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Monoclonal antibodies as enhancers of the host's immunoresponse against the tumour Hakan Mellstedt Cancer Center Karolinska, Department of Oncology, Karolinska Hospital, Stockholm, Sweden Introduction antigen with a certain degree of specificity even if the normal counterpart is a cell structure of a normal non-transformed cell. Monoclonal antibodies (MAb) might induce tumour cell death by a multitude of mechanisms of actions. Principally monoclonal antibodies can be used unconjugated or conjugated to a toxic substance. So far, unconjugated MAb have been most successful and used extensively for treatment of malignant diseases. Several unconjugated therapeutic monoclonal antibodies are on the market and there are a lot more to be launched. Unconjugated MAb have two fundamentally different ways of action. If the MAb recognise a target structure involved in cell proliferation or apoptosis, the MAb may cause programmed cell death or tumour cell cycle arrest by binding to the relevant domain of the tumour antigen and deliver a signal inducing tumour destruction in vivo without activating the immune system [1]. Monoclonal antibodies may also enhance various immune effector functions which can mediate tumour cell destruction. Immune functions which spontaneously might kill tumour cells include antibodies, unspecific cytotoxic cells (monocytes/macrophages, NK cells, granulocytes, eosinophils) and specific killer cells (various T lymphocyte subsets). In this paper, host's immune responses against the tumour enhanced by monoclonal antibodies are reviewed. Monoclonal antibodies interactions with the immune system MAb might induce tumour cell death by activating various immune effector functions (Table 1). Monospecific antibodies and ADCC Cells participating in ADCC (monocytes/macrophages, NK cells, granulocytes) express IgG Fcreceptors. The human Fc-part of the immunoglobulin molecule more efficiently interacts with human Fc-receptors than the mouse IgG Fc-region. Thus, chimeric, humanised ('CDR'-grafted) and human MAb are more effective in activating ADCC activities than mouse MAb and should therefore in this regard be of preference to utilise. To increase the ADCC capability, cytokines might be added which enhance various immune effector functions, not only ADCC, utilised by monoclonal antibodies (Table 2). These cytokines might also augment the intratumoural unspecific inflammatory response, and thereby contribute to an increased bystander killing [3]. Recognition structure A lot of antigenic structures in various malignancies are available for passive specific immunotherapy. It is generally considered that structures which can evoke a natural humoral IgG response should preferentially be utilised for antibody therapy. Using the SEREX technology more than 600 different tumour antigens have been identified able to induce a spontaneous anti-tumour IgG response [2]. Such a host response indicates that the antigen is altered from self and an Table 1 Immune mediated mechanisms of actions of monoclonal antibodies ADCC (antibody dependent cellular cytotoxicity) CDC (complement dependent cytolysis) Induction of inflammatory response/bystander killing Induction of an idiotypic network response/humoral and cellular anti-tumour immunity 191 192 H. Mellstedt Table 2 Cytokines to combine with therapeutic MAb to enhance the host's immune responses Cytokine Activating immune functions GM-CSF M-CSF G-CSF IL-2 ot/y-Interferon ADCC ADCC ADCC ADCC ADCC (monocytes/macrophages, granulocytes, NK cells), idiotypic network response (antigen presentation) (monocytes/macrophages) (granulocytes) (monocytes/macrophages, NK cells), expand tumour specific T cells (monocytes/macrophages, NK cells) upregulate tumour antigens, expand tumour specific T cells Bispecific monoclonal antibodies An increased recruitment of effector cells to the tumour lesion might also be achieved by using bispecific antibodies binding with one F(abi)-arm to the tumour cells and the other to effector cells. Examples of recognition structures on effector cells utilised for bispecific monoclonal antibody constructs are CD 16 (NK cells, monocytes), CD64 (monocytes, activated granulocytes), CD3 (T cells), CD28 (signalling molecule on T cells) etc. The monovalent binding to the effector cells must induce a signal activating the immune cells with release of lytic proteins, otherwise antibody treatment has to be combined with cytokines activating the appropriate effector cell. Bispecific antibodies binding to various effector surface cell structures are in clinical testing. The idiotypic network cascade According to the idiotypic network theory by N. Jerne antibodies and cells interact through idiotypes to maintain immune homeostases [4]. This hypothesis is applicable for the therapeutic effect of MAb. When a therapeutic antibody (idiotypic antibody, abi) is given an immune response is induced against the idiotypes of abi (CDR (complementary determining region)). Antibodies recognising idiotypes of abi are called anti-idiotypic antibodies (ab2). A complementary T cell response is also induced (T 2 ). Amino acid sequences within the CDR regions of ab^ have homologies with sequences of the nominal antigen recognised by abi. Thus, at>2 represent an 'internal image of the antigens'. According to the theory, an immune response is induced