优化葡萄膜黑色素瘤的 TIL 治疗：从皮肤黑色素瘤中习得与未习得的经验教训

Adoptive transfer of tumor infiltrating lymphocytes (TIL-ACT) is a personalized cancer therapy that harnesses the anti-tumor activity of tumor resident T cells through ex vivo activation and expansion. This therapy involves the infusion of a single dose of ex vivo expanded TIL together with high dose IL-2 following a preparative lymphodepleting chemotherapy.

The United States Food and Drug Administration approved lifileucel in 2024 as the first autologous TIL product for patients with advanced cutaneous melanoma (CM), adding to the list of approved immunotherapies for this highly immunogenic cancer.

However, the role for TIL-ACT in other solid tumors is unclear, especially for poorly immunogenic cancers with low tumor mutational burden. In this review, we describe the historical development of TIL-ACT, summarize the clinical results in advanced CM, and describe the novel application of TIL-ACT to metastatic uveal melanoma (UM), a prototypic immunotherapy-resistant solid tumor.

We will highlight key biologic differences between CM and UM, their consequential influence on the manufacturing of UM-specific TIL products, and the development of novel biomarkers for precision TIL-ACT for metastatic UM. What is this review article about? Adoptive transfer of tumor infiltrating lymphocytes (TIL-ACT) is a personalized immunotherapy that was recently approved by the United States Food and Drug Administration for treatment of refractory advanced cutaneous melanoma (CM), a notably immunogenic cancer.

However, its role in the treatment of poorly immunogenic solid tumors is unclear.

Here, we describe the development of TIL-ACT for treatment of metastatic uveal melanoma (UM), a prototypic poorly immunogenic cancer. What are the major findings? Unlike CM, UM is resistant to immune checkpoint inhibition (ICI).

However, studies have revealed that most UM metastases naturally harbor TIL with potent autologous anti-tumor reactivity. Ex vivo expansion and intravenous infusion of these TIL can mediate cancer regression in 35% of metastatic UM patients, including ICI refractory individuals.

These findings establish that potent immune cells do exist within select UM metastases and that they can be exploited using TIL-ACT but not other forms of immunotherapy. Biomarkers enabling identification of UM-specific TIL are being developed to improve personalized TIL-ACT for UM patients.

How will this have broad impact in the field of immunotherapy? Development of TIL-ACT for metastatic UM provides novel therapeutic options for this cancer with unmet medical need. These translational efforts may serve as a blueprint for the treatment of other immunotherapy-resistant cancers.