Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised “proof-of-principle” phase II study

Abstract

BackgroundVaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed.Methods/DesignThis is a phase II, “proof-of-principle”, randomized, open-label trial of vaccination with autologous DC loaded with tumor lysate or homogenate in metastatic melanoma patients combined with immunomodulating RT and/or preleukapheresis IFN-α. All patients will receive four bi-weekly doses of the vaccine during the induction phase and monthly doses thereafter for up to a maximum of 14 vaccinations or until confirmed progression. Patients will be randomized to receive:(1.) three daily doses of 8 Gy up to 12 Gy radiotherapy delivered to one non-index metastatic field between vaccine doses 1 and 2 and, optionally, between doses 7 and 8, using IMRT-IMAT techniques;(2.) daily 3 MU subcutaneous IFN-α for 7 days before leukapheresis;(3.) both 1 and 2;(4.) neither 1 nor 2.At least six patients eligible for treatment will be enrolled per arm. Daily 3 MU IL-2 will be administered subcutaneously for 5 days starting from the second day after each vaccine dose. Serial DTH testing and blood sampling to evaluate treatment-induced immune response will be performed. Objective response will be evaluated according to immune-related response criteria (irRC).DiscussionBased upon the emerging role of radiotherapy as an immunologic modifier, we designed a randomized phase II trial adding radiotherapy and/or preleukapheresis IFN-α to our DC vaccine in metastatic melanoma patients. Our aim was to find the best combination of complementary interventions to enhance anti-tumor response induced by DC vaccination, which could ultimately lead to better survival and milder toxicity.

Phase 1/2 study of immunotherapy with dendritic cells pulsed with autologous tumor lysate in patients with refractory bone and soft tissue sarcoma

“…Since the first report of DC-based immunotherapy demonstrated that DCs pulsed with a tumor antigen could elicit specific tumor-reactive T cells and showed clinical efficacy in patients with lymphoma, 8 a number of clinical trials of immunotherapy using DCs pulsed with tumor antigens have been reported. 9,10,[25][26][27] Although a number of these previous clinical trials have shown the safety of DC-based immunotherapy and reported activation of the immune response by the treatment, the efficacy of such immunotherapy is currently seen in only a subset of cancer patients. Reyes et al 26 reported that TL-pulsed DCs significantly decreased prostate-specific antigen levels without adverse reactions in patients with castrationresistant prostate cancer.…”

Dendritic cell therapy in melanoma

“…DC vaccines have been used to activate the immune system in autologous and allogenic vaccination strategies using peptides or tumour lysates (15)(16)(17)(18). However, the response rates using DC vaccines have been usually low ranging from 10% to 20%, although they are the only immunotherapy so far that increases patient survival rates.…”

Trial watch: Dendritic cell-based anticancer therapy

“…[221][222][223][224][225]229,232,234,240,243,245,246,[249][250][251] Alternatively, DC-based interventions were administered together with cytokine-induced killer (CIK) cells, 220,233,247,[252][253][254][255] adoptively transferred T lymphocytes, 226,236,239,248,256,259 chemotherapy, 227,228,237 immunostimulatory cytokines, 230,235,242 TLR agonists, 257 or radiation therapy. 233,238,256,262,263 As for the main oncological indications investigating in this context, 7 trials enrolled melanoma patients, 226,230,236,238,250,251 4 subjects with pancreatic carcinoma, 220,227,…”