Updated clinical efficacy and translational biomarker analysis of tumor infiltrating lymphocyte therapy (LM103) in metastatic melanoma

Background: Tumor-infiltrating lymphocytes (TIL) adoptive therapy has shown clinical efficacy for metastatic melanoma refractory to anti-PD-1 therapy. This phase I clinical trial evaluated the safety and efficacy of TILs (LM103) in advanced Chinese patients (pts) with melanoma, and explored correlative biomarkers. Methods: Pts with metastatic melanoma progressing on standard therapies, had both resectable and measurable tumors were eligible to be enrolled. Pts received a lymphodepletion regimen before the intravenous autologous LM103 infusion and then high dose IL-2 for 6 doses (200000IU/Kg, 1 dose per day) to support T cell survival and proliferation. Primary endpoint was safety; secondary endpoints included efficacy and translational analysis. Results: Fourteen pts (4 males; aged 26-70 yrs) were enrolled: 5 acral, 4 cutaneous, 4 mucosal, and 1 unknown primary. Infused autologous TIL contained 3.58-19.47x10^ 10 viable cells. The most frequent treatment-emergent adverse events (TEAEs) were myelosuppression (100%), fever (85.7%), rash (71.4%), and alopecia (71.4%). Grade 3-4 TEAEs included leukopenia (85.7%), neutropenia (78.6%), lymphopenia (78.6%), fever (71.4%), thrombocytopenia (57.1%), and anemia (28.6%). The ORR and DCR per RECIST v1.1 were 35.7% and 85.7%, respectively. With a median follow-up of 5.51 months, the median PFS and OS were 4.52 months (95% CI, 2.07 to 14.31) and 16.58 months (95% CI, 5.16 to NA), respectively. Immunofluorescence analysis and whole-exome sequencing for the baseline tumors did not reveal any significant difference in the infiltration of multiple immune cell populations and tumor mutation burden, respectively, between responders (Rs) and non-responders (NRs). T cell receptor-sequencing (TCR-seq), flow cytometry analysis and ELISA were performed for the TIL infusion products and the peripheral blood of patients at various time points before and after infusion. The frequency of shared T cell clones between TIL infusion products and post-infusion peripheral blood maintained >60% till 6 month after infusion, indicating that LM103 TILs persisted well in vivo . The frequencies of dominant T cell clones of infused TILs were higher in Rs than in NRs, implying a correlation between TILs persistence and clinical outcome. In addition, the IFN-gamma level in the peripheral blood at Week 6 of NRs was significantly higher than that of Rs while other cytokine (such as TNF-alpha, IL-2, TGF-beta1 etc) levels were similar between these two groups. Percentage of CD3+, CD4+ or CD8+ T cells in the peripheral blood was also not significantly different between R and NRs. Conclusion: LM103 TIL therapy demonstrated manageable safety and encouraging efficacy in treatment-refractory melanoma. Clinical response correlated with the persistence and expansion of infused TIL clones, instead of baseline tumour features. Trial registration number: CTR20233999.