Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Cancer Immunotherapy: More Is (Much) Better Yosef Yarden1 and Michael Sela2
Departments of 1Biological Regulation and 2Immunology, Weizmann Institute of Science, Rehovot, Israel.
Corresponding Author: Yosef Yarden, Department of Biological Regulation, Weizmann Institute of Science, 1 Herzl Street, Rehovot 76100, ISRAEL. Phone: +972 8 934 3974; Fax: +972 8 934 2488; E-mail: [email protected]
Running Title: Synergistic Mixtures of Anticancer Antibodies
Disclosure of Potential Conflicts of Interest The authors are inventors of patents in the field of immunotherapy. Y. Yarden reports receiving
a
commercial
research
grant
from
Merck
Serono
and
is
a
consultant/advisory board member for Symphogen.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Summary Although antibodies against EGFR and HER2 are used to treat cancer, only some patients respond and resistance often emerges. Jacobsen and colleagues present in this issue experimental evidence favoring replacement of the currently applied monoclonal antibodies with oligoclonal mixtures of six synergistic antibodies, simultaneously engaging EGFR, HER2 and also HER3.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
In this issue of Clinical Cancer Research, Jacobsen and colleagues (1) describe a novel strategy to inhibit solid tumors by using multiple antibodies. Attempts to precisely intercept pathogenic agents date back to 1906 and the “Magic Bullet” concept of Paul Ehrlich, which has inspired generations of physicians and drug developers: drugs and dyes alike might selectively home at disease-causing agents, while ignoring neighboring healthy tissues. Seventy years later, César Milstein and Georges Köhler developed the hybridoma technique for the production of monoclonal antibodies (mAbs). The first anti-cancer mAbs were approved for patient treatment around the end of the 20th century. They included trastuzumab (Herceptin™), an antiHER2 mAb, and cetuximab (Erbitux™), which binds with the epidermal growth factor receptor (EGFR). The turn of the millennium has witnessed an unprecedented avalanche of anti-cancer agents, such that mAbs are becoming one of the best exemplifications of Ehrlich’s visionary “magic bullets”: they are available in practically unlimited amounts and they might be engineered to evade anti-antibody responses in patients. In addition, their remarkable homogeneity makes the pharmacology and clinical approval of mAbs relatively straightforward. However, unlike vaccination, which represents a form of active immunotherapy, treatment of patients with recombinant antibodies (passive immunotherapy) avoids essential features of the natural immune response, such as gradually increasing strength of antigen recognition (affinity maturation), immunoglobulin class switching from pentavalent IgM to bivalent IgG molecules, and memory conferred by antibodyproducing B-lymphocytes. In addition, unlike the uniform, monoclonal antibodies used in cancer therapy, the human immune response often generates antibodies to multiple, sometimes homologous antigens presented by the invader, and each antigen is decorated by many different antibodies, each recognizing a distinct epitope
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
(polyclonal antiserum). As demonstrated by Jacobsen and colleagues (1), adopting the polyclonal nature of the B-cell immune response, as well as simultaneously engaging several closely related and collaborating antigens, might enhance anti-tumor efficacy of the presently applied monoclonal antibodies. The antigens selected by Jacobsen and colleagues are three receptors for growth factors, namely EGFR, HER2 (a co-receptor) and HER3, which binds ligands called neuregulins. Because the fourth member of the human EGF receptor family (HER4, also called ERBB4) is expressed also in cardiac and in nerve cells, it was not targeted. Physiological activation of these receptors by their ligands absolutely depends on formation of dimers, either hetero-dimers or the less active, homodimers. Especially active heterodimers are EGFR-HER2, which employ the mitogen-activated protein kinase (MAPK) pathway, and HER2-HER3 dimers, which recruit the phosphoinositide 3-kinase (PI3K) cascade. Accordingly, anti-cancer therapeutic antibodies might block growth factor binding (e.g., cetuximab and panitumumab), or they can paralyze the receptor’s ability to assist other, ligand-occupied receptors (e.g., trastuzumab and pertuzumab) (2). Besides their activation by growth factors, constitutively active, aberrant forms of HER proteins are frequently detected in cancer. Examples include receptors harboring activating mutations or internal deletions, and overexpressed receptors. However, due to their extensive crosstalk and functional redundancy, clinically meaningful and long-lasting blockade of HER proteins, both mutant and wild type forms, has turned out to be an immense pharmacological challenge (3). For example, breast cancer patients treated with trastuzumab often develop resistance that might be due to up-regulation of EGFR (4) or one of its ligands. Likewise, resistance of colorectal cancer patients to cetuximab is
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
