EDITORIAL Cancer Immunotherapy - Ingenta Connect

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Cancer Immunotherapy: Does an Increasing Arsenal of Tools Point to More Fruitful ... Since the start of immunotherapy of cancer in 1891 with the use of Coley's ...

Editorial

Anti-Cancer Agents in Medicinal Chemistry, 2014, Vol. 14, No. 2

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EDITORIAL Cancer Immunotherapy: Does an Increasing Arsenal of Tools Point to More Fruitful Avenues for Research? Since the start of immunotherapy of cancer in 1891 with the use of Coley’s toxin [1], knowledge on cancer immunology has tremendously expanded especially in the last two decades. For example, the discovery of Toll-like receptors (TLRs) in 1990s explained the mechanism of Coley’s toxin as the activation of the TLR4 and TLR9 signaling pathways. This leads to cytokine production and activation of natural killer (NK) and cytotoxic T lymphocytes (CTLs) [2]. In this special issue of “Immunomodulatory molecules in anti-cancer immunotherapy”, the focus is on emerging molecules that affect immune responses in cancer therapy. Current cancer immunotherapy can be divided into 4 categories: monoclonal antibody-based therapy, therapeutic cancer vaccine, adoptive immune cell transfer therapy and non-specific immunostimulating therapy. Conventional cancer therapies also involve host immunity [3]. Chemotherapy and radiotherapy were previously considered as immunosuppressive but recent studies have suggested that the dying tumor cell induced by these therapeutic modalities could elicit danger signals that alert the immune system. This will cause the release of tumor-associated antigens leading to an immune response against the tumor [4]. These therapeutic modalities can also suppress regulatory T cells. Such suppression leads to an enhanced immune response. Phenotypic expression of tumor cell is affected by nontoxic concentrations of chemotherapeutic agents with alterations of tumorassociated antigens, MHC molecules, intercellular adhesion molecules or antigen processing machinery. Such alterations sensitize the tumor cells to recognition and destruction by immune cells [3]. Leukocytopenia induced by chemotherapeutic drugs destroys the immunosuppressive elements and as such offers the host an opportunity to reconstitute an anti-cancer immune system with lymphocyte repopulation after chemotherapy [5]. Some chemotherapeutic agents are able to enhance the function of dendritic cells [6]. Targeted therapy of cancer by small molecule kinase inhibitors is mediated by interrupting protein-protein interaction in vivo such that specific signal pathways that are critical for cancer cell growth are blocked. This is achieved by a variety of ways, e.g. inhibiting immune suppressor cells, activating effector cells and/or transforming cancer cells to be more susceptible to immunocytoxicity [3]. Thus, immune cell mediated killing is likely to be a central premise of cancer therapy (Fig. 1).

Fig. (1). Immunotherapy is very likely a key point in the cancer therapy. Conventional cancer therapies such as chemotherapy, radiotherapy and small molecule kinase inhibitor play a role in immune-mediated killing mechanism.

Immunotherapy is usually targeted at specific cancer-associated antigen and thus the classical cancer classification based on specific organ is unsuitable to define the indication of immunotherapy. Moreover, it is difficult to determine the optimal dosage and schedule of any immunological based therapy and consequently the dosing regimens of many clinical trials are educated guesses [7]. The half-life of a drug which is traditionally used to define the schedule of chemical agent in vivo is not applicable in determining the dosing schedule in immunotherapy because the effects of immunotherapy are often delayed. This temporal lag is caused by the recruitment of lymphocytes and activation of a variety of signal pathways. Additionally, when certain immunotherapeutic agents are combined with chemotherapeutic agents or small molecule kinase inhibitors, the dosing regimen is critical. For example, Sunitinib administration followed by cancer vaccine induced enhanced Th1 and CTL responses while coadministration resulted in a decrease of T lymphocytes [8]. Finally, the classical assessment of response of cancer to various agents by volumetry has been suggested as being unsuitable for immunotherapy as tumor regression induced by immunotherapy usually follows initial progression or the presence of new lesions [7]. Thus, a prolonged observation is desirable to assess the response of immunotherapy. In this special issue, various approaches are presented. Using an in vitro murine breast cancer model constructed in a 3D chitosan-alginate polyelectrolyte complex scaffold, Phan-Lai et al. demonstrated that intratumoral over-expression of CCL21 and IFN improved tumor specific T cell recruitment, enhanced Th cell activity and promoted lymphocyte cytotoxicity [9]. Van Meir et al. reviewed clinical outcomes in patients with advanced cervical cancer that had immunotherapy with/without chemotherapy [10]. The poxvirus-based cancer vaccine, especially the new poxvirus strains that are currently under development for cancer immunotherapy is the focus of Izzi et al’s paper [11].

