- Email: [email protected]
Therapeutic Monoclonal Antibodies: Introduction
THERAPEUTIC MONOCLONAL ANTIBODIES
Therapeutic Monoclonal Antibodies: Introduction
I
n the late 1970s the hybridoma methodology invented in 1975 by Cesar Milstein and George J. F. Kohler was enthusiastically and successfully applied by tumor immunologists to produce a large number of human tumor antigen (TA)-specific mouse monoclonal antibodies. The high degree of specificity of these reagents that could be produced for the first time in large amount and in a standardized way generated a significant level of enthusiasm among clinical oncologists who felt to have in their hands for the first time the “right reagents” to “cure” cancer. As a result many TA-specific monoclonal antibodies were tested in clinical settings at many centers. Not surprisingly, most, if not all, of the clinical trials failed and in some cases the administration of mouse monoclonal antibodies that recognize poorly characterized TA caused toxicity, including treatment-related deaths. These disappointing clinical results generated a significant level of skepticism among clinical oncologists and tumor immunologists about the usefulness of TAspecific mouse monoclonal antibodies for the treatment of malignant diseases. The negative attitude towards TA-specific monoclonal antibodies also was enhanced by the major progress made at the same time in the identification and characterization of Tcell–defined TA and by the conviction that T-cell– based immunity and not humoral immunity was the key player in the control of tumor growth. The poor image of TA-specific monoclonal antibodies in the scientific community made things quite difficult for TA-specific monoclonal antibody aficionados in terms of grant funding and job opportunities both at academic institutions and in pharmaceutical companies. Things changed dramatically in 1997 when the CD20-specific monoclonal antibody rituximab was approved by the US Food and Drug Administration for the treatment of non-Hodgkin lymphoma. Since then, TA-specific monoclonal antibodies have become widely used therapeutic agents in the clinical setting. Furthermore, there has been a growing interest in developing novel monoclonal antibodies to previously unidentified clinically relevant molecules that can be used as targets Conflicts of interest: none 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.09.011
556
of immunotherapy. In parallel, there have been major efforts to improve the therapeutic efficacy of the available TA-specific monoclonal antibodies. The latter approaches have greatly benefited from the significant progress made in our understanding of the multiple mechanisms utilized by TA-specific monoclonal antibodies to exert their anti-tumor effects and in the technology to modify the functional characteristics of monoclonal antibodies. Figure 1 lists the mechanisms that have been exploited to design immunotherapeutic strategies for the treatment of malignant diseases using TAspecific monoclonal antibodies. Besides activation of immunologic effector mechanisms such as complement and Fc receptor bearing cells, TA-specific monoclonal antibodies can interfere with the activation of signaling pathways involved in cancer cell proliferation, survival, and migration and/or can induce apoptosis of cancer cells. In addition they can target to cancer cells chemotherapeutic agents, cytokines, radioisotopes, and/or toxins, thus increasing their concentration in the tumor microenvironment and minimizing, if not eliminating, the side effects associated with the systemic administration of these agents. A more recent application of TAspecific monoclonal antibodies has been their use to target to the tumor microenvironment cells such as natural killeer cells and T cells, thus targeting tumors with cellular immunity without the need to generate a TA-specific T-cell immunity. Among the latter strategies the one that is attracting much attention is that which relies on the transduction of naı¨ve T cells with chimeric antigen receptors. The latter contain variable regions of TA-specific antibodies linked to activation molecules. While the latter provide the signals leading to T-cell activation, the former endow naı¨ve T cells with TA-specificity. This approach is being explored in a rather aggressive way by several biotechnology and big pharma companies with or without the participation of academic institutions. Major investments have been made in recent years in order to evaluate the clinical significance of this strategy; therefore it is likely that in the near future we will have the clinical data to assess this elegant technology, which exploits the advantages of cellular and humoral immunity and at the same time minimizes the interference of their limitations.
Seminars in Oncology, Vol 41, No 5, October 2014, pp 556-558
Therapeutic monoclonal antibodies
A
557
B
C
Figure 1. Mechanisms utilized by tumor antigen-specific monoclonal antibodies to mediate anti-tumor effects. CAR, chimeric antigen receptor; mAb, monoclonal antibody; TCR, T-cell receptor.
