Phenotypic and Functional Characteristics of CD8+ T Cells Predict Clinical Outcome Following TIL Therapy in a...

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is a highly personalized cancer immunotherapy. In the randomized phase III clinical trial [TIL-Netherlands Cancer Institute (NKI)/National Center for Cancer Immune Therapy (CCIT)], TIL therapy significantly improved progression-free survival (PFS) compared with ipilimumab in patients with unresectable stage IIIC and IV cutaneous melanoma. This study aimed to define the phenotypic and functional characteristics of the infused TIL associated with the best overall response (BOR) and PFS.

Using flow cytometry, we profiled infusion products from all 80 patients treated with TILs in the TIL-NKI/CCIT trial and correlated the results with BOR and PFS. We established autologous tumor cell lines from 24 patients and assessed the antitumor reactivity of the infused CD4+ and CD8+ T cells through coculture assays and intracellular cytokine staining. We quantified tumor-reactive TILs relative to baseline tumor volume and monitored their persistence in the peripheral blood for up to 24 months after infusion.

Responding patients received a higher absolute number of CD8+TCRαβ+ T cells than nonresponders (P = 0.0290). The frequency of infusion product CD8+TCRαβ+ T cells was strongly associated with PFS at 6 months (P < 0.0001). The number of tumor-reactive CD8+ T cells infused, normalized to baseline tumor burden, correlated with BOR (P = 0.0352) and PFS at 6 months (P = 0.0007), with sustained peripheral blood persistence of tumor-reactive CD4+ and CD8+ T cells predictive of durable clinical response.

CD8+ T-cell phenotype, tumor reactivity, and in vivo persistence emerged as strong predictors of clinical outcome. Our data identify CD8+ T cells as a key determinant of therapeutic efficacy.