell therapy is a two-component infusion system of autologous sCAR-T cells and a targeted antibody switch, which turns on and off the CAR-T cells.7,8,9 The switch activates the CAR-T cells and induces tumor cell killing. The CAR-T cells (lacking 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. Fesnak AD, et al. Engineered T Cells: The Promise and Challenges of Cancer Immunotherapy. Nat Rev Cancer. 2016;16(9):566-581.
  4. Mohanty R, et al. CAR T cell therapy: A new era for cancer treatment (Review). Oncology Reports. 2019;42(6)2183-2195.
  5. Mehrabadi AZ, et al. Therapeutic potential of CAR T cell in malignancies: A scoping review. Biomedicine and Pharmacotherapy. 2022;146:112512.
  6. Xie G, et al. CAR-NK cells: A promising cellular immunotherapy for cancer. BioMed Pharmacother. 2022;146:112512.
  7. 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.
  8. 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.
  9. 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.