CAR-T therapies have demonstrated great efficacy in hematologic malignancies and some solid tumors in early phase clinical trials. However, CAR-T cells may elicit some expected and unexpected toxicities such as cytokine release syndrome, tumor lysis syndrome, neurologic toxicity, on-target/off-tumor recognition, and anaphylaxis. In addition, theoretical toxicities such as insertional oncogenesis, graft versus host disease, and off-target/off-tumor antigen recognition, may be related to CAR-T cell therapy as well. Safety risk is the main concern in the development of new drugs and therapeutic novelties. Evaluation of the toxicity on animal models is essential to assure the safety and right of subjects. With extensive experience on preclinical in vivo research and project management, Creative Biolabs provides CAR-T cell toxicity evaluation service, by utilizing appropriate models, designing comprehensive research practices and handling high-quality in vivo studies.
Toxicities of CAR-T therapy.
C Bonifant et al. 2016
We provide the following toxicological study services on CAR-T cell therapy.
The safety of CAR-T cell therapy is evaluated by standard toxicological studies. Body weight, feed consumption, behavior, morphology, ophthalmologic and pathologic characteristics are closely monitored. After specific end point, a complete necropsy including assessment of organ weight and histopathology analysis is conducted.
Cytokine Release Analysis
To date, the most prevalent side effect of CAR-T cell therapy is the onset of immune activation, also known as cytokine release syndrome (CRS). Cytokines can support the amplification and persistence of CAR-T cells in vivo. On the other hand, sudden elevation of cytokine levels usually leads to high fever, fatigue, hypotension, and nausea, which can further result in life threatening reactions. Therefore, the cytokine level information in animal models is of great value for risk management of CAR-T cell therapy. Creative Biolabs offers multiplex cytokine release analysis with ELISA or cytokine array for evaluating your CAR-T cells. Both time course and end point cytokine release analysis will be conducted.
Tumor Lysis Analysis
CAR-T cells bind the cognate antigen on the target tumor cells and kill them. The rapid destruction of large amount of tumor cells lead to tumor lysis syndrome due to the abrupt release of cellular toxic products, causing a set of systemic metabolic disturbances. This side effect elicits safety concerns of CAR-T cell therapy. Creative Biolabs offers tumor lysis analysis during CAR-T cell evaluation in animal models for toxicity and safety assessment. The analysis mainly contains chromium release cytotoxicity assay, potassium phosphate levels analysis and serum uric acid level analysis.
On-Target/off-Tumor Toxicologic Effect Analysis
In most cases, the target of CAR may not be specific for tumor cells and expresses in healthy tissues at low levels as well. Therefore, CAR-T cells may target these normal cells and results in adverse reactions ranging from manageable and acceptable lineage depletion (B cell aplasia) to severe toxicity that may cause death. Creative Biolabs provides on-target/off-tumor toxicologic effect analysis that mainly contains cell content analysis, animal necropsy and histological analysis.
Tumorigenicity study is performed in immunocompromised animals to assess the potential of ectopic tissue formation or cell phenotypic stability of CAR-T cells. The engineered T cells are administrated with at least three dose groups (including positive control). Animals are palpated for mass presence weekly and tissues are preserved for histologic and cell detection. The study typically lasts the whole lifespan of the animals.
Other toxicities, such as neurologic toxicity, anaphylaxis, graft versus host disease, and off-target/off-tumor antigen recognition will also be closely monitored during the study.
All of the studies are conducted in a GLP-compliant and IACUC-regulated facility. We are pleased to share our precious experience on CAR-T cell toxicity evaluation with our clients. Our experienced experts will help you design the program that best meet your purpose and expedite your CAR-T cell therapy to clinical trials.
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