Researchers propose test system for assessment of CAR-T cell-associated toxicity

Employees of the Translational Oncology Laboratory at the Institute of Fundamental Medicine and Biology have created three-dimensional cell structures—spheroids based on tumor and stromal cells to assess the toxicity of cell therapy drugs.

CAR-T cell therapy is an innovative method of cancer treatment based on the use of genetically modified patient cells "trained" to recognize the tumor.

Lead Research Associate, Associate Professor Regina Miftakhova explains, "The process begins with the isolation of T-lymphocytes, which are elements of the patient's immune system. These cells are then modified in the laboratory to express a chimeric antigenic receptor (CAR) capable of recognizing specific molecules on the surface of tumor cells. Once modified, the T-cells are multiplied in the lab and injected back into the patient's body, where they target the tumor cells, helping to destroy them."

The use of CAR-T therapy carries the risk of systemic side effects.

"The most common toxic reactions associated with this therapy are cytokine release syndrome (CRS) and neurotoxicity, known as immune effector cell associated neurotoxicity syndrome (ICANS). CRS and ICANS were much discussed during the coronavirus pandemic, when the cytokine storm was one of the major causes of multi-organ failure and patient death. In the same way, the use of CAR-T drugs can lead to an aggressive attack of the immune system, which manifests itself in the form of fever, and later can lead to organ failure," says Research Associate Aigul Rakhmatullina.

Despite active research into T-cell biology and the development of new CAR-T cell therapy drugs, there remain many unresolved issues, she notes.

"One of the key issues complicating the development of safer cell therapies is the lack of adequate in vitro models to assess immune and neurotoxicity," the young scientist explains. "Most preclinical studies have used tumor cell cultures as target cells for CAR-T cells. However, toxicity results from the interaction of CAR-T cells with other cells in the body (immune, stromal and endothelial cells), making it impossible to assess toxicity based on culture of one cell type alone. This is followed by studies in laboratory mice, but human and mouse immunology differ significantly. As a result, we get the main data on the toxicity of drugs only during clinical trials."

The KFU scientists suggested that cell systems consisting of multiple cell types have great potential as models for assessing toxicity.

In a paper published in Cells, the study participants provided evidence that multicomponent tumor-stromal spheroids (CSS) can serve as an effective in vitro model for CAR-T-mediated toxicity studies.

"Our results show," adds Rakhmatullina, "that CSS containing prostate carcinoma cells with increased expression of the chimeric antigen receptor (CAR) CD19 exhibit increased secretion of IL-8, MCP-1, and IP-10 cytokines associated with immune toxicity in the presence of anti-CD19 CAR-T cells compared to spheroids composed of single cell types."

Assessment of CAR-T drugs toxicity at the stage of primary laboratory studies using the test system created at KFU will significantly reduce the costs of their preclinical and clinical studies and improve their safety.

The research was funded by the federal budget subsidy (Project No. FZSM-2022-0016).

More information:
Multicellular Cancer-Stroma Spheres (CSS) for In Vitro Assessment of CAR-T Cell-Associated Toxicity
www.researchgate.net/publicati … -Associated_Toxicity

Provided by Kazan Federal University