Practice Update | Onology

MELANOMA 23

Adoptive transfer of tumor- infiltrating lymphocytes for metastatic uveal melanoma The Lancet Oncology Take-home message

These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune- based therapies for this cancer.

• In this ongoing phase II trial, 21 patients with metastatic ocular melanoma were treated with autologous tumor-infiltrating lymphocytes (TILs). Based on RECIST criteria, 1 of 20 evaluable patients achieved a complete response and 6 patients achieved a partial response, including 2 who have not yet achieved a maximum response. Prior to immune checkpoint blockade, 3 of the responders were refrac- tory. Common toxic events (grade ≥3) included neutropenia, lymphopenia, and thrombocytopenia (100% of patients for all three toxicities); anemia (67%); and infection (29%). Sepsis-induced multiorgan failure resulted in 1 treatment-related death. • In patients with metastatic uveal melanoma, tumors regressed after the adoptive transfer of autologous TILs, which suggests metastatic uveal melanoma is not resistant to immunotherapy and that additional research is warranted.

Abstract BACKGROUND Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular vari- ants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autol- ogous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma. METHODS In this ongoing single-centre, two- stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed met- astatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Coopera- tive Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to pro- cure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m(2)] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose inter- leukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. FINDINGS From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal mela- noma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16–59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial

autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immu- notherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol 2017 Apr 07;[EPub Ahead of Print], SS Chandran, RP Somerville, JC Yang, et al.

response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lym- phopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death second- ary to sepsis-induced multiorgan failure. INTERPRETATION To our knowledge, this is the first report describing adoptive transfer of

VOL. 1 • NO. 2 • 2017