Phase III randomized, double-blinded, placebo-controlled multicenter trial of melapuldencil-t: autologous dendritic cells loaded with irradiated autologous tumor cells (dc-tc) in gm-csf in patients with metastatic melanoma
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Background
Genomic analyses have shown that melanoma patients have hundreds to thousands of non-synonymous
mutations including unique tumor associated antigens (TAA) that can be recognized
by their immune systems. The efficacy of anti-checkpoint monoclonal antibodies provides
further proof that host recognition of TAA exists, but many patients do not benefit
from such therapy, perhaps because they lack sufficient TAA recognition. One way to
enhance TAA recognition is immunization. The best source of TAA may be autologous
tumor cells that self-renew and proliferate in tissue culture (patient specific tumor
stem cells). Sequential Phase II trials in metastatic melanoma patients tested the
clinical benefit of repeated s.c. injections of autologous dendritic cells loaded
with antigens from irradiated tumor cells derived from autologous melanoma cell lines
(DC-TC), and suspended in GM-CSF. In a single arm trial 5-year survival was 50% for
54 patients treated with DC-TC. In a randomized Phase II trial, 2-year survival was
72% for 18 DC-TC patients compared to 31% in the control arm (HR = 0.27, p = 0.007).
Toxicities associated with DC-TC were minimal (n = 72). Improvements in manufacturing
have increased the probability of establishing a cell line and decreased the time
needed to produce the product. Melapuldencel-T (DC-TC) has shown sufficient promise
to receive special product assessment (SPA) and fast track designation in association
with approval of this pivotal Phase III trial.
Trial design
This is a Phase III, double-blinded, randomized, placebo-controlled trial. Eligible
patients will have stage IV or recurrent stage III melanoma with at least one lesion
amenable to surgical resection. Resected tumor is transferred to a manufacturing facility
where a cell suspension is placed in specially formulated cell culture media, then
cells from spheroids are isolated, and then expanded to at least 100 million cells.
After successful establishment of a cell line and referral for treatment, 250 patients
with good performance status (ECOG 0-1) will be stratified by whether they have no
evidence of disease, non-measurable disease by RECIST, or measureable disease with
elevated LDH or without elevated LDH. They undergo leukapheresis, and are randomized
2:1 to receive either DC-TC or autologous mononuclear cells. Both products are suspended
in 500 µg of GM-CSF and injected weekly for 3 weeks, and then monthly for 5 months.
The endpoint is overall survival with death from any cause the major endpoint. [NCT01875653].
This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (
http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited. The Creative Commons Public Domain Dedication
waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Conference name:
Society for Immunotherapy of Cancer 29th Annual Meeting