Practice Update

Adoptive transfer of tumor-

infiltrating lymphocytes for metastatic

uveal melanoma

The Lancet Oncology

Take-home message

•

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

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

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.

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.

MELANOMA

VOL. 1 • NO. 2 • 2017