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

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 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.

Conflict of interest statement

Conflicts of Interest: None

DECLARATION OF INTERESTS: CAK reports personal fees from Cell Design Labs and Obsidian Therapeutics unrelated to the submitted work. The other authors declared no conflicts of interest.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. In vitro assessment of autologous tumor reactivity found within TIL infusion

(A.) Frequency of tumor-reactive T cells within the TIL infusion product as determined by the sum of the flow cytometric measurements of the T cell activation markers, OX40 (CD134) on CD4+ T cells and 4-1BB (CD137) on CD8+ T cells following overnight co-culture with cryopreserved autologous tumor digests. Percentages represent mean of triplicate cultures. (B.) Tumor induced IFN-γ production by TIL as determined by ELISA of the supernatant following overnight co-culture with cryopreserved autologous tumor digests minus the background seen against autologous APCs (negative control). IFN-γ values represent the mean of triplicate cultures. (*) indicates undetectable levels based upon the sensitivity of the respective assays. N/A indicates data not available due to insufficient quantities of cryopreserved tumor targets.

Figure 2. Clinical responses in metastatic uveal melanoma patients after TIL therapy

(A.) Waterfall plot demonstrating the maximum percentage decrease in the sum of the reference diameters of the target lesions from baseline to nadir, as assessed by the investigator. Data are shown for patients who underwent at least one tumor assessment after treatment (n=20). Orange bars specify patients who had not responded after receiving prior immune checkpoint blockade; blue bars indicate patients who had not received prior immune checkpoint blockade. The horizontal dashed lines indicate a 30% reduction in the tumor burden in the target lesions (the cut-off for objective response by RECIST criteria). Each of the patients achieving ≥ 30% reduction were confirmed responders by RECIST criteria. The percentage increase was truncated at 100%. ‘+’ indicates ongoing response at time of report. (B.) Spider plots depicting pattern of changes in cumulative target lesion size over time for each patient (n=20) after TIL therapy.

Figure 3. Association between clinical response and pre-treatment TIL reactivity

TIL administered to responding (R, n=5) and non-responding (NR, n=12) patients were compared based upon their (A.) frequency of tumor-reactive T cells, (B.) absolute numbers of infused tumor-reactive T cells, and (C.) levels of IFN-γ release after autologous tumor stimulation. Each dot represents an individual infused TIL product that underwent reactivity testing. Exploratory in vitro criteria defining TIL with sufficient (orange shading) and insufficient (blue shading) anti-tumor reactivity are shown. Statistical comparisons were performed with the Wilcoxon rank-sum test. P values are 2-tailed, but have not been adjusted for multiple comparisons. Bar denotes median value.