Dendritic cell vaccination of patients with metastatic colorectal cancer
ABSTRACT
Colorectal cancer is with more than 4000 new cases every year the third most common cancer in Denmark. Metastases are most often found in the liver, and 20-25% of the patients have synchronous metastases to the liver at time of primary diagnosis. Other frequent sites for metastases are lungs and lymph nodes. Without treatment the median survival for patients with metastatic colorectal cancer is 7-9 months. Patients receiving systemic or regional chemotherapy now have a median survival of approximately 20 months. Up to 40% of the patients undergoing intended curative surgery subsequently relapse with local or distant disease, and approximately 80% of the relapses appear within the first 3 years. If the cancer metastasises, and the chances of radical surgery are eliminated, the prognosis is poor. The aim of the present study was to evaluate the clinical and immunological effects of treating patients with disseminated colorectal cancer with a dendritic cell based cancer vaccine (MelCancerVac). The vaccine consisted of dendritic cells generated from autologous mononuclear cells pulsed with an allogeneic tumor cell lysate, selected for its high expression of cancer associated antigens. A clinical phase I study evaluating tolerability and toxicity of the treatment was established. Six patients with progressive disease were included and the analysis revealed that the treatment was well tolerated and not associated with toxicity. A subsequent clinical phase II study evaluating the activity of the treatment with CT-scan based measurements of tumors (RECIST), self reported quality of life (SF-36), and clinical evaluation was established. Out of twenty included patients with progressive disease, seventeen received intervention with the vaccine. Stable disease was achieved in four patients and two of these remained stable throughout the entire study period. Quality of life remained for most parameters included in the evaluation high and stable. The immunological consequences of the treatment were evaluated with plasma- and serum-levels of inflammatory and non-inflammatory markers (the following 10 cytokines: GM-CSF, INF-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-alpha, and in addition the inflammatory chemokines MIP-1beta, Eotaxin and IP-10) and biomarkers CEA and TIMP-1. These analyses showed that the vaccine induced increasing levels of Th1 cytokines such as GM-CSF, TNF-alpha, IFN-gamma, and IL-2 in patients achieving stable disease. Patients with progressive disease had increasing levels of CEA and TIMP-1, while patients achieving stable disease maintained relatively stable levels. Conclusively, treatment with this dendritic cell based cancer vaccine was non-toxic and safe, clinical response in terms of stable disease was achieved in 24% of the patients, and the patients maintained a high quality of life during treatment. The immunological analyses indicated that the treatment resulted in favourable anticancer responses in the patients‘ immune system in terms of polarisation towards a Th1 dominated response potentially directed against tumor cells. Since no partial or complete responses were observed and since the number of patients was relatively low these results have to be interpreted with caution. Moreover, phase II study designs do not lead to final conclusions regarding clinical efficacy, which must be validated in larger prospective, randomised and controlled studies.