Promising Response To Autologous TIL Infusion In Metastatic Uveal Melanoma

Tumour-infiltrating lymphocyte therapy can lead to tumour regression in patients with metastatic uveal melanoma

medwireNews: The adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could be a promising therapeutic option for patients with metastatic uveal melanoma, suggests an interim analysis of a phase II trial.

As reported in The Lancet Oncology, 35% of 20 evaluable patients who received an autologous TIL infusion achieved a response according to the RECIST criteria.

Of the responders, one had a complete response, including regression of multiple hepatic metastases, which, at the time of data cutoff, was ongoing at 21 months. The other six achieved a partial response, with two responses ongoing at 4 months and the remainder ranging from 3 to 9 months.

Furthermore, three of the responders were “highly treatment-refractory” having progressed after treatment with immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1, says the team from the National Cancer Institute in Bethesda, Maryland, USA.

The trial results shows that this immunotherapeutic modality can elicit clinical responses in patients with metastatic uveal melanoma, “a cancer that currently has no standard effective treatments”, write Udai Kammula and co-researchers.

They continue: “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.”

The authors of a related commentary describe the findings as “intriguing”, but highlight that overall response rate “is not an established surrogate for progression-free or overall survival in uveal melanoma and must be interpreted with caution.”

Due to the small sample size, the results “must be considered preliminary, requiring confirmation in a larger patient population”, they say, adding that “[f]urther long-term data on durability of disease control and survival outcomes in uveal melanoma will be critical in assessing the clinical efficacy of TIL therapy in this population.”

Nonetheless, the commentators Kimberly Komatsubara and Richard Carvajal, both from Columbia University Medical Center in New York, USA, believe that “these data provide important evidence that the immune system can be harnessed to treat uveal melanoma and serves to identify adoptive transfer of TILs as a high-priority avenue of further research for patients with this disease.”

 

In the first part of the two-stage trial, 27 patients with metastatic uveal melanoma underwent metastasectomy to provide tissue for generating TILs, but six did not receive treatment due to insufficient TIL expansion, inadequate in vitro antitumour activity or ineligibility for protocol-defined therapy. An additional patient was recruited in the expansion stage, which was initiated after the initial efficacy endpoint was met, and was included in the current analysis.

In all, 21 participants received one cycle of a nonmyeloablative lymphodepleting conditioning chemotherapy regimen comprising cyclophosphamide 60 mg/kg daily for 2 days followed by fludarabine 25 mg/m2 daily for 5 days. This was followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 (720,000 IU/kg) every 8 hours.

Udai Kammula et al observed no acute toxicities related to the TIL infusion, while toxicities attributable to interleukin-2 were “generally mild” and resolved quickly.

However, all patients experienced transient haematological side effects of grade 3 or worse, including lymphopenia, neutropenia and thrombocytopenia, which they say “were anticipated from the lymphodepleting chemotherapy regimen.”

Infections were recorded in 29% of patients – these were generally low grade and resolved after immune reconstitution, except in one case where the patient died as a result of sepsis-induced multiorgan failure after contracting severe respiratory syncytial virus pneumonia, the team reports.

References

Chandran SS, Somerville RPT, Yang JC, et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol; Advance online publication 7 April 2017. doi: http://dx.doi.org/10.1016/S1470-2045(17)30251-6

Komatsubara KM, Carvajal RD. Adopting a new stance on immunotherapy for uveal melanoma. Lancet Oncol; Advance online publication 7 April 2017. doi: http://dx.doi.org/10.1016/S1470-2045(17)30254-1

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