M O L E C U L A R O N C O L O G Y 9 ( 2 0 1 5 ) 1 8 9 1 e1 8 9 3
available at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/molonc
Editorial
Cancer immunotherapy e Converting immune failure to clinical response5
In 2013, cancer immunotherapy was selected as breakthrough of the year by the journal Science. After decades of disappointment with therapeutic vaccines that were by and large ineffective (Klebanoff et al., 2011; Rosenberg et al., 2004), it is now clear that current immunotherapeutic strategies can cure patients, even when conventional therapy is insufficient. The tide has changed, but why and how? By definition, anti-tumor immunity has failed when cancer is diagnosed in a patient; the same mechanisms that prevent autoimmune disease or protect us from immune-mediated damage following chronic exposure to microbes, prevail. While immunological tolerance is important to prevent disease, it is also the main cause of failure to reject cancer. Fortunately, researchers have demonstrated that tolerance can be partly reversed, and based on these findings new immunotherapeutic strategies have been generated that have brought about clinical success stories. A well-known example is treatment with so-called checkpoint inhibitors, monoclonal antibodies that block co-inhibitory molecules expressed on T cells, serving as immunological brakes. Another example on how to effectively enhance the host antitumor defense is the infusion of tumor-infiltrating lymphocytes (TIL) that were taken out of the inhibitory tumor context and expanded ex vivo. It now seems clear that clinically effective T cells in both of these strategies recognize peptides encoded by mutated DNA sequences. These can be “seen” as foreign by the T cells, similar to recognition of microbial peptides. In contrast, T cells that recognize non-mutated peptides from wild type proteins with high-affinity have been deleted during thymic development. This is likely the mechanism behind the lack of clinical responses when such antigens are used in therapeutic vaccines. However, although more recent cancer immunotherapy strategies can enhance anticancer immunity in many patients, the majority still does not experience clinical responses. In such cases, transfer of immunity from a donor might circumvent tolerance in the patient. Examples of strategies include therapeutic antibodies (originating from
5
mice), T cells or NK cells (in stem cell transplants from human donors) or DNA encoding immune receptors. A wide range of immunotherapeutic modalities is thus available, and the possibility to combine these with each other, as well as with standard anti-cancer treatment, provides even more options. In this issue, experts in the field discuss new opportunities for how to overcome tolerance to cancer at multiple levels, and by a multitude of strategies. While immunotherapy is often referred to as the new, magic bullets, cell-based immunotherapy has been used routinely in leukemia patients since E. Donnall Thomas performed the first bone marrow transplantation in the late 1950s (Thomas et al., 1957). For many patients, donorderived cells represent the only curative option, but one that comes at a heavy cost, as the treatment-related toxicity and mortality is high. In part, this is due to our inability to isolate T cells that selectively kill the leukemic cells from those that react with healthy tissues and cause graft-versus-host disease (GVHD). In this issue, Jedema and Falkenburg discuss how allo-reactive T cells can be more specifically targeted to leukemia in an HLA-matched or -mismatched setting (Jedema and Falkenburg, this issue). For decades, it has been clear that natural killer (NK) cells from HLA-mismatched donors also mediate killing of leukemic cells. As reviewed by Malmberg and colleagues, recent insights into the functional plasticity and adaptive capabilities of NK cells open new opportunities for NK cell-based cancer immunotherapy (Liu et al, this issue). In the 1980s, Rosenberg and colleagues showed that TILs isolated from the patient’s own tumor have antitumor reactivity upon expansion and reinfusion. Clinical trials have now applied this approach at multiple centers, and it is well established that TILs are highly effective in treatment of malignant melanoma. Haanen and colleagues review the experience with TILs in melanoma and discuss the therapeutic potential in other cancer types (Geukes Foppen et al, this issue). Quezada and colleagues review the mechanism of action and clinical results utilizing well-known checkpoint inhibitors
This is a contribution to the special issue edited by Johanna Olweus, Cancer Immunotherapy.