against idiotypic structures of ab2- Antibodies against CDR regions of ab 2 are called anti-anti-idiotypic antibodies (ab3) which have the same specificity as abi and can thus bind to the tumour antigen and induce tumour lysis by ADCC and CDC. Also a T cell response (T3) is evoked which recognise peptides of the nominal tumour antigen presented by MHC molecules on the tumour cells. The mechanism for induction of a T3 response is not quite clear. Other mechanisms than presentation of ab2 idiotypic peptides Therapeutic MAb Idiotypic MAb AnU-anti-Wiotypic antibody Ab, Antigen-presenting cells present Ab, to the Immune system Anti-ioTolypic antibody Ab, Antigen-presenting eel Internal image ol the antigen' Fig. 1. Presentation of an idiotypic network response in MAb (abi) treated patients. T2 = cells recognising idiotypic/isotypic structures on abi. T3 = T cells recognising idiotypic structures on at>2 and the nominal antigen. Thi = CD4 T helperi cells with delayed type histosensitivity reactivity. Monoclonal antibodies as enhancers of the host's immunoresponse against the tumour by antigen presenting cells are probably operating. A schematic presentation of the idiotypic network applicable for therapeutic monoclonal antibodies is depicted in Fig. 1. Several studies have shown the induction of an at>3 response in patients given monoclonal antibodies. Induction of an ab3 response has been shown to statistically significant correlate to the clinical outcome [5,6]. Moreover, in a few studies a tumour directed T3 response has also been shown and indicated to be of clinical importance [7,8]. Phenotypically, T3 cells seemed to be of type I of the CD4 phenotype. Comparison of the ability of mouse MAb as opposed to chimeric or humanised monoclonal antibodies to induce an idiotypic response is scanty. Mouse MAb 17-1A was superior compared to the chimeric variant in inducing an ab2 response [6]. Further studies are required to fully elucidate this issue but it might be expected that mouse MAb may be more efficient in inducing an idiotypic network response than the chimeric or humanised variants as the 'foreign' Fc-part of the mouse monoclonal antibodies may be a stronger adjuvant than the human Fc-part. The idiotypic network response can be augmented by adding cytokines. GM-CSF activates dendritic cells and has been shown to increase the frequency of patients mounting an ab3 response as well as the ab3 titres [6]. EL-2 might also be of value as it might expand tumour antigen specific T3 cells. Furthermore, the induction of an idiotypic network response is probably most efficient when the tumour load is low, and when the production of tumour derived suppressive factors is minimal. This particular mechanism of action favours the use of monoclonal antibodies in the adjuvant setting. Monoclonal antibodies activating specific T cell responses 193 plastic B cells through a signalling event and thereby increase the load of tumour antigens to be presented by anti-CD40 monoclonal antibodies activated APC [9]. Such antibodies are now going into clinical testing and might also be used in non-haematological malignancies as well for activation of APC to increase the capacity of these cells to present tumour antigens from sequestering tumour cells. Anti-CD40 antibody induced T cell response is mainly of the CD8 phenotype and does not seem to require the induction of CD4 helper T cells. BAT monoclonal antibody A similar principle as for the anti-CD40 monoclonal antibodies has been reported for an antibody called BAT [10,11]. In preclinical models this antibody induced tumour regression and prolonged survival in xenograft models of human tumours. The antibody seemed to be optimally functioning if the tumour has induced a tumour specific immune response. The BAT antibody then stimulates proliferation/activation of T cells and NK cells to reject the tumour. The recognition structure for this antibody is not yet defined, but the antigen is present on B cells, T cells and NK cells. Anti-CD40 and BAT MAb are examples of two antibodies which utilise a quite new target for monoclonal antibody therapy of cancer, i.e. anti-tumour immune effector cells and not the tumour cells themselves. This therapeutic principle seems to require the presence of anti-tumour lymphocytes. The existence of natural occurring tumour specific T cell immunity seems to be frequently encountered than expected for many tumours. Moreover, the immune system is most likely best preserved in the adjuvant setting which supports the notion that also these antibodies should preferentially be given to patients in the adjuvant setting, i.e. after removal of the massive tumour load, which previously has induced a tumour specific cellular immune response. Anti-CD40 monoclonal antibodies CD40 is an essential structure for activation of antigen presenting cells (APC) and B cells. In experimental systems, anti-CD40 monoclonal antibodies have been shown to eradicate large lymphomas. The mechanism of action is most likely explained by activation of a specific T cell response against the tumour. Binding of CD40 MAb to neoplastic B cells may render these cells more immunogenic. The antibody might also activate APC which presents tumour antigens from destroyed tumour cells. In addition anti-CD40 MAb might also induce apoptosis of neo- Concluding remarks Unconjugated monoclonal antibodies use