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Editorial

Leuci et al. focused on the adoptive cancer immunotherapy with NK, CIK and iNKT cells and presented the expansion protocols and clinical experience [12]. van de Wall et al. presented a comprehensive review on recent developments on HPV-specific immunotherapy in preclinical models as well as the results of a few clinical trials [13]. A review of the therapeutic vaccines for non-small cell lung cancer that have been tested in clinical trials was presented by Ma & Tang [14]. Jin et al. discussed dsRNA triggered signals and their consequent clinical utility [15]. The current knowledge of garlic organosulfur compounds and their immunomodulating activities in cancer chemoprevention was reviewed by Schäfer et al. [16]. Villalba et al. raised an intriguing topic, i.e. treatment of cancer by interfering with its energy metabolism and discussed its significance in immunotherapy for blood-borne malignancies [17]. Significant advances in cancer immunotherapy have led to promising research outcomes. However further translational research is required. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

[11] [12] [13] [14] [15] [16] [17]

Bickels, J.; Kollender, Y.; Merinsky, O.; Meller, I. Coley's toxin: historical perspective. Isr. Med. Assoc. J., 2002, 4(6), 471-472. Hennessy, E.J.; Parker, A.E.; O'Neill, L.A. Targeting Toll-like receptors: emerging therapeutics? Nat. Rev. Drug Discov., 2010, 9(4), 293-307. Hodge, J.W.; Ardiani, A.; Farsaci, B.; Kwilas, A.R.; Gameiro, S.R. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin. Oncol., 2012, 39(3), 323-339. Ma, Y.; Kepp, O.; Ghiringhelli, F.; Apetoh, L.; Aymeric, L.; Locher, C.; Tesniere, A.; Martins, I.; Ly, A.; Haynes, N.M.; Smyth, M.J.; Kroemer, G.; Zitvogel, L. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin. Immunol., 2010, 22(3), 113-124. Williams, K.M.; Hakim, F.T.; Gress, R.E. T cell immune reconstitution following lymphodepletion. Semin. Immunol., 2007, 19(5), 318-330. Shurin, G.V.; Tourkova, I.L.; Kaneno, R.; Shurin, M.R. Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J. Immunol., 2009, 183(1), 137-144. Lesterhuis, W.J.; Haanen, J.B.; Punt, C.J. Cancer immunotherapy--revisited. Nat. Rev. Drug Discov., 2011, 10(8), 591-600. Farsaci, B.; Higgins, J.P.; Hodge, J.W. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int. J. Cancer, 2012, 130(8), 1948-1959. Phan-Lai, V.; Kievit, F.M.; Florczyk, S.J.; Wang, K.; Disis, M.L.; Zhang, M. CCL21 and IFN recruit and activate tumor specific T cells in 3D scaffold model of breast cancer. Anticancer Agents Med. Chem., 2014, 14(2), 204-210. Van Meir, H.; Kenter, G.G.; Burggraaf, J.; Kroep, J.R.; Welters, M.J.P.; Melief, C.J.M.; van der Burg, S.H.; Van Poelgeest M.I.E. The need for improvement of the treatment of advanced and metastatic cervical cancer, the rationale for combined chemo-immunotherapy. Anticancer Agents Med. Chem., 2014, 14(2), 190-203. Izzi, V.; Buler, M.; Masuelli, L.; Giganti, M.G.; Modesti, A.; Bei, R. Poxvirus-based vaccines for cancer immunotherapy: New insights from combined cytokines/co-stimulatory molecules delivery and “uncommon” strains. Anticancer Agents Med. Chem., 2014, 14(2), 183-189. Leuci, V.; Mesiano, G.; Gammaitoni, L.; Todorovic M.; Giraudo, L.; Carnevale-Schianca, F.; Aglietta, M.; Sangiolo, D. Ex vivo-activated MHCunrestricted immune effectors for cancer adoptive immunotherapy. Anticancer Agents Med. Chem., 2014, 14(2), 211-222. Van de Wall, S.; Nijman, H.W.; Daemen, T. HPV-specific immunotherapy: Key role for immunomodulators. Anticancer Agents Med. Chem., 2014, 14(2), 265-279. Ma, K.; Tang, Y.H. Therapeutic vaccines explored in patients with non-small cell lung cancer. Anticancer Agents Med. Chem., 2014, 14(2), 256-264. Jin, B.; Cheng, L.F.; Wu, K.; Yu, X.H.; Yeo, A.E.T. Application of dsRNA in cancer immunotherapy: current status and future trends. Anticancer Agents Med. Chem., 2014, 14(2), 241-255. Schäfer, G.; Kaschula, C.H. The immunomodulation and anti-inflammatory effects of garlic organosulfur compounds in cancer chemoprevention. Anticancer Agents Med. Chem., 2014, 14(2), 233-240. Villalba, M.; Lopez-Royuela, N.; Krzywinska, E.; Rathore, M.G.; Hipskind, R.A.; Haouas, H.; Allende-Vega, N. Chemical metabolic inhibitors for the treatment of blood-borne cancers. Anticancer Agents Med. Chem., 2014, 14(2), 223-232.

Bo Jin, M.D., Ph.D. (Guest Editor) Professor of Medicine Department of Gastroenterology The 309th Hospital of the Chinese People’s Liberation Army Beijing, China Tel: 86-1-338-120-7136 Fax: 86-1-06-858-9301 E-mail: [email protected]

Anthony E.T. Yeo, M.D., Ph.D., MPH (Co-Guest Editor) Consultant Highland Park, New Jersey USA Tel: +1-415-370-6770 E-mail: [email protected]