1892
M O L E C U L A R O N C O L O G Y 9 ( 2 0 1 5 ) 1 8 9 1 e1 8 9 3
targeting CTLA-4 and PD-1 (Sledzinska et al, this issue). Moreover, they share new insights into the mechanism of action of a number of co-inhibitory molecules that might be targets of future immunotherapies. Several other reviews in this issue discuss the opportunity of combination therapies including checkpoint inhibition. An alternative approach to enhance a systemic anti-tumor T-cell response in patients is to evoke inflammation locally in the tumor and facilitate efficient presentation of the antigens that are at hand to T cells. Such “in situ vaccination” strategies are reviewed by Brody and colleagues (Hammerich et al, this issue). The described strategies to induce or augment cellular immunity are to a large extent “shot-gun” approaches. By contrast, therapeutic antibodies represent the ultimate targeted therapy. It took more than 20 years to translate Kohler and Milstein’s method for producing monoclonal antibodies into an FDA-approved therapeutic agent. However, persistence in this research area was generously rewarded, and today therapeutic antibodies represent one of the fastest growing areas in oncology. Current antibodies target wildtype surface proteins with cell type-restricted expression. In this issue, Ferrone and colleagues challenge this dogma and review strategies to extend the targets of antibodies to intracellular proteins (Wang et al, this issue). The success of therapeutic antibodies spurred research on targeted cell-based therapy. New and robust techniques for gene transfer to human T lymphocytes open a wide range of new opportunities to arm T cells with receptors that have defined specificity. The first major breakthrough came from genetic transfer of engineered antibodies. Chimeric Antigen Receptors (CARs) are fusion constructs consisting of the antigen-binding moiety of antibodies and transmembrane signaling proteins from T cells. As reviewed by Whilding and Maher, a cell-based effector arm led to a tremendous increase in antibody efficacy in leukemia (Whilding and Maher, this issue). The authors also discuss opportunities to extend the use of CARs to treatment of solid tumors. Karpanen and Olweus review the next challenge, which is to develop high-throughput systems for identification of safe targets, and of safe and effective tumor-targeted T-cell receptors (Karpanen and Olweus, this issue). Success in this area will greatly increase the number of therapeutic targets since Tcell receptors can recognize peptides from intracellular proteins. In the era of personalized medicine, cancer immunotherapy adds a new level of complexity to the term. In addition to delivering the anti-cancer drug with optimal dose and scheduling for each individual, the optimal anti-cancer drug may have to be derived from components of the patient’s own immune system, or from a donor selected to match each patient. Personalized immunotherapy raises important questions related to pre-clinical screening systems and the design of clinical trials. For example, the importance of mouse models in testing of small molecule drugs is unquestionable, but the relevance of such models is doubtful for preclinical safety evaluation of immunotherapeutic strategies where human immune cells are part of the effector arm. Thus, concerted efforts are required to standardize preclinical screening approaches in silico and in vitro, as discussed in this issue. Furthermore, the scarcity of relevant
animal models put even more emphasis on innovative and stepwise clinical trials that challenge traditional protocol design. It is not known why some patients successfully respond to therapy while others progress on the same regime. Combinatorial approaches might in such cases be required rather than a switch of strategy, and Sathyanarayanan and Neelapu discuss how we can maneuver in the jungle of therapeutic possibilities that arise (Sathyanarayanan and Neelapu, this issue). Selecting the right patient for the right treatment is one important component of such trials. In fact, the degree of lymphocyte-infiltration in tumor is in many cases the best prognostic marker of response to therapy, but the significance varies with cancer type and molecular subtype, as reviewed by Quigley and Kristensen (Quigley and Kristensen, this issue). High-throughput sequencing technologies furthermore provide a new tool for the precise identification of T-cell clones that respond to immunotherapy, as reviewed by Robins and colleagues (Kirsch et al, this issue). In addition to the potential therapeutic utility of this information, the possibility to accurately and quantitatively follow T-cell repertoires by parallel tracking in tumor, blood and other tissues over time represent valuable biomarkers to predict response. The ultimate aim in oncology is to target molecules that are altered as a result of cancer-specific gene mutations. With high-throughput DNA sequencing it is now feasible to perform exome sequencing of any given tumor and map mutations as part of routine diagnostics. A disappointing fact is, however, that most mutations are patient-specific, and the mutated protein may not be druggable with existing inhibitors. The prospect of mutation-directed immunotherapy could change the situation dramatically. DNA and RNA sequence information from tumors can be combined with computer algorithms to predict peptides encoded by mutated genes that can evoke an immune response. The patient can be monitored for presence of T cells responding to the mutations. Out of several alternative future immunotherapeutic applications of this information, such T cells could be selected and expanded in vitro for re-infusion into the patient, their T-cell receptors used in gene therapy and/or the peptides synthesized and used for vaccination purposes. The rapid technological development, in terms of turn-around times for exome sequencing, bioinformatic prediction, and T-cell receptor sequencing, hold promise to make such personalized approaches a reality for certain patient groups in relatively few years. The search for immunotherapy targets might therefore end up being the most important rationale for both exome and RNA sequencing of tumors where the aim is to develop truly personalized medicine. The scientific challenges are accompanied by a number of non-scientific challenges not reviewed in the current issue. These include logistic, regulatory and financial obstacles, many of which are similar to those faced by other personalized medicine strategies. However, the efficacy of immunotherapy is likely to pave the way for new solutions to overcome these hurdles as the application of immunotherapy becomes more widespread. The recent commercial interest of large pharmaceutical companies in adoptive cell therapy approaches, boosted by the promising results with CAR- and TCR-based gene therapies, is one example. It is our hope
M O L E C U L A R O N C O L O G Y 9 ( 2 0 1 5 ) 1 8 9 1 e1 8 9 3
that the current issue will educate a broader community about the realities and potentials of cancer immunotherapy, and inspire research leading to new insights in how we can convert even more immune failures into clinical responses.