multiple mechanisms to destroy tumour cells in vivo. Antibodies may bind to tumour cells and interact with the immune system to kill tumour cells preferentially by activating cytotoxic cells, induce an unspecific inflammatory response and an anti-tumour immunity through the idiotypic network. Monoclonal antibodies might also directly bind to anti-tumour immune effector cells and enhance their ability to destroy 194 H. Mellstedt Table 3 Suggestions for monoclonal antibodies therapy directed to enhance the host's immune responses against the tumour - Treat patients when the tumour load is small, e.g. in the adjuvant setting - Use a monoclonal antibody binding to a tumour structure recognised by the host's immune system - Combine the tumour targeting monoclonal antibody with an antibody activating immune effector cells capable of recognising the tumour - Add cytokines which upregulate tumour antigens, augment the functional activity of cytotoxic cells, stimulate dendritic cells and expand tumour specific T cells tumour cells. All these functional activities can be enhanced by the addition of various cytokines. Moreover, the capability of the host's immune system to destroy tumour cells is more pronounced when the immune system is well preserved, i.e. in the adjuvant setting. Based on these data, unconjugated monoclonal antibodies with different mechanisms of action should be combined together with appropriate cytokines in the adjuvant setting to exert a maximum anti-tumour effect. A summary of suggestions for future directions on the use of unconjugated monoclonal antibodies to enhance the host's immune responses against the tumour is given in Table 3. References 1 Cragg M, French R, Glennie M. Signaling antibodies in cancer therapy. Curr Opin Immunol 1999; 5: 541-547. 2 Tiireci 0 , Sahin U, Zwich C, et al. Exploitation of the antibody repertoire of cancer patients for the identification of human tumor antigens. Hybridoma 1999; 18: 23-28. 3 Shetye J, Ragnhammar P, Liljefors M, et al. Immunopathology of metastases in patients of colorectal carcinoma treated with monoclonal antibody 17-1A and granulocyte macrophage colony-stimulating factor. Clin Cancer Res 1998; 4: 1921-1929. 4 Jeme NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974; 125: 373-389. 5 Wagner U, Schlebusch H, Kohler S, et al. Immunological responses to the tumor-associated antigen CA125 in patients with advanced ovarian cancer induced by the murine monoclonal anti-idiotype vaccine ACA125. Hybridoma 1997; 1: 33-40. 6 Fagerberg J, Ragnhammar P, Liljefors M, et al. Humoral anti-idiotypic and anti-anti-idiotypic immune response in cancer patients treated with monoclonal antibody 17-1 A. Cancer Immunol Immunother 1996; 42: 81-87. 7 Fagerberg J, Hjelm A-L, Ragnhammar P, et al. Tumor regression in monoclonal antibody-treated patients correlates with the presence of anti-idiotype-reactive T lymphocytes. Cancer ' Res 1995; 55: 1824-1827. 8 Kosmas C, Man S, Epenetos AA, Courtenay-Luck NS. The role of humoral and cellular immunity in patients developing human anti-murine immunoglobulin antibody responses after radioimmunotherapy. Br J Cancer 1990; 62: 85-88. 9 French R, Chan C, Tutt A, Glennie M. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 1999; 5: 548-553. 10 Hardy B, Kovjazin R, Raiter A, et al. A lymphocyte-activating monoclonal antibody induces regression of human tumors in severe combined immunodeficient mice. Proc Nad Acad Sci USA 1997; 94: 5756-5760. 11 Raiter A, Novogrodsky A, Hardy B. Activation of lymphocytes by BAT and anti CTLA-4: comparison of binding to T and B cells. Immunol Lett 1999; 69: 247-251. CHALLENGE YOUR EXPERT SESSIONS Chronic lymphocytic leukaemia: risk-adapted therapy. Dendritic cell therapy. Embryonic genes in cancer. Extranodal Iymphoma. Geriatric oncology. How to improve effects of radiation and how to control its toxicity. Marine organisms and other novel natural sources of new cancer drugs. Optimal treatment of thymoma. Pregnancy and malignancy. Tamoxifen vs newer SERMs: What is the evidence? Therapeutic use of peptide receptor binding radionuclides. Thrombosis in cancer patients. Dieter K. Hossfeld Medical University Clinic Department of Oncology-Hematology Hamburg, Germany Laurence Zitvogel Institut Gustave Roussy Villejuif, France Harry A. Drabkin University of Colorado, Health Sciences Center Division of Medical Oncology Denver, USA Franco Cavalli and Emanuele Zucca Oncology Institute of Southern Switzerland Division of Medical Oncology Bellinzona, Switzerland Matti S. Aapro Institut Multidisciplinaire d'Oncologie Clinique de Genolier Genolier, Switzerland Anna Gregor Western General Hospital Department of Clinical Oncology Lothian University Hospitals NHS Trust, Edinburgh Scotland, UK Gilberto Schwartsmann Hospital de Clinicas de Porto Alegre Universidade Federal Do Rs Servico de Oncdlogia Clinicd Porto Alegre, Brazil Giuseppe Giaccone Free University Hospital Department of Oncology Amsterdam, Netherlands Nicholas Pavlidis University ofloannina, School of Medicine Department of Medical Oncology Ioannina, Greece Anthony Howell Christie Hospital, CRC Department of Oncology Manchester, United Kingdom Eric P. Krenning Department of Nuclear Medicine University Hospital and Erasmus University Rotterdam, The Netherlands H.F.P. Hillen University Hospital Maastricht Department of Internal Medicine Maastricht, The Netherlands