The above-mentioned strategies are discussed in the reviews included in this issue of Seminars in Oncology. Each contributor has been encouraged not to provide an extensive review of the information available in the literature, but to focus on the discussion of the challenges we face and need to overcome to optimize the use of TA-specific monoclonal antibodies in the clinical setting. A very large number of patients with various types of malignancies has been treated in a relatively short time with TA-specific monoclonal antibodybased immunotherapy. The number of treated patients will continue to increase because the clinical results are excellent and because the experience we will continue to acquire by treating patients will help us to develop strategies to minimize or even eliminate treatment-associated side effects. Therefore, a large amount of information is available. The following are the points which in my opinion are noteworthy: 1. Lack of expression of the targeted TA in normal tissues does not appear to be an absolute requirement for the selection of a TA as a target of antibody-based immunotherapy. There are several examples of TA that are expressed in normal tissues and nevertheless immunotherapy can control tumor growth or eliminate tumors without causing treatment-associated side effects. One
such example is epidermal growth factor receptor (EGFR), which has a broad distribution in normal tissues. Nevertheless, administration of EGFRspecific monoclonal antibodies such as cetuximab to patients with head and neck cancer or with colon cancer does not appear to cause severe side effects because of the binding of monoclonal antibodies to normal tissues expressing EGFR. Expression level of targeted TA in normal cells as compared to that in malignant cells and more importantly effect of TA-specific monoclonal antibodies on signaling pathway(s) in normal cells as compared to that in malignant cells may underlie the differential effect of TA-specific monoclonal antibodies on malignant cells and on normal cells. To the best of my knowledge no experimental data are available in this regard. This type of information would be very useful to set the criteria to select the TA-specific monoclonal antibodies to be developed for therapeutic use. 2. Combination with chemotherapeutic agents and/ or with signal transduction pathway inhibitors has been shown to enhance the anti-tumor activity of several TA-specific monoclonal antibodies. In addition to the additive or synergistic effect of these combinations as far as the antitumor effect is concerned, the combination of
558
TA-specific monoclonal antibodies with agents that use a different mechanism of action may be useful to counteract the escape mechanism (s) used by tumor cells to avoid immune recognition and destruction. The rational choice of agents to be combined with TA-specific monoclonal antibodies will greatly benefit from information about the mechanisms of action of the agents to be combined and more importantly about how they influence each other. 3. According to the cancer stem cell theory a major cause of failure of current chemo- and radiotherapy is represented by the chemo- and radio-resistance of cancer-initiating cells (CICs). These cells which at variance from differentiated cancer cells survive chemo- and radiotherapy are postulated to play a major role in metastatic spread and disease recurrence. Evidence begins to be available that immunotherapy with TA-specific monoclonal antibodies can target not only differentiated cancer cells, but also CICs. Whether the targeting of CICs in addition to that of differentiated cancer cells has an impact on the clinical course of the disease, as implied by the suggested role of CICs in metastatic spread and in disease recurrence and by the results obtained in several animal model systems, remains to be determined. 4. Resistance of cancer cells to the anti-tumor activity of immunotherapy with TA-specific monoclonal antibodies remains a major obstacle to the successful application of this type of immunotherapy in a clinical setting. Tumor cells’ genetic instability, development of escape mechanisms by tumor cells to avoid immune recognition and destruction and/or selective pressure imposed on tumor cell population by the applied immunotherapy lead to the outgrowth of a tumor cell
S. Ferrone
subpopulation with the “resistance” phenotype. Detailed characterization of the underlying molecular mechanism(s) will be required for the rational design of strategies to counteract these mechanisms. It is a general experience that only a proportion of the patients with a given type of tumor treated with immunotherapy with TA-specific monoclonal antibodies responds to the therapy. At present we do not know why this happens and we do not have biomarkers to identify the subpopulation of patients responsive to the applied immunotherapy with TA-specific monoclonal antibodies. The ability to identify “responsive” patients would avoid exposing patients who are not likely to respond to the risks associated with the administration of TAspecific monoclonal antibodies and would reduce the financial burden imposed on health systems by the high cost of monoclonal antibodies. In spite of its importance this topic is not discussed in this issue of Seminars since in our opinion we do not have sufficient information to discuss it. Let’s hope that granting agencies and pharmaceutical companies will set up systems to stimulate research in this area. In closing this Introduction I would like to thank Dr Michael J. Mastrangelo, the Editor in Chief, for having given me the opportunity to edit this issue of Seminars in Oncology and for his support and guidance, the contributors for having submitted excellent papers, and the Elsevier staff for excellent managerial assistance.