attributable, in many cases, to emergence of KRAS mutations (5), or less frequently, to HER2 amplification (6). To circumvent both structural plasticity and the functional redundancy of the HER network, Jacobsen and colleagues undertook a dual pronged attack (see Figure 1): First, they simultaneously targeted EGFR, HER2 and HER3, such that evasion mechanisms were blocked. Second, because pairs of mAbs engaging mutually nonoverlapping epitopes robustly eliminate the target (7, 8), and a similar HER2-targeting pair has been approved for treatment of mammary tumors (9), the authors employed pairs rather than single mAbs. This strategy translated to application of a mixture of six mAbs, which they denoted Pan-HER. As expected, each of the selected pairs synergistically inhibited metabolic activity of epithelial cells, in vitro, and more strongly sorted their targets for degradation than did the respective single mAbs. When combined, the three mAb pairs comprising Pan-HER exhibited even stronger and wider inhibitory effects on a surprisingly wide spectrum of tumor cell lines, including some expressors of mutant forms of TP53 and KRAS. In support of an ability to overcome emergent (secondary) resistance, Pan-HER retained potency in the presence of ligands of EGFR (EGF) and HER3 (neuregulin 1). Likewise, PanHER prevented compensatory HER up-regulation, which often accompanies responses to single receptor blockers. Similarly, Pan-HER arrested cells that acquired, in vitro, resistance to the inhibitory effects of cetuximab, trastuzumab or pertuzumab. Ultimately, the authors tested Pan-HER on several hard-to-treat cancer models, in animals, including xenografts derived from ovary, colorectal, lung and pancreas cancer patients (PDX models). In all models, Pan-HER outperformed cetuximab and trastuzumab, and in some models the inhibitory action was not only sustained but also persisted after withdrawal of the mixture of six antibodies.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
What could possibly underlie the relatively high potency of Pan-HER in animal models? One clue is the requirement that none of the six mAbs of Pan-HER shares target epitopes with the other five mAbs. Because the study made use of athymic nude mice, it is possible that Pan-HER was able to recruit six times more natural killer (NK) lymphocytes to cancer cells, as compared to any single mAb. In support of this scenario, the effector domains (called Fc) of anti-HER2 monoclonals are required for optimal in vivo activity of antibody mixtures (10). Because immunohistochemical analysis of some xenografts revealed marked downregulation of all three receptors following treatment with Pan-HER, the authors raise the possibility that Pan-HER effectively eliminates receptors for EGF-family survival factors. Yet another open issue relates to the safety of co-applying six different antibodies. It is conceivable that skin, gastrointestinal or other adverse effects will limit clinical application of Pan-HER. Hence, it would be worthwhile testing less complex mixtures of 2-4 mAbs, which are expected to be less toxic and, presumably, as effective as Pan-HER. This option has been supported by pancreatic cancer studies that utilized mixtures comprising anti-HER2 and anti-EGFR antibodies (11, 12). A similar option is offered by recombinant bispecific antibodies able to simultaneously bind two HER proteins. Clearly, more studies in animal models and in patients are needed in order to unravel the true therapeutic potential of Pan-HER and similar oligoclonal approaches. Such future endeavors seem worthy, since they might open a new era in cancer immunotherapy. Grant Support Y. Yarden was supported by the European Research Council, the Seventh Framework Programme of the European Commission, the German-Israeli Project Cooperation (DIP/DFG), the Marvin Tanner Laboratory for Research on Cancer, the Israel Cancer
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Research Fund, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. M. Sela was supported by the M.D. Moross Institute for Cancer Research. Y. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair, and M. Sela is the incumbent of the W. Garfield Weston Chair. References 1.
Jacobsen HJ, Poulsen TT, Dahlman A, Kjaer I, Koefoed K, Sen JW, et al. Pan-
HER, an antibody mixture simultaneously targeting EGFR, HER2, and HER3 effectively overcomes tumor heterogeneity and plasticity. Clin Cancer Res 2015 Apr 23. [Epub ahead of print]. 2.
Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, et al.
Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127-37. 3.
Kruser TJ, Wheeler DL. Mechanisms of resistance to HER family targeting
antibodies. Exp Cell Res 2010;316:1083-100. 4.
Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et
al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 2007;13:4909-19. 5.
Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al.
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486:532-6. 6.
Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et
al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 2011;3:99ra86.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
7.
Ben-Kasus T, Schechter B, Lavi S, Yarden Y, Sela M. Persistent elimination
of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: relevance of receptor endocytosis. Proc Natl Acad Sci U S A 2009;106:3294-9. 8.
Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS, et al.
Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A 2005;102:1915-20. 9.
Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, et al.
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, doubleblind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71. 10.
Spiridon CI, Guinn S, Vitetta ES. A comparison of the in vitro and in vivo
activities of IgG and F(ab')2 fragments of a mixture of three monoclonal antiHer-2 antibodies. Clin Cancer Res 2004;10:3542-51. 11.
Maron R, Schechter B, Mancini M, Mahlknecht G, Yarden Y, Sela M.
Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2. Proc Natl Acad Sci U S A 2013;110:15389-94. 12.
Larbouret C, Gaborit N, Chardes T, Coelho M, Campigna E, Bascoul-Mollevi
C, et al. In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' downregulation and dimers' disruption. Neoplasia 2012;14:121-30.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Figure 1. Moving away from monoclonal anti-cancer antibodies to synergistic polyclonal mixtures of antibodies? Many currently approved protocols of cancer therapy make use of a single monoclonal antibody, in combination with a chemotherapeutic agent (not shown). However, due to adaptive biochemical mechanisms, including stimulation of alternative receptor dimers and downstream pathways, cancer cells might evade the inhibitory effect of singly applied monoclonal antibodies. Jacobsen and colleagues propose in this issue of Clinical Cancer Research an alternative protocol: By applying a mixture of three pairs of monoclonal antibodies, each pair directed against a distinct growth factor receptor, the strategy they propose might overcome patient resistance and also enhance anti-tumor effects. Note that the tradeoffs in implementing the proposed protocol would involve relatively complicated approval procedures and higher costs of manufacturing.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Figure 1: Current therapies
Future therapies?
Allow resistance Modestly effective Single-agent approval Expensive
Overcome resistance Highly effective Multiagent approval Very expensive
Active
Inactive
Inactive
Inactive
Growth signals
© 2015 American Association for Cancer Research
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Cancer Immunotherapy: More Is (Much) Better Yosef Yarden and Michael Sela Clin Cancer Res Published OnlineFirst May 27, 2015.
Updated version Author Manuscript
E-mail alerts Reprints and Subscriptions Permissions
Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Cancer Immunotherapy: More Is (Much) Better Yosef Yarden1 and Michael Sela2
Departments of 1Biological Regulation and 2Immunology, Weizmann Institute of Science, Rehovot, Israel.
Corresponding Author: Yosef Yarden, Department of Biological Regulation, Weizmann Institute of Science, 1 Herzl Street, Rehovot 76100, ISRAEL. Phone: +972 8 934 3974; Fax: +972 8 934 2488; E-mail: [email protected]
Running Title: Synergistic Mixtures of Anticancer Antibodies
Disclosure of Potential Conflicts of Interest The authors are inventors of patents in the field of immunotherapy. Y. Yarden reports receiving
a
commercial
research
grant
from
Merck
Serono
and
is
a
consultant/advisory board member for Symphogen.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Summary Although antibodies against EGFR and HER2 are used to treat cancer, only some patients respond and resistance often emerges. Jacobsen and colleagues present in this issue experimental evidence favoring replacement of the currently applied monoclonal antibodies with oligoclonal mixtures of six synergistic antibodies, simultaneously engaging EGFR, HER2 and also HER3.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
In this issue of Clinical Cancer Research, Jacobsen and colleagues (1) describe a novel strategy to inhibit solid tumors by using multiple antibodies. Attempts to precisely intercept pathogenic agents date back to 1906 and the “Magic Bullet” concept of Paul Ehrlich, which has inspired generations of physicians and drug developers: drugs and dyes alike might selectively home at disease-causing agents, while ignoring neighboring healthy tissues. Seventy years later, César Milstein and Georges Köhler developed the hybridoma technique for the production of monoclonal antibodies (mAbs). The first anti-cancer mAbs were approved for patient treatment around the end of the 20th century. They included trastuzumab (Herceptin™), an antiHER2 mAb, and cetuximab (Erbitux™), which binds with the epidermal growth factor receptor (EGFR). The turn of the millennium has witnessed an unprecedented avalanche of anti-cancer agents, such that mAbs are becoming one of the best exemplifications of Ehrlich’s visionary “magic bullets”: they are available in practically unlimited amounts and they might be engineered to evade anti-antibody responses in patients. In addition, their remarkable homogeneity makes the pharmacology and clinical approval of mAbs relatively straightforward. However, unlike vaccination, which represents a form of active immunotherapy, treatment of patients with recombinant antibodies (passive immunotherapy) avoids essential features of the natural immune response, such as gradually increasing strength of antigen recognition (affinity maturation), immunoglobulin class switching from pentavalent IgM to bivalent IgG molecules, and memory conferred by antibodyproducing B-lymphocytes. In addition, unlike the uniform, monoclonal antibodies used in cancer therapy, the human immune response often generates antibodies to multiple, sometimes homologous antigens presented by the invader, and each antigen is decorated by many different antibodies, each recognizing a distinct epitope
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
