Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Multifunctional T Cell

Multifunctional T Cell

CONTACT US

Summary

Before this study, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro–generated monocyte-derived dendritic cells. This means that cells undergo an extensive in vitro manipulation. This clinical study aims to show the efficacy of primary CD1c+ myeloid dendritic cells, which are naturally circulating in the blood. The dendritic cell therapy was carried out on fourteen stage IV melanoma patients. The results of this trial show that therapeutic vaccination against melanoma with small amounts of myeloid dendritic cells is feasible and without substantial toxicity growth.

Introduction

Fifteen metastatic melanoma patients stage IV or irresectable stage IIIc (according to the 2009 American Joint Committee on Cancer staging system) were enrolled in this phase I/II feasibility study. One patient was excluded from analysis due to a protocol violation; the patient did not meet an inclusion criterion.

Eligibility criteria included a measurable target lesion, HLA-A0201 phenotype, histologically documented melanoma expressing gp100 (compulsory) and tyrosinase (non-compulsory), no serious active infection or immunosuppressive conditions, serum LDH concentration within normal limits, and WHO performance status 0 or 1.

Methodology

MDCs were directly isolated from apheresis products using the fully closed immunomagnetic CliniMACS isolation. After apheresis and CliniMACS isolation, mDCs were cultured overnight (16 hours) at a concentration of 106 cells/mL in X-VIVO-15 containing 2% pooled human serum, supplemented with 800 U/mL recombinant human GM-CSF and 1 mg/mL keyhole limpet hemocyanin (KLH) for immunomonitoring.

This procedure gave rise to mature mDCs meeting the following release criteria: more than 50% viability, high expression of MHC class I, MHC class II, CD83, and CD86. Part of these mDCs were directly loaded with the melanoma-associated HLA-A0201–restricted peptides gp100154-162 (KTWGQYWQV), gp100280-288 (YLEPGPVTA), and tyrosinase369-377 (YMNGTMSQV) for the first vaccination, which was given directly after the peptide loading.
The remainder of the mDCs was frozen with 10% DMSO for subsequent vaccinations or DTH. Upon subsequent vaccinations/DTH, frozen mDCs were thawed and loaded with the melanoma- associated peptides. The peptide-loaded mDCs were administered intranodally in a clinially tumor-free lymph node under ultrasound guidance.

Treatment

Patients were vaccinated with autologous mDCs loaded with HLA-A0201–binding tumor peptides derived from the melano- ma-associated antigens gp100 and tyrosinase. The first patient received a maximum of 3×106 mDCs per vaccination, patients 2 and 3 received maximally 5×106 mDCs per vaccination, and patients 4 and 5 received maximally 10×106 mDCs per injection. Three subsequent intranodal injections were given once every two weeks followed by a DTH challenge.The peptide-loaded mDCs were administered intranodally in a clinically tumor-free lymph node under ultrasound guidance.

Results

MDC vaccination induces anti-KLH responses in metastatic melanoma patients

For immunomonitoring purposes and to provide CD4+ T-cell help, all DCs have been loaded with the control antigen KLH. PBMCs, isolated after each vaccination, showed increased proliferation upon stimulation with KLH after the first cycle of vaccinations in 11 of 13 patients, indicating that the vaccine effectively induced de novo immune responses in these patients. We also followed the levels of serum anti-KLH antibody after each cycle of vaccinations. In 4 of 13 patients, anti- KLH IgG could be detected. Patient VI-B-01 showed a clear IgG response after the second cycle of mDC vaccinations, which coincided with the presence of anti-KLH IgA. Anti-KLH IgM was not detected.

Clinical responses

Five patients showed at least stable disease upon the first vaccination cycle (7, 12, 15, 18, and 35+ months duration, respectively) and were therefore eligible for an additional vaccination cycle consisting of another three mDC vaccinations. In two of these patients, disease progression occurred after the second vaccination cycle. The three remaining patients also received a third cycle of three mDC vaccinations, of which one M1a, one M1b, and one M1c patient.

All patients were evaluated for clinical response at 3-month intervals with CT scans. Two patients showed objective tumor responses, which coincided with the presence of functional T cells in peripheral blood and DTH skin tests. CT scans of patient VI-B-13 showed evident regression of pulmonary and mediastinal nodal metastases already after one cycle of DC vaccinations, which converted into a complete response after the second cycle of DC vaccinations. The patient is in ongoing complete remission and good clinical condition 35 months after initiation of vaccinations with mDCs.

Conclusion

In conclusion, this showed that vaccination of metastatic melanoma patients with primary mDC is feasible and safe and results in the induction of effective antitumor immune responses that coincide with improved progression-free survival.

Article Reference link: click here

Scientific article publishing date : 28/12/2015

Immucura identifier : BSC21_044EN

ALL SCIENTIFIC PAPERS
CONTACT US