What is CAR T-cell therapy?
Car-t cell therapy involves genetically engineering T cells isolated from patients or allogeneic donors to express chimeric antigen receptors (CAR) that specifically recognize and kill tumor cells.
As a "living" drug, CAR-T therapy is very different from traditional drugs. It is a new type of precision targeted therapy for the treatment of tumors. Compared with traditional chemotherapy and hematopoietic stem cell transplantation, it is more precise in killing tumor cells and significantly reduces toxic side effects while improving efficacy.
Diagram of CAR T cell treatment process (Hucks et al., 2019)
Cytokines in CAR-T cell therapy
Cytokines are pleiotropic and diverse, and enhancing T-cell activation signaling by transgenic expression of cytokines or engineered cytokine receptors has become one of the important strategies for CAR-T therapy. Cytokines not only enhance the expansion and persistence of CAR-T cells, but also enhance their function in immunosuppressive TME.
Cytokines, including interleukins, tumor necrosis factor, interferons, chemokines, colony-stimulating factors, growth factors, etc., are involved in the activation, proliferation, differentiation and survival of various immune cells. CAR-T cells can regulate immune function, and their combination with cytokines can achieve synergistic effects, which has great potential for application in cancer therapy.
The γ-chain co-receptor family, which includes IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, plays a key role in T cell differentiation, proliferation and internal environment stabilization. The receptors for these cytokines include a common gamma chain (γc) and a separate receptor chain for each. IL-2 and IL-15 share IL-2Rβ. Their downstream signals activate members of the STAT family. These cytokines play a role in the proliferation, survival and persistence of CAR-T cells both in vitro and in vivo.
The IL-1 superfamily of cytokines includes IL-1α, IL-1β, IL-33, IL-1Ra, IL-18, IL-37, IL-36Ra, IL-36α, IL-36β, IL-36γ, and IL-38, which play important roles in innate and adaptive immunity.
The IL-12 cytokine family includes IL-12, IL-23, IL-27, and IL-35, which have different roles in innate and adaptive immune responses, with IL-12 and IL-23 having pro-inflammatory effects, IL-27 having pro- and anti-inflammatory effects, and IL-35 having anti-inflammatory effects.
Cytokines not only enhance the antitumor activity of CAR-T cells, but also modulate other cells within the TME and induce or enhance endogenous tumor-specific immune responses.
Cytokine-release syndrome in CAR-T therapy
Like other anti-cancer drugs, CAR-T therapy has its side effects, such as cytokine storm, neurotoxicity, lifelong B-cell loss, and the most fatal one is cytokine release syndrome (CRS).
CRS, also known as cytokine storm, is a severe systemic inflammatory response syndrome caused by the activation of immune cells and the release of large amounts of cytokines (e.g., interferon, interleukin IL, chemokines, tumor necrosis factor, etc.).
The development of CRS after CAR-T cell therapy (Tvedt et al., 2021)
In order to better understand the functions played by different cytokines in CAR-T therapies, develop more functional applications of cytokines, and evaluate the safety of CAR-T therapies, Creative Proteomics can provide Luminex multiplex assay technology to simultaneously detect multiple cytokine levels during the development of therapies, such as TNF-α, IFN-γ, IL-6, IL-10, GM-CSF.
References:
- Tvedt, T. H. A., et al. (2021). Cytokine release syndrome in the immunotherapy of hematological malignancies: The biology behind and possible clinical consequences. Journal of Clinical Medicine, 10(21), 5190.
- Hucks, G., & Rheingold, S. R. (2019). The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. Blood cancer journal, 9(2), 1-9.