UCLA researchers in the Departments of Surgical Oncology and Microbiology, Immunology, & Molecular Genetics. have developed a CAR-T therapy that targets TYRP-1 for the treatment of melanoma.
BACKGROUND: Immune checkpoint blockade (ICB) is a rapidly emerging immunotherapy approach that uses patients’ immune cells to treat cancer. In contrast to conventional methods like small molecule chemotherapeutics, or more extreme measures like targeted surgery, ICB relies on the ability of the immune system to very specifically recognize tumor cells. Unfortunately, while ICB in melanoma leads to durable responses in a fraction of patients, most patients still do not respond to these therapies or relapse after treatment. A potential alternative approach are Chimeric Antigen Receptor (CAR) T-cell therapies. CARs are artificial receptors that have been engineered to give T cells the ability to target a specific antigen on cancer cells. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor: effectively retaining their initial specificity. While remarkable responses have been obtain for the treatment of leukemia and lymphoma, treatment of solid tumors remain still a challenge, in part due to the lack of suitable targets. Therefore, an ongoing need exists to develop CAR-T cell therapies that are specific for tumor-associated antigens that display low expression in otherwise healthy tissue: creating a highly tumor-specific CAR T-cell therapy with low potential toxicity.
INNOVATION: Drs. Cristina Puig-Saus, Antoni Ribas, and Yvonne Chen have developed a CAR-T therapy that targets Tyrosinase-related protein 1 (TYRP-1) for the treatment of melanoma. Utilizing modular DNA assembly and high-throughput characterization methods, the researchers have developed a panel of CARs with varying targeting efficiencies in response to TYRP-1: allowing the selection of the ideal construct that achieves therapeutic efficacy while avoiding potential toxicity against healthy tissue. Researchers further demonstrated that TYRP-1 CAR-T cells could effectively target a variety of patient-derived and murine melanoma cell lines with high levels of TYRP-1 expression, sparing normal cells with lower antigen expression. As a proof of principle study for the clinical relevance of the derived CAR treatment, researchers found that TYRP-1 CAR-T cells can exert tumor control and elimination on established murine melanoma models (e.g., B16-F10), without observed toxicity. Similarly, the TYRP1 CAR-T cell therapy leads to tumor control and elimination in patient-derived tumors models of cutaneous, acral, and uveal melanoma in mice. Therefore, the proposed CAR-T cell therapy utilizing TYRP-1 targeting may present a practical pathway to the more widespread adoption of T cell therapies for melanoma treatment.
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DEVELOPMENT-TO-DATE: The study has been validated in a panel of patient-derived cutaneous, acral, mucosal, and uveal melanoma cell lines in vitro and in vivo in immunodeficent mice showing complete tumor elimination in the majority of tumor models. In addition, the treatmentshowed efficacy in treating B16-F10 melanoma in immunocompetent mice. An FDA pre-IND was successfully held and IND submission is planned for October 2025.
Related Papers (from the inventors only): Jilani S, Saco JD, Mugarza E, Pujol-Morcillo A, Chokry J, Ng C, Abril-Rodriguez G, Berger-Manerio D, Pant A, Hu J, Gupta R, Vega-Crespo A, Baselga-Carretero I, Chen JM, Shin DS, Scumpia P, Radu RA, Chen Y, Ribas A, Puig-Saus C. CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes. Nat Commun. 2024 Feb 9;15(1):1244. doi: 10.1038/s41467-024-45221-2. PMID: 38336975; PMCID: PMC10858182.
KEYWORDS: Adoptive cell transfer, chimeric antigen receptor, CAR, ACT, melanoma, cell therapy, gene therapy, immunotherapy