HiCAR Construction Service

All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

Equipped with state-of-the-art facilities and experienced immunology experts, Creative Biolabs has expanded its service capabilities to offer a fully integrated HiCAR construction service. This new platform will accelerate the timeline for cell and gene therapy development to best suit your program requirements.

Background of HiCAR technology

Chimeric antigen receptors (CAR) T cell therapy has generated exciting anticancer activities in recent years. Although the technology has achieved considerable progress in clinical cancer immunotherapy, which has also raised concerns associated with the "on-target off-tumor" effect, especially in healthy tissues expressed low level targeted antigen.

An attractive strategy to distinguish healthy tissue from cancer cells would be to dependent on key characters of the tumor microenvironment (TME). TME has been relevant to several conditions, such as, nutrient depletion, low extracellular pH (acidosis), and low oxygenation (hypoxia). Particularly, hypoxic microenvironment is a hallmark of the tumor microenvironment, often with < 1-2% oxygenation levels. Therefore, hypoxic microenvironment could as an advantage to boost CAR-T cell technology development to improve discrimination between tumoral and healthy tissues.

Creative Biolabs has developed a HiCAR technology platform. In which design require both antigen-recognition and hypoxia sensing to generate optimal T cell activity, thereby reducing on-target off-tumor toxicity. This design, using the oxygen-dependent degradation domain (ODD), can be especially useful for targeting common antigens presented by normal and neoplastic tissues.

Mechanism of HiCAR technology

Under the normoxic environment within normal tissues, HiCAR-engineered T cells maintain minimal surface CAR expression using the ubiquitination-proteasome degradation pathway. Hypoxia is a common hallmark of multiple solid tumors, and an increase in surface CAR presentation is shown on these engineered T cells when they are exposed to hypoxia within solid tumors. The insertion of a hypoxia-responsive element (HRE) upstream of a lentiviral vector promoter containing the HiCAR construct enhances the surface CAR expression to increase cytolytic potency under hypoxia.

Fig.1 Schematic diagram of the working principle of HiCAR.

As an approach that takes advantage of environmental signal integration within a CAR design, HiCAR sensors are prone to rapid switch-down, which would protect distant healthy tissues. Besides providing additional levels of safety by minimizing "on-target/off-tumor" effects, HiCAR can also expand the number of surface antigens available for therapeutic purposes.

Creative Biolabs' scientists are dedicated to bringing together years of valuable experience to help our clients shorten the clinical study journey. We are committed to providing HiCAR platform to reducing the overall project development timeline for our clients. For further details, please don't hesitate to contact us and see how we can help you reach your clinical vision.

References

Juillerat A, Marechal A, Filhol J M et al. An oxygen sensitive self-decision making engineered CAR T-cell. Scientific Reports. 2017, 7:39833.
Liao Q B, He H, Mao Y et al. Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing. Biomarker Research. 2020, 8:56.