Combined Therapy of CTLA-4 and 4-1BB

Introduction to CTLA-4 and 4-1BB

In recent years, immune checkpoint molecules, a variety of stimulatory or inhibitory regulators, can be found on many immune cells, such as T cells and B cells. Nowadays, immunotherapy targeting different immune checkpoint proteins has been generated for treating various types of human diseases. Among them, approved cancer immunotherapy targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can reverse T cell exhaustion and enhance stronger immune responses in the tumor microenvironment (TME).

Given the great clinical successes targeting CTLA-4, other immune checkpoints have been widely studied for selecting more suitable Treg targets. 4-1BB, a co-stimulatory receptor, plays an important role in boosting T cell-mediated immune responses on both the innate and adaptive immune arms. The expression level of 4-1BB can unregulated on effector T cells after activation. Also, The unique ability of 4-1BB to enhance robust effector responses in a variety of tumor immune-related lymphocyte subsets makes it a uniquely attractive target for immunotherapy. Therefore, a series of novel therapeutic approaches combining antibodies to target co-stimulatory receptors, like 4-1BB, has been designed for augmenting antitumor effector functions.

Fig.1 Current and emerging targets for therapeutic modulation of the anti-tumor immune response. (Vilgelm, 2016)

Combined Therapy of CTLA-4 and 4-1BB

In the past few decades, immune checkpoint therapy with monoclonal antibodies targeting CTLA-4 has shown promising data in the treatment of many cancer types. However, not all patients can respond to this therapy. Numerous data have indicated that combining immunotherapies targeting immune checkpoints with co-stimulatory receptors can greatly attenuate immune responses and prevent autoimmunity. Normally, 4-1BB can be activated and conjugated with TCR signaling pathways to further enhance the proinflammatory and cytotoxic activity of anti-tumor. Recent reports have revealed that combined therapy of CTLA-4 and 4-1BB can produce durable responses and improve the success rate of immunotherapies in clinical use. For example, several mice studies have illustrated an effective therapeutic benefit of combining 4-1BB agonists with the CTLA-4 blockade. The data have suggested that this combined therapy has a synergistic effect on tumor rejection and tumor inhibition.

Besides, combination therapy with anti-CTLA-4 and anti-4-1BB antibodies has been treated in mice with MC38 tumors. The results have indicated that the combination of the two antibodies can trigger long-time immune responses and lead to CD8 T-cell-mediated tumor rejection. It should be a novel method to simultaneously improve anti-antitumor activity and reduce autoimmunity in TME.

As a global CRO company, Creative Biolabs works on a broad spectrum of immune checkpoint-targeted combined therapy discovery and development services for the treatment of various human disease types. If you want to know more about our services, please feel free to contact us for more information.

Reference

1. Vilgelm, A. E.; et al. Combinatorial approach to cancer immunotherapy: strength in numbers. Journal of leukocyte biology. 2016, 100(2): 275-290.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.