Advancements in Melanoma Therapy: Exploring the Potential of TYRP1-TCB and Immunomodulatory Agents

Over the last ten years, checkpoint inhibitors have become key in treating melanoma, highlighting the growing importance of immunotherapy. Despite this, challenges such as treatment discontinuation due to side effects and relapse persist, leaving few options for those who do not respond to CPI. The search for innovative and more potent immunotherapies, especially in combination therapies, is imperative. Although bispecific antibodies like blinatumomab have been approved for blood cancers, their benefits in solid tumors are harder to establish. Melanoma's high T cell presence makes it a prime candidate for synthetic immunity research.

This study introduces a new, potent treatment method involving a T cell-engaging bispecific antibody that targets a melanoma-specific antigen. The TYRP1 antigen, involved in melanin production and overexpressed in over half of metastatic melanoma cases, is the focus of this therapy. The TYRP1-TCB is a 2+1 format bispecific antibody that binds to TYRP1 on cancer cells and CD3 on T cells. Since CD3 bispecific molecules bypass the need for HLA expression or antigen presentation, they can counteract immune evasion, offering a new foundation for improved checkpoint inhibitor therapy combinations.

In vitro results showed TYRP1-TCB's strong ability to eliminate melanoma cells, activate T cells, and stimulate cytokine production with an EC50 range of 30-1500 pM. Preclinical studies with a murine model demonstrated significant efficacy against melanoma that is resistant to anti-PD1 or anti-PD-L1 therapies. The combination with immunomodulatory agents further enhanced the treatment's effectiveness. These findings suggest the potential for clinical trials of TYRP1-targeted CD3 bispecific antibodies in metastatic melanoma patients.

Citation: Nicolini VG, Waldhauer I, Freimoser-Grundschober A, et al. A novel approach to melanoma treatment with TYRP1-TCB and immunomodulatory agents [abstract]. Proceedings of the American Association for Cancer Research Annual Meeting; 2020 Apr 27-28 & Jun 22-24; Philadelphia, PA: AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-389.