Soldano Ferrone, MD, PhD Massachusetts General Hospital Boston, MA, Guest Editor E-mail: [email protected]
Therapeutic Monoclonal Antibodies: Introduction
I
n the late 1970s the hybridoma methodology invented in 1975 by Cesar Milstein and George J. F. Kohler was enthusiastically and successfully applied by tumor immunologists to produce a large number of human tumor antigen (TA)-specific mouse monoclonal antibodies. The high degree of specificity of these reagents that could be produced for the first time in large amount and in a standardized way generated a significant level of enthusiasm among clinical oncologists who felt to have in their hands for the first time the “right reagents” to “cure” cancer. As a result many TA-specific monoclonal antibodies were tested in clinical settings at many centers. Not surprisingly, most, if not all, of the clinical trials failed and in some cases the administration of mouse monoclonal antibodies that recognize poorly characterized TA caused toxicity, including treatment-related deaths. These disappointing clinical results generated a significant level of skepticism among clinical oncologists and tumor immunologists about the usefulness of TAspecific mouse monoclonal antibodies for the treatment of malignant diseases. The negative attitude towards TA-specific monoclonal antibodies also was enhanced by the major progress made at the same time in the identification and characterization of Tcell–defined TA and by the conviction that T-cell– based immunity and not humoral immunity was the key player in the control of tumor growth. The poor image of TA-specific monoclonal antibodies in the scientific community made things quite difficult for TA-specific monoclonal antibody aficionados in terms of grant funding and job opportunities both at academic institutions and in pharmaceutical companies. Things changed dramatically in 1997 when the CD20-specific monoclonal antibody rituximab was approved by the US Food and Drug Administration for the treatment of non-Hodgkin lymphoma. Since then, TA-specific monoclonal antibodies have become widely used therapeutic agents in the clinical setting. Furthermore, there has been a growing interest in developing novel monoclonal antibodies to previously unidentified clinically relevant molecules that can be used as targets Conflicts of interest: none 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2014.09.011
556
of immunotherapy. In parallel, there have been major efforts to improve the therapeutic efficacy of the available TA-specific monoclonal antibodies. The latter approaches have greatly benefited from the significant progress made in our understanding of the multiple mechanisms utilized by TA-specific monoclonal antibodies to exert their anti-tumor effects and in the technology to modify the functional characteristics of monoclonal antibodies. Figure 1 lists the mechanisms that have been exploited to design immunotherapeutic strategies for the treatment of malignant diseases using TAspecific monoclonal antibodies. Besides activation of immunologic effector mechanisms such as complement and Fc receptor bearing cells, TA-specific monoclonal antibodies can interfere with the activation of signaling pathways involved in cancer cell proliferation, survival, and migration and/or can induce apoptosis of cancer cells. In addition they can target to cancer cells chemotherapeutic agents, cytokines, radioisotopes, and/or toxins, thus increasing their concentration in the tumor microenvironment and minimizing, if not eliminating, the side effects associated with the systemic administration of these agents. A more recent application of TAspecific monoclonal antibodies has been their use to target to the tumor microenvironment cells such as natural killeer cells and T cells, thus targeting tumors with cellular immunity without the need to generate a TA-specific T-cell immunity. Among the latter strategies the one that is attracting much attention is that which relies on the transduction of naı¨ve T cells with chimeric antigen receptors. The latter contain variable regions of TA-specific antibodies linked to activation molecules. While the latter provide the signals leading to T-cell activation, the former endow naı¨ve T cells with TA-specificity. This approach is being explored in a rather aggressive way by several biotechnology and big pharma companies with or without the participation of academic institutions. Major investments have been made in recent years in order to evaluate the clinical significance of this strategy; therefore it is likely that in the near future we will have the clinical data to assess this elegant technology, which exploits the advantages of cellular and humoral immunity and at the same time minimizes the interference of their limitations.
Seminars in Oncology, Vol 41, No 5, October 2014, pp 556-558
Therapeutic monoclonal antibodies
A
557
B
C
Figure 1. Mechanisms utilized by tumor antigen-specific monoclonal antibodies to mediate anti-tumor effects. CAR, chimeric antigen receptor; mAb, monoclonal antibody; TCR, T-cell receptor.
