A Phase I Clinical Study of Autologous Dendritic Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma

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Summary

In multiple myeloma (MM), cellular immunotherapy is emerging as a potential therapeutic treatment. A potent immunotherapeutic agent (VAX-DC/MM) was made using Dendritic Cells (DCs) with autologous myeloma cells irradiated with ultraviolet B. VAX-DC/MM therapy worked on stabilizing the disease activity in heavily pretreated MM cases and finally, it was well-tolerated.

Introduction

15 patients with relapsed or refractory multiple myeloma with the median age of 62.5 years (range, 47-75 years old) and 5 (41.6%) patients were over 65 years old. According to the International Staging System (ISS), five (41.7%) patients had ISS III, five (41.7%) had ISS II, and two (16.7%) had ISS I at initial diagnosis.

Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

Methodology

After performing leukapheresis to the patients, peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation at 1200×g for 25 min on lymphoprepTM solution.
Monocytes were separated from PBMCs by density gradient centrifugation using percoll® solution and were allowed to adhere to culture flasks. After 30 min, non-adherent cells were removed and adherent cells were culture to generated DCs in serum-free medium, CellGenixTM GMP DC with 50 ng/mL recombinant (rh) GM-CSF and 25 ng/mL rhIL-4. On day 5, CD138+ cells were isolated from bone marrow mononuclear cells of patient with MM using CD138 microbeads, as a tumor antigen, irradiated with UVB, and then incubated overnight at 37oC in humidified 5% CO incubator.
On day 6, the immature DCs were harvested and activated by addition of LPS at 1 μg/mL, polyinosinic:polycytidylic acid [Poly(I:C)] at 20 μg/mL, recombinant IFNα-2a at 3,000 U/mL and IFN-γ at 200 U/mL, and were loaded with UVB-irradiated dying myeloma cells and keyhole limpet hemocyanin (KLH) protein (5 ng/mL) after 2 hours. On day 8, mature DCs were harvested and cryopreserved in liquid nitrogen until used.
For the generation of alpha-type 1-polarized DCs (αDC1s), IL-1β at 25 ng/mL, TNF-α at 50 ng/mL, Roferon®-A at 3000 U/mL, IFN-γ at 1,000 U/mL, and Poly(I:C) at 20 μg/mL were used on day 6.

Treatment

Patients received the intradermal VAX-DC/MM injection every week for 4 weeks. Patients were treated with 5 × 106 or 10 × 106 cells, with nine patients treated at a higher dose. The median time from diagnosis to VAX-DC/MM therapy was 56.6 months (range, 28.5–130.5).

Results

Adverse events
Treatment was generally well-tolerated regardless of cell dose of VAX-DC/MM, and there were no grade 3 or 4 adverse events. The most frequent adverse events were injection-site reactions (12 patients); all were self-limiting and resolved within 1 week. Other common adverse events were myalgia (4 patients), fever (2 patients), and chills (2 patients). Transient grade 1 lymphocytopenia and thrombocytopenia developed in two patients each. Two patients had subclinical hypothyroidism prior to treatment, but VAX-DC/MM therapy did not affect the level of thyroid hormone.

Immunological and Clinical responses
Over a follow-up period of a median 16.1 months (range, 5.5-23.1), eight patients progressed, and all patients were still alive. The median progression-free survival was 2.9 months (95% CI = 2.7-3.2 months). Five of eight patients who had progressive disease received salvage therapy. Four patients received lenalidomide and dexamethasone and all had partial responses. One patient received bortezomib retreatment and showed stable disease. Three patients who initially had progressive disease after VAX-DC/MM therapy showed stable disease without further increases in monoclonal paraprotein. These three patients did not receive salvage therapy after VAX-DC/ MM therapy and were observed at 18.0, 16.3, and 6.6 months.

Conclusion

In conclusion, VAX-DC/MM therapy, regardless of cell dose, was well-tolerated, and most patients showed an immunological response and disease stabilization.

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Scientific article publishing date : 10/01/2017

Immucura identifier : BSC21_071EN

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