CER mechanism of action
CERs are unique, genetically engineered, multifunctional proteins comprising extracellular, transmembrane, and intracellular domains that are linked to induce target-specific anti-tumor effects.
The CER construct is designed to be multifunctional
- The CER T cell’s phagocyte receptor component binds to the stress-induced ligand on tumor cells
- Binding to the stress ligand mediates capture and uptake of tumor cell fragments.
- The transmembrane domain links the receptor to intracellular domains.
- The APC-like intracellular domain allows for enhanced processing and presentation of tumor-specific antigens, which is expected to amplify the body’s endogenous adaptive T-cell response against the tumor.
- The intracellular signaling domain(s) activate T-cells, leading to cytotoxic killing of the targeted tumor
First-generation CER T cells target tumor-specific stress ligands
Our first-generation CER T cells employ a naturally occurring phagocyte receptor that binds to the phospholipid phosphatidylserine (PS) externalized on the surface of stressed or damaged tumor cells. PS normally is present on the inside of a cell’s plasma membrane, but shifts to the external leaflet in pathologic settings such as in transformed or virally infected cells, or under stress conditions. Tumor-targeting cytotoxic agents can also further induce PS exposure on tumor cells. The activated CER T cell then synergizes with the cytotoxic agent to induce and enhance anti-tumor effects.
CER T cells are designed to have a dual mechanism of action
CER-T cells function at the interface of the innate and adaptive immune systems, making them uniquely suited for cancer immunotherapy. Binding of the CER induces phagocyte-like engulfment activity of the CER T cell via tumor-agnostic stress ligands. The intracellular domains of the CER have the capacity to induce the complementary effects of
- Direct tumor killing mediated by CER T cells
- Secondary endogenous immune responses through APC-like presentation of tumor-associated antigens
Thus, CERo’s technology has the potential to overcome major barriers to successful adoptive cell therapy by (a) enhancing T cell antigen processing and presentation (b) improving tumor cell clearance and (c) overcoming tumor heterogeneity.
With respect to tumor-associated barriers, drug-inducible stress ligands, unlike protein antigens, are not under genetic control. Thus, tumor heterogeneity in terms of target expression, which can lead to escape of target-negative cells, is unlikely to be a cause of relapse with CER T-cell therapy.
CER T cells also have the potential to overcome tumor microenvironmental immune suppression. One mechanism by which tumor cells escape immune surveillance is by disabling the process of tumor antigen uptake, processing, and presentation, resulting in poor cytotoxic anti-tumor immune responses. The additional APC-like activity of CER T cells has the capacity to prime tumor-specific cytotoxic T cells, leading to a robust secondary immune response sufficient for tumor eradication. Indeed, studies have shown that infiltration of T cells, especially CD8 T cells into tumor microenvironment, correlates with better prognosis in multiple malignancies such as lymphoma, breast, lung, melanoma, colorectal, and brain cancer.