Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients with Pretreated Advanced Melanoma

Pre and post response

Pre and post response

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Summary

The current study focuses on patients with stage III or IV melanoma who have experienced treatment failure with at least one prior line of systemic treatment. DCs were harvested and co- electroporated with TriMix-mRNA and mRNA encoding one of four melanoma-associated antigens linked to an HLA class II targeting signal. The result of the combination of TriMixDC-MEL and ipilimumab is tolerable and leads to an encouraging rate of highly durable tumour responses in patients with pretreated advanced melanoma.

Introduction

39 patients ages 18 years; with histologically confirmed, unresectable, stage III or IV melanoma with measurable disease, who experienced treatment failure with at least one prior line of systemic treatment. WHO performance status of 0, 1, or 2; normal hematologic, liver, and renal function tests; and negative serologic tests for HIV, syphilis, hepatitis B, and hepatitis C

Methodology

TriMixDC-MEL Production
Immature DCs were generated by culturing monocytes in the presence of 1% autologous plasma, granulocyte- macrophage colony-stimulating factor (GMC-SF), and IL-4. After leukapheresis, monocytes were enriched by plastic adherence. On day 6, DCs were harvested and co- electroporated with TriMix-mRNA (CD40L-, CD70-, and caTLR4-encoding mRNA) and mRNA encoding one of four melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, or
gp100) linked to an HLA class II targeting signal. After electroporation, the four different TriMixDC-MEL cellular constituents were mixed at equal ratios and cryopreserved. DCs were thawed 2 to 3 hours before injection.

Treatment

Eligible patients received ipilimumab intravenously (IV) at a dose of 10 mg/kg over a period of 90 minutes once every 3 weeks for four doses. One hour after the end of the ipilimumab administration, TriMixDC- MEL was administered intravenously (20×106 DCs) and intradermally (4×10 DCs). In the first 18 patients, one TriMixDC-MEL administration was performed 2 weeks before combined administration with
ipilimumab.

Results

Safety
Grade 2 TriMixDC-MEL dermal injection site reactions were observed in all patients. Chills (grade 1 to 2) occurring within the first hour after intravenous infusion of TriMixDC-MEL occurred in 38% of patients, and mild flu-like symptoms (within the first 72 hours after infusion) occurred in 85% of patients. A total of 14 patients (36%) developed treatment-related grade 3 or 4 AEs. Allimmune-related AEs were managed using established treatment algorithms. Grade 1 to 2 dermatitis (diffuse itching, erythema) was the most frequent AE and was reported by 64% of patients. Systemic corticosteroids were required to manage immune- related AEs in 18 patients (46%). No treatment-related deaths occurred. Treatment-related AEs were completely reversible in all patients except for hypopituitarism requiring continued hormonal substitution in all affected patients.

Tumor Response and Duration of Response
The investigator-assessed best ORR by irRC was 38%, including eight patients (20%) with a complete response (CR) and seven patients (18%) with a partial response (PR). Seven of the eight complete responses and one of the seven partial responses were ongoing at the time of this analysis. Median follow-up time for patients with an ongoing response is 36 months (range, 22 to 43 months). Tumor responses occurred by an atypical pattern in four patients (10%). An additional six patients (15%) experienced stable disease that persisted for a median of 9.5 months (range, 5 to 20 months).

Over-all Survival and Progression-fee Survival
The disease control rate (DCR) at 6 months was 51% (95% CI, 36% to 67%). At the time of data analysis, a total of 31 patients (79%) had been diagnosed with progression of disease. The estimated median PFS was 27 weeks (95% CI, 9 to 44 weeks). The 1-year, 2-year, and 3-year PFS rates were 33% (95% CI, 18% to 48%), 22% (95% CI, 9% to 36%), and 18% (95% CI, 5% to 31%), respectively. The median follow-up time for the 14 surviving patients was 157 weeks (range, 72 to 185 weeks). The estimated median OS was 59 weeks (95% CI, 40 to 79 weeks). The 1-year, 2-year, and 3-year OS rates were 59% (95% CI, 43% to 74%), 38% (95% CI, 23% to 53%), and 34% (95% CI, 19% to 50%), respectively.

Conclusion

The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma.

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Scientific article publishing date : 20/4/2016

Immucura identifier : BSC21_047EN

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