(polyclonal antiserum). As demonstrated by Jacobsen and colleagues (1), adopting the polyclonal nature of the B-cell immune response, as well as simultaneously engaging several closely related and collaborating antigens, might enhance anti-tumor efficacy of the presently applied monoclonal antibodies. The antigens selected by Jacobsen and colleagues are three receptors for growth factors, namely EGFR, HER2 (a co-receptor) and HER3, which binds ligands called neuregulins. Because the fourth member of the human EGF receptor family (HER4, also called ERBB4) is expressed also in cardiac and in nerve cells, it was not targeted. Physiological activation of these receptors by their ligands absolutely depends on formation of dimers, either hetero-dimers or the less active, homodimers. Especially active heterodimers are EGFR-HER2, which employ the mitogen-activated protein kinase (MAPK) pathway, and HER2-HER3 dimers, which recruit the phosphoinositide 3-kinase (PI3K) cascade. Accordingly, anti-cancer therapeutic antibodies might block growth factor binding (e.g., cetuximab and panitumumab), or they can paralyze the receptor’s ability to assist other, ligand-occupied receptors (e.g., trastuzumab and pertuzumab) (2). Besides their activation by growth factors, constitutively active, aberrant forms of HER proteins are frequently detected in cancer. Examples include receptors harboring activating mutations or internal deletions, and overexpressed receptors. However, due to their extensive crosstalk and functional redundancy, clinically meaningful and long-lasting blockade of HER proteins, both mutant and wild type forms, has turned out to be an immense pharmacological challenge (3). For example, breast cancer patients treated with trastuzumab often develop resistance that might be due to up-regulation of EGFR (4) or one of its ligands. Likewise, resistance of colorectal cancer patients to cetuximab is
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
attributable, in many cases, to emergence of KRAS mutations (5), or less frequently, to HER2 amplification (6). To circumvent both structural plasticity and the functional redundancy of the HER network, Jacobsen and colleagues undertook a dual pronged attack (see Figure 1): First, they simultaneously targeted EGFR, HER2 and HER3, such that evasion mechanisms were blocked. Second, because pairs of mAbs engaging mutually nonoverlapping epitopes robustly eliminate the target (7, 8), and a similar HER2-targeting pair has been approved for treatment of mammary tumors (9), the authors employed pairs rather than single mAbs. This strategy translated to application of a mixture of six mAbs, which they denoted Pan-HER. As expected, each of the selected pairs synergistically inhibited metabolic activity of epithelial cells, in vitro, and more strongly sorted their targets for degradation than did the respective single mAbs. When combined, the three mAb pairs comprising Pan-HER exhibited even stronger and wider inhibitory effects on a surprisingly wide spectrum of tumor cell lines, including some expressors of mutant forms of TP53 and KRAS. In support of an ability to overcome emergent (secondary) resistance, Pan-HER retained potency in the presence of ligands of EGFR (EGF) and HER3 (neuregulin 1). Likewise, PanHER prevented compensatory HER up-regulation, which often accompanies responses to single receptor blockers. Similarly, Pan-HER arrested cells that acquired, in vitro, resistance to the inhibitory effects of cetuximab, trastuzumab or pertuzumab. Ultimately, the authors tested Pan-HER on several hard-to-treat cancer models, in animals, including xenografts derived from ovary, colorectal, lung and pancreas cancer patients (PDX models). In all models, Pan-HER outperformed cetuximab and trastuzumab, and in some models the inhibitory action was not only sustained but also persisted after withdrawal of the mixture of six antibodies.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
What could possibly underlie the relatively high potency of Pan-HER in animal models? One clue is the requirement that none of the six mAbs of Pan-HER shares target epitopes with the other five mAbs. Because the study made use of athymic nude mice, it is possible that Pan-HER was able to recruit six times more natural killer (NK) lymphocytes to cancer cells, as compared to any single mAb. In support of this scenario, the effector domains (called Fc) of anti-HER2 monoclonals are required for optimal in vivo activity of antibody mixtures (10). Because immunohistochemical analysis of some xenografts revealed marked downregulation of all three receptors following treatment with Pan-HER, the authors raise the possibility that Pan-HER effectively eliminates receptors for EGF-family survival factors. Yet another open issue relates to the safety of co-applying six different antibodies. It is conceivable that skin, gastrointestinal or other adverse effects will limit clinical application of Pan-HER. Hence, it would be worthwhile testing less complex mixtures of 2-4 mAbs, which are expected to be less toxic and, presumably, as effective as Pan-HER. This option has been supported by pancreatic cancer studies that utilized mixtures comprising anti-HER2 and anti-EGFR antibodies (11, 12). A similar option is offered by recombinant bispecific antibodies able to simultaneously bind two HER proteins. Clearly, more studies in animal models and in patients are needed in order to unravel the true therapeutic potential of Pan-HER and similar oligoclonal approaches. Such future endeavors seem worthy, since they might open a new era in cancer immunotherapy. Grant Support Y. Yarden was supported by the European Research Council, the Seventh Framework Programme of the European Commission, the German-Israeli Project Cooperation (DIP/DFG), the Marvin Tanner Laboratory for Research on Cancer, the Israel Cancer
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Research Fund, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. M. Sela was supported by the M.D. Moross Institute for Cancer Research. Y. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair, and M. Sela is the incumbent of the W. Garfield Weston Chair. References 1.
