Clinical Benefit of Allogeneic Melanoma Cell Lysate–Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients

Abstract

Purpose: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. Experimental Design: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83-and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 × 10 6 cells per dose) at biweekly intervals. Results: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders. Conclusion: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726-36) The efficacy of therapeutic cancer vaccines in humans has in general been poor (1-3). An overall objective response rate of only 3.3% was observed in 1,306 vaccine treatments of cancer patients with advanced disease (3). This lack of success might reflect poor immunogenicity of the adopted tumor-associated antigens (TAA) as well as downmodulation of tumor-associated antigenicity in advanced tumors (4). Local and systemic suppression mediated by the growing tumor and its environment, including activation and stimulation of regulatory T lymphocytes (Treg), tolerogenic dendritic cells (DC), myeloid-derived suppressor cells, and angiogenic factors, can also counteract vaccine-based immunotherapy (5). In clinical trials that have used autologous DC-based vaccinations, differentiated and immunogenic DCs generated ex vivo from peripheral blood monocytes were pulsed or transfected with a variety of TAA. This approach might more effectively expose the immune system of the patient to immunogenic TAA, and because the DCs are already differentiated, may overcome the tolerogenic tumor environment in the patient. This view is supported by theoretical (4) as well as practical considerations. Preclinical s...

Induction of CTLs by DCs pulsed with K-ras mutant peptide on the surface of nanoparticles in the treatment of pancreatic cancer

“…Although this study confirmed that whole cell antigen induced an ideal antitumor immune response, it contained the normal cellular components, which make immune tolerance and autoimmunity possible. Additionally, the tumor antigen content cannot be easily controlled, which causes difficulty in the application of DC-sensitized antigen (27)(28)(29).…”

Trial watch

“…These studies have been performed in a very wide range of settings, encompassing B-cell lymphoma, 152 chronic lymphocytic leukemia (CLL), 148 , 153 - 156 cutaneous T-cell lymphoma (CTCL), 157 glioma, 158 - 161 glioblastoma multiforme (GBM), 162 - 165 thyroid carcinoma, 166 , 167 non-small cell lung carcinoma (NSCLC), 168 - 170 breast carcinoma, 171 , 172 mesothelioma, 173 hepatocellular carcinoma (HCC), 174 , 175 intrahepatic cholangiocarcinoma, 176 melanoma, 177 - 193 pancreatic carcinoma, 194 colorectal carcinoma (CRC), 195 - 200 renal cell carcinoma (RCC), 171 , 201 - 210 prostate cancer, 211 , 212 pediatric malignancies, 213 - 215 and mixed advanced cancers 216 - 219 . Taken together, the results of these studies were very encouraging as they indicated that (1) DCs pulsed ex vivo with tumor cell lysates or with cancer cells succumbing to apoptosis can be administered to patients in the absence of particular toxicity, and that (2) this approach leads to the activation of an immune response in a very large proportion of cases.…”

Cytokine Antibody Arrays in Biomarker Discovery and Validation

“…In order to find biomarkers for monitoring cancer vaccine efficacy, Toh, et al, measured expression profiles of 507 proteins using biotin-label-based antibody array in cultures of dendritic cells obtained as from colorectal cancer patients, both before vaccination and at 2 months and 4 months postvaccination [77]. When samples were compared from postvaccination (month 2 and 4) and pre-vaccination, 58 and 47 differentially expressed proteins were identified, respectively.…”