The above-mentioned strategies are discussed in the reviews included in this issue of Seminars in Oncology. Each contributor has been encouraged not to provide an extensive review of the information available in the literature, but to focus on the discussion of the challenges we face and need to overcome to optimize the use of TA-specific monoclonal antibodies in the clinical setting. A very large number of patients with various types of malignancies has been treated in a relatively short time with TA-specific monoclonal antibodybased immunotherapy. The number of treated patients will continue to increase because the clinical results are excellent and because the experience we will continue to acquire by treating patients will help us to develop strategies to minimize or even eliminate treatment-associated side effects. Therefore, a large amount of information is available. The following are the points which in my opinion are noteworthy: 1. Lack of expression of the targeted TA in normal tissues does not appear to be an absolute requirement for the selection of a TA as a target of antibody-based immunotherapy. There are several examples of TA that are expressed in normal tissues and nevertheless immunotherapy can control tumor growth or eliminate tumors without causing treatment-associated side effects. One
such example is epidermal growth factor receptor (EGFR), which has a broad distribution in normal tissues. Nevertheless, administration of EGFRspecific monoclonal antibodies such as cetuximab to patients with head and neck cancer or with colon cancer does not appear to cause severe side effects because of the binding of monoclonal antibodies to normal tissues expressing EGFR. Expression level of targeted TA in normal cells as compared to that in malignant cells and more importantly effect of TA-specific monoclonal antibodies on signaling pathway(s) in normal cells as compared to that in malignant cells may underlie the differential effect of TA-specific monoclonal antibodies on malignant cells and on normal cells. To the best of my knowledge no experimental data are available in this regard. This type of information would be very useful to set the criteria to select the TA-specific monoclonal antibodies to be developed for therapeutic use. 2. Combination with chemotherapeutic agents and/ or with signal transduction pathway inhibitors has been shown to enhance the anti-tumor activity of several TA-specific monoclonal antibodies. In addition to the additive or synergistic effect of these combinations as far as the antitumor effect is concerned, the combination of
558
TA-specific monoclonal antibodies with agents that use a different mechanism of action may be useful to counteract the escape mechanism (s) used by tumor cells to avoid immune recognition and destruction. The rational choice of agents to be combined with TA-specific monoclonal antibodies will greatly benefit from information about the mechanisms of action of the agents to be combined and more importantly about how they influence each other. 3. According to the cancer stem cell theory a major cause of failure of current chemo- and radiotherapy is represented by the chemo- and radio-resistance of cancer-initiating cells (CICs). These cells which at variance from differentiated cancer cells survive chemo- and radiotherapy are postulated to play a major role in metastatic spread and disease recurrence. Evidence begins to be available that immunotherapy with TA-specific monoclonal antibodies can target not only differentiated cancer cells, but also CICs. Whether the targeting of CICs in addition to that of differentiated cancer cells has an impact on the clinical course of the disease, as implied by the suggested role of CICs in metastatic spread and in disease recurrence and by the results obtained in several animal model systems, remains to be determined. 4. Resistance of cancer cells to the anti-tumor activity of immunotherapy with TA-specific monoclonal antibodies remains a major obstacle to the successful application of this type of immunotherapy in a clinical setting. Tumor cells’ genetic instability, development of escape mechanisms by tumor cells to avoid immune recognition and destruction and/or selective pressure imposed on tumor cell population by the applied immunotherapy lead to the outgrowth of a tumor cell
S. Ferrone
subpopulation with the “resistance” phenotype. Detailed characterization of the underlying molecular mechanism(s) will be required for the rational design of strategies to counteract these mechanisms. It is a general experience that only a proportion of the patients with a given type of tumor treated with immunotherapy with TA-specific monoclonal antibodies responds to the therapy. At present we do not know why this happens and we do not have biomarkers to identify the subpopulation of patients responsive to the applied immunotherapy with TA-specific monoclonal antibodies. The ability to identify “responsive” patients would avoid exposing patients who are not likely to respond to the risks associated with the administration of TAspecific monoclonal antibodies and would reduce the financial burden imposed on health systems by the high cost of monoclonal antibodies. In spite of its importance this topic is not discussed in this issue of Seminars since in our opinion we do not have sufficient information to discuss it. Let’s hope that granting agencies and pharmaceutical companies will set up systems to stimulate research in this area. In closing this Introduction I would like to thank Dr Michael J. Mastrangelo, the Editor in Chief, for having given me the opportunity to edit this issue of Seminars in Oncology and for his support and guidance, the contributors for having submitted excellent papers, and the Elsevier staff for excellent managerial assistance.
Soldano Ferrone, MD, PhD Massachusetts General Hospital Boston, MA, Guest Editor E-mail: [email protected]