May 14, 2016
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Ipilimumab, cellular therapy show promise for advanced melanoma

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Treatment with autologous monocyte-derived, mRNA-electroporated dendritic cells plus ipilimumab appeared tolerable and produced durable tumor responses in patients with advanced, pretreated melanoma, according to the results of a phase 2 study.

Researchers previously demonstrated that the immune stimulatory capacity of autologous monocyte-derived dendritic cells is enhanced with coelectroporation with mRNA encoding CD40 ligand, CD70, and constitutively activated TLR4, also called TriMix-DC.

TriMixDC-MEL — a mixture of TriMix-DC coelectroporated with one of four melanoma-associated antigens fused to an HLA class II targeting signal — has also shown antitumor activity as a monotherapy in patients with advanced pretreated melanoma, according to study background.

Because ipilimumab (Yervoy, Bristol-Myers Squibb) has improved OS in this patient population and may enhance the effects of TriMixDC-MEL, Bart Neyns, MD, PhD, head of clinic at Universitair Ziekenhuis Brussels, and colleagues evaluated the efficacy of the combination in 39 patients (mean age, 46 years; range, 24-70; 59% men) with advanced pretreated melanoma.

A majority of patients (82%; n = 32) had metastases to visceral sites, including the brain (n = 7). Prior treatments in the cohort included cytotoxic chemotherapy (46%), BRAF inhibitor (51%), MEK inhibitor (7.7%), interferon alfa-2b (18%) and intradermal dendritic cells (10%).

Patients received TriMixDC-MEL (4 x 106 cells administered intradermally plus 20 x 106 administered via IV) plus 10 mg/kg ipilimumab every 3 weeks for up to four administrations.

Patients who remained progression free were assigned to maintenance therapy every 12 weeks.

The 6-month disease rate, determined by immune-related response criteria, served as the primary endpoint.

Median follow-up was 36 months (range, 22-43).

Fifteen patients discontinued treatment during induction due to progressive disease (n = 7) or toxicity (n = 8).

The researchers observed a 6-month disease control rate of 51% (95% CI, 36-67), with an overall tumor response rate of 38%. They observed eight complete responses and seven partial responses.

At the time of reporting, seven complete responses and one partial response remained ongoing.

Twenty-five patients have died, all due to progressive disease. Median OS in the cohort was 59 weeks (95% CI, 40-79), and estimated median PFS was 27 weeks (95% CI, 9-44).

Thirty-six percent of patients experienced grade 3 or grade 4 immune-related adverse events.

The most common any-grade adverse events included local dendritic cell injection site skin reactions (100%), flu-like symptoms (84%), dermatitis (64%), transient post-infusion chills (38%), diarrhea or colitis (15%), hypophysitis (15%) and hepatitis (13%).

No grade 5 adverse events occurred.

Sixteen patients discontinued ipilimumab due to progressive disease (n = 12) or toxicity (n = 4).

“On the basis of our observations, combinations of autologous TriMix-DC therapy and checkpoint inhibitors deserve further evaluation in prospective clinical trials,” Neyns and colleagues wrote. – by Cameron Kelsall

Disclosure: Neyns reports honoraria and institutional research funding from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, and Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.