Elsevier

The Lancet Oncology

Volume 18, Issue 6, June 2017, Pages 792-802
The Lancet Oncology

Articles
Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study

https://doi.org/10.1016/S1470-2045(17)30251-6Get rights and content

Summary

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 variants 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 autologous 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 metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure 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/m2] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-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. The trial is registered at ClinicalTrials.gov, number NCT01814046.

Findings

From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma 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 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 lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure.

Interpretation

To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. 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. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality.

Funding

Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Introduction

Uveal melanoma is the most common primary malignancy arising within the adult eye. Overall, however, this is a rare cancer with an annual incidence of about six per million in the USA, accounting for 3·7% of all melanomas.1 These tumours originate within the pigmented uveal tract (which includes the choroid, ciliary body, and iris) and are notable for characteristic cytogenetic changes,2 oncogenic mutations in GNAQ or GNA11,3, 4 and an unusual predilection to aggressively metastasise to the liver, resulting in a dismal prognosis.5 Although a variety of immune-based therapies have shown efficacy in metastatic melanoma of cutaneous origin,6, 7, 8, 9, 10 their use in uveal variants has been disappointing.11, 12, 13, 14, 15, 16, 17, 18, 19, 20 These findings have led to speculation that melanomas arising within the eye might represent an immunotherapy-resistant variant.21

Recently, we discovered an immunogenic subset of uveal melanoma based on in-vitro reactivity profiling of tumour-infiltrating lymphocytes (TILs) isolated from freshly resected liver metastases.22 In the present study, we sought to determine if adoptive transfer of such TILs could mediate cancer regression in patients with metastatic uveal melanoma, especially after previous immunotherapy failure. Adoptive T-cell therapy using autologous TILs has been reported to induce salvage responses in a variety of refractory solid tumours23, 24 with durable and complete regression in patients with metastatic cutaneous melanoma.8 However, the efficacy of TIL therapy in patients with uveal melanoma has not been formally investigated. Here we report, to our knowledge, the first clinical and immunological findings after adoptive TIL transfer in patients with metastatic uveal melanoma.

Research in context

Evidence before this study

Before undertaking this study, we searched PubMed without date restrictions with the terms “metastatic uveal melanoma” and “immunotherapy” for articles published in any language. Although a variety of immune-based therapies have been efficacious in patients with metastatic cutaneous melanoma, their use in uveal melanoma has been disappointing. Recent reports evaluating immune checkpoint blockade therapy via anti-CTLA-4, anti-PD-1, and anti-PD-L1 have cumulatively shown limited efficacy in patients with metastatic uveal melanoma. These findings have led to speculation that melanomas arising from the uveal tract might be an immunotherapy-resistant variant. There are no published reports investigating the efficacy of adoptive transfer of tumour-infiltrating lymphocytes (TILs) in metastatic uveal melanoma.

Added value of this study

This report describes the largest cohort of patients with metastatic uveal melanoma treated with adoptive transfer of autologous TILs. An interim analysis of this ongoing trial found seven (35%) of 20 evaluable patients had objective tumour regression according to Response Evaluation Criteria in Solid Tumors. One patient achieved complete tumour regression of numerous hepatic metastases, currently ongoing at 21 months post therapy. To our knowledge, this is the first report of the use of TIL transfer to mediate objective tumour responses in patients with metastatic uveal melanoma, including individuals whose disease was refractory to immune checkpoint blockade.

Implications of all the available evidence

Adoptive T-cell therapy using autologous TILs has been reported to induce salvage responses in a variety of refractory solid tumours. This study now shows that this immunotherapeutic approach can also induce clinical responses in patients with metastatic uveal melanoma, a cancer that currently has no standard effective treatments. These initial findings challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer.

Section snippets

Study design and participants

This two-stage phase 2 clinical trial was done in the Surgery Branch of the National Cancer Institute (NCI). The first stage of the study was designed to initially evaluate activity in 19 patients as a basis to determine whether an expansion stage was warranted. To be eligible for the trial, patients had to be aged 16 years or older with a histologically confirmed diagnosis of metastatic ocular melanoma. Given our interest in evaluating the therapeutic response of metastatic melanoma arising

Results

Overall, 27 patients with metastatic uveal melanoma were eligible for the initial and expansion stages of the clinical trial and underwent metastasectomies for the purpose of generating therapeutic TILs (appendix p 2). Large-scale expansion of TILs was possible in 26 (96%) patients. Among the patients with available TILs, five patients did not undergo TIL therapy. Two patients had subsequently become ineligible for protocol therapy (one patient had a new clinically significant cardiac

Discussion

We report the largest cohort of patients with metastatic uveal melanoma treated with adoptive transfer of autologous TILs. We observed that a single infusion of TILs after a non-myeloablative lymphodepleting conditioning regimen could induce objective tumour regression in seven (35%) of 20 patients, including individuals whose disease was refractory to immune checkpoint blockade. One highly pretreated patient showed durable complete regression of numerous hepatic metastases that is ongoing

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