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Cancer Control Combination Therapy of Cancer – Escalating the Effect of Dendritic Cell-based Cancer Vaccine in the Tumour Micro-environment Hyunah Lee Office of the Biomedical Professors, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Abstract A key factor in initiating and operating the immune system against tumour cells, the dendritic cell (DC) has been regarded as the next possible breakthrough in new cancer therapy. However, the results of more than 15 years of clinical studies with DC vaccine revealed the difficulties fulfilling this expectation. Evidence has disclosed that the DC activation required for proper tumour-specific effector CD4+ and CD8+ T cell stimulation is inhibited in the micro-environment of tumour. Studies have further reported that DC phenotypes in tumour tissue and draining lymph nodes are mostly immature, which results in regulatory immune responses. Also, the existence of MDSCs and TAMs adversely affect both DC function and immune suppression in the cancer-environment. In this review, efforts to overcome the tumour or host-dependent hindering which inhibit the effect of cancer vaccine will be discussed. The combination therapy of cancer with DC vaccine and other immune modulators may improve the clinical efficacy. Keywords Dendritic cell (DC) vaccine, combination therapy, tumour micro-environment, antibodies, cytokines, chemotherapeutics, myeloid derived suppressor cells (MDSCs) Disclosure: The author has no conflicts of interest to declare. Received: 3 September 2012 Accepted: 1 October 2012 Citation: European Oncology & Haematology, 2012;8(4):261–4 Correspondence: Hyunah Lee, 50 IL-Won Dong, Kang-Nam Gu, 135-710, Seoul, Republic of Korea. E: andyjosh@skku.edu The role of the dendritic cell (DC) is at the centre of the immune system by initiating, progressing and regulating the responses against pathogens, include tumours. After the first successful clinical achievement in DC-based immunotherapy trials in follicular lymphoma and melanoma in the mid-1990s, 1,2 the DC vaccine used to treat patients with cancer such as melanoma, lymphoma and renal cell carcinoma. 3–7 However clinical expectations have not been fulfilled due to an overall clinical response rates of under 10–15 %, the usual response rates observed in various types of immunotherapies. 6–11 The meta analysis performed with 906 prostate and renal cell cancer (RCC) patients in 29 separate DC vaccine clinical trials revealed the objective response rates, 7.7 % in prostate cancer and 12.7 % in RCC. 12 If the stable disease rate was combined as clinical benefit rate (CBR), much better response rate was counted (54 % in prostate cancer and 48 % in RCC). Although the clinical expectation has not been satisfied, the outcomes of many clinical trials with tumour antigen-loaded conventional DCs have provided proof that therapeutic immunity can be elicited. 13–15 And statistically significant effect of DC-mediated cellular immune response and of DC dose on CBR was proved in meta-analysis. 12 The clinical data has helped to establish a standard for properly activated DCs with appropriate form and doses of loading antigens.These activated DCs can migrate to the lymph nodes which then initiate and expand tumour-specific CD4+ and CD8+ T cell responses and later induce meaningful therapeutic responses in patients. Several mechanisms involved in unsatisfactory anti-tumour responses of DC vaccine in the clinic. Mechanisms include; the presence of suppressive leukocytes like myeloid derived suppressor cells © TOUCH MEDICAL MEDIA 2012 (MDSCs), tumour associated macrophages (TAMs) with or without the presence of constitutive p-STAT3 signalling, immunoediting, abnormal tumour vasculature inhibiting effector T cell entry or tumour cell interaction with the stromal environment. 15–20 On the other hand, in order to improve the DC vaccine clinical efficacy, it is critical to control the therapeutic DC quality and standardise the vaccine design and protocol. Looking at this very view, several investigators have analysed DC vaccine problems in their publications. 4,6,13,15,21–23 One of the efforts is using allogeneic cells, since the DCs isolated from cancer patients express impaired characters for generation of the tumour-specific immunity. 24 Thus, without further discussing about the DC vaccine quality, tumour tissue or host side hindering factors and the possibility of improving antitumour immune-therapeutic efficacy will be discussed in this review. Dendritic Cells in Cancer Patients DCs are lymphocytes in the immune system which control overall immunity by interacting with other immune cells, including T cell, B cell and natural killer (NK) cells. 6,25–26 DCs themselves are a complicated system consisting of various anatomic localisations, subsets and functions that are correlated with one another. DCs control the immune system, not only in stimulatory but also in regulatory immunity as professional APC. 23,25 In cancer tissues or cancer-draining lymph nodes, DCs are found as resting, non-activated and immature cells. 27–31 Tumour-induced immunosuppressive milieu generally causes a decrease in the numbers of conventional myeloid DCs in patients. 27 In rodent models, immature myeloid DCs promote the expansion of regulatory T cells (Treg) in tumour-draining lymph 261