Combined Therapy of CTLA-4 and GITR

Introduction to GITR

Glucocorticoid-induced TNFR-related (GITR) is a member of the tumor necrosis factor receptor superfamily (TNFRSF) that plays a critical role in regulating immune response and inflammation. In particular, GITR is a type I transmembrane glycoprotein that is composed of two extracellular domains, a transmembrane domain, as well as two cytoplasmic domains. The PEEE motif of GITR can bind with the TNF receptor-associated factors (TRAF) and trigger the activation of NF-κB pathways. GITR can be expressed on a variety of cells or tissues, such as T cells and natural killer (NK) cells. Moreover, GITR is involved in the activation of MAPK-pathway and the proliferation of CD4⁺ CD25⁺ regulatory T cell (Treg).

Currently, pilot studies have shown that GITR can be up-regulated on any activated T cells in humans, making this a potential surface T cell marker. As a result, a wide battery of immunotherapies targeting GITR agonist antibodies or natural ligands has been generated for treating various tumors. For instance, the safety profile and anti-tumor activity of the anti-GITR antibody have been tested in mice with melanoma. It provides mechanistic preclinical evidence to rationally combine GITR agonism with other immune-checkpoint therapies in future clinical use.

Combined Therapy of CTLA-4 and GITR

In many kinds of tumor models, tumor-infiltrating regulatory T cells can suppress T-cell-mediated immune responses and both can express cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and GITR. As an attractive target for immunotherapy, the mechanisms of action of these CTLA-4 blockades and the preclinical or clinical evidence of antitumor activity have been used and approved in different cancer treatments. However, recent reports have revealed that the therapeutic effect of CTLA-4-based therapy is still relatively low or incomplete in the treatment of certain tumor types. Fortunately, the validation of GITR as an additional pathway of immune modulation has been broadly studied. Numerous data have suggested that GITR can enhance effector T cell functions and inhibit Treg suppression, which can further compensate for the lack of CTLA-4-mediated therapy.

Therefore, the combined therapy of CTLA-4 and GITR has been reported and has exhibited a stronger recovery of T cell function compared with either monotherapy. For example, CTLA-4-blockade and a combination of GITR-ligation therapy have been developed and evaluated on mice models of liver cancer. The results have indicated that mice treated with this combined therapy can enhance the activation of T cells and have stronger antitumor immune responses. Also, the combined therapy with monoclonal antibodies targeting immune checkpoint CTLA-4 and GITR has shown safety and efficacy in different pre-clinical tumor models.

As a consequence, Creative Biolabs works on a wide spectrum of combined immune checkpoint therapy development services for preventing or treating many human disease types. In particular, we have established an advanced novel immune checkpoints discovery platform that enables us to offer a series of high-quality candidate targets for drug development. Please do not hesitate to contact us for more information.

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