Co-Stimulatory TNFR Agonism for Cancer Immunotherapy: Past, Current, and Future Perspectives

What is it about?

The article discusses the tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF), which are important regulators of the immune system. Targeting these receptors for immunotherapy is attractive but has been under-exploited. The focus is on co-stimulatory members of TNFRSF, their role in optimal immune response generation, and the rationale behind targeting them for immunotherapy. The efficacy and limitations of currently available agents are discussed, along with the development of next-generation immunostimulatory agents. Pre-clinical studies have shown promising results with agonistic antibodies targeting TNFRSF, but translation to the clinic has been difficult. The article also mentions the success of checkpoint blockade antibodies and the potential for combining these two strategies. The challenge remains to evoke powerful, curative immune responses while avoiding toxicity.

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Why is it important?

The research discusses the importance of targeting the tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) in immunotherapy. These receptors play a crucial role in regulating the immune system, and their targeting has the potential to provide anti-tumor efficacy. Understanding the rationale behind targeting TNFRSF members and the challenges in translating pre-clinical success to clinical application is essential for developing effective treatments. Key Takeaways: 1. TNFFSF and TNFRSF are important regulators of the immune system, influencing proliferation, survival, differentiation, and function of immune cells. 2. Agonistic targeting of co-stimulatory TNFRSF members, such as CD27, OX40, 4-1BB, TNFR2, and GITR, has shown promising results in pre-clinical tumor models, stimulating robust anti-tumor responses. 3. The translation from pre-clinical studies to the clinic has been difficult, with conventional monoclonal antibodies (mAbs) failing to achieve significant response rates or producing toxicity. Combining checkpoint blockade antibodies with TNFR targeting may improve outcomes. 4. New strategies, such as targeted agonism and bispecific agents delivering multiple mechanisms of action with a single agent, hold potential for enhanced success rates in immunotherapy.