Jacobsen HJ, Poulsen TT, Dahlman A, Kjaer I, Koefoed K, Sen JW, et al. Pan-
HER, an antibody mixture simultaneously targeting EGFR, HER2, and HER3 effectively overcomes tumor heterogeneity and plasticity. Clin Cancer Res 2015 Apr 23. [Epub ahead of print]. 2.
Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, et al.
Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2002;2:127-37. 3.
Kruser TJ, Wheeler DL. Mechanisms of resistance to HER family targeting
antibodies. Exp Cell Res 2010;316:1083-100. 4.
Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et
al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 2007;13:4909-19. 5.
Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al.
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486:532-6. 6.
Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et
al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 2011;3:99ra86.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
7.
Ben-Kasus T, Schechter B, Lavi S, Yarden Y, Sela M. Persistent elimination
of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: relevance of receptor endocytosis. Proc Natl Acad Sci U S A 2009;106:3294-9. 8.
Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS, et al.
Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A 2005;102:1915-20. 9.
Swain SM, Kim SB, Cortes J, Ro J, Semiglazov V, Campone M, et al.
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, doubleblind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71. 10.
Spiridon CI, Guinn S, Vitetta ES. A comparison of the in vitro and in vivo
activities of IgG and F(ab')2 fragments of a mixture of three monoclonal antiHer-2 antibodies. Clin Cancer Res 2004;10:3542-51. 11.
Maron R, Schechter B, Mancini M, Mahlknecht G, Yarden Y, Sela M.
Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2. Proc Natl Acad Sci U S A 2013;110:15389-94. 12.
Larbouret C, Gaborit N, Chardes T, Coelho M, Campigna E, Bascoul-Mollevi
C, et al. In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors' downregulation and dimers' disruption. Neoplasia 2012;14:121-30.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Figure 1. Moving away from monoclonal anti-cancer antibodies to synergistic polyclonal mixtures of antibodies? Many currently approved protocols of cancer therapy make use of a single monoclonal antibody, in combination with a chemotherapeutic agent (not shown). However, due to adaptive biochemical mechanisms, including stimulation of alternative receptor dimers and downstream pathways, cancer cells might evade the inhibitory effect of singly applied monoclonal antibodies. Jacobsen and colleagues propose in this issue of Clinical Cancer Research an alternative protocol: By applying a mixture of three pairs of monoclonal antibodies, each pair directed against a distinct growth factor receptor, the strategy they propose might overcome patient resistance and also enhance anti-tumor effects. Note that the tradeoffs in implementing the proposed protocol would involve relatively complicated approval procedures and higher costs of manufacturing.
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Figure 1: Current therapies
Future therapies?
Allow resistance Modestly effective Single-agent approval Expensive
Overcome resistance Highly effective Multiagent approval Very expensive
Active
Inactive
Inactive
Inactive
Growth signals
© 2015 American Association for Cancer Research
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 27, 2015; DOI: 10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Cancer Immunotherapy: More Is (Much) Better Yosef Yarden and Michael Sela Clin Cancer Res Published OnlineFirst May 27, 2015.
Updated version Author Manuscript
E-mail alerts Reprints and Subscriptions Permissions
Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-15-0996 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].
Downloaded from clincancerres.aacrjournals.org on May 28, 2015. © 2015 American Association for Cancer Research.