1893
Johanna Olweus Oslo University Hospital Radiumhospitalet, Department of Cancer Immunology, Institute for Cancer Research, Ullernchausseen 70, N-0310 Oslo, Norway E-mail address: [email protected]
R E F E R E N C E S
Klebanoff, C.A., Acquavella, N., Yu, Z., Restifo, N.P., 2011. Therapeutic cancer vaccines: are we there yet? Immunol. Rev. 239, 27e44. Rosenberg, S.A., Yang, J.C., Restifo, N.P., 2004. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909e915. Thomas, E.D., Lochte Jr., H.L., Lu, W.C., Ferrebee, J.W., 1957. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 257, 491e496.
Johanna Olweus received her M.D. and her Ph.D. from the University of Bergen, Norway. She is a specialist in Immunology and Transfusion medicine and since 2008 Full Professor at the University of Oslo and Head of Department of Cancer Immunology at the Institute for Cancer Research, Oslo University Hospital Radiumhospitalet. Since 2013 she is the Director of K.G. Jebsen Center for Cancer Immunotherapy. Olweus and her research group are focused on the development of new strategies for T-cell based cancer immunotherapy and in-depth mechanistic analyses of the immune responses in clinical immunotherapy trials.
http://dx.doi.org/10.1016/j.molonc.2015.10.017 1574-7891/ª 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
available at www.sciencedirect.com
ScienceDirect www.elsevier.com/locate/molonc
Editorial
Cancer immunotherapy e Converting immune failure to clinical response5
In 2013, cancer immunotherapy was selected as breakthrough of the year by the journal Science. After decades of disappointment with therapeutic vaccines that were by and large ineffective (Klebanoff et al., 2011; Rosenberg et al., 2004), it is now clear that current immunotherapeutic strategies can cure patients, even when conventional therapy is insufficient. The tide has changed, but why and how? By definition, anti-tumor immunity has failed when cancer is diagnosed in a patient; the same mechanisms that prevent autoimmune disease or protect us from immune-mediated damage following chronic exposure to microbes, prevail. While immunological tolerance is important to prevent disease, it is also the main cause of failure to reject cancer. Fortunately, researchers have demonstrated that tolerance can be partly reversed, and based on these findings new immunotherapeutic strategies have been generated that have brought about clinical success stories. A well-known example is treatment with so-called checkpoint inhibitors, monoclonal antibodies that block co-inhibitory molecules expressed on T cells, serving as immunological brakes. Another example on how to effectively enhance the host antitumor defense is the infusion of tumor-infiltrating lymphocytes (TIL) that were taken out of the inhibitory tumor context and expanded ex vivo. It now seems clear that clinically effective T cells in both of these strategies recognize peptides encoded by mutated DNA sequences. These can be “seen” as foreign by the T cells, similar to recognition of microbial peptides. In contrast, T cells that recognize non-mutated peptides from wild type proteins with high-affinity have been deleted during thymic development. This is likely the mechanism behind the lack of clinical responses when such antigens are used in therapeutic vaccines. However, although more recent cancer immunotherapy strategies can enhance anticancer immunity in many patients, the majority still does not experience clinical responses. In such cases, transfer of immunity from a donor might circumvent tolerance in the patient. Examples of strategies include therapeutic antibodies (originating from
5
mice), T cells or NK cells (in stem cell transplants from human donors) or DNA encoding immune receptors. A wide range of immunotherapeutic modalities is thus available, and the possibility to combine these with each other, as well as with standard anti-cancer treatment, provides even more options. In this issue, experts in the field discuss new opportunities for how to overcome tolerance to cancer at multiple levels, and by a multitude of strategies. While immunotherapy is often referred to as the new, magic bullets, cell-based immunotherapy has been used routinely in leukemia patients since E. Donnall Thomas performed the first bone marrow transplantation in the late 1950s (Thomas et al., 1957). For many patients, donorderived cells represent the only curative option, but one that comes at a heavy cost, as the treatment-related toxicity and mortality is high. In part, this is due to our inability to isolate T cells that selectively kill the leukemic cells from those that react with healthy tissues and cause graft-versus-host disease (GVHD). In this issue, Jedema and Falkenburg discuss how allo-reactive T cells can be more specifically targeted to leukemia in an HLA-matched or -mismatched setting (Jedema and Falkenburg, this issue). For decades, it has been clear that natural killer (NK) cells from HLA-mismatched donors also mediate killing of leukemic cells. As reviewed by Malmberg and colleagues, recent insights into the functional plasticity and adaptive capabilities of NK cells open new opportunities for NK cell-based cancer immunotherapy (Liu et al, this issue). In the 1980s, Rosenberg and colleagues showed that TILs isolated from the patient’s own tumor have antitumor reactivity upon expansion and reinfusion. Clinical trials have now applied this approach at multiple centers, and it is well established that TILs are highly effective in treatment of malignant melanoma. Haanen and colleagues review the experience with TILs in melanoma and discuss the therapeutic potential in other cancer types (Geukes Foppen et al, this issue). Quezada and colleagues review the mechanism of action and clinical results utilizing well-known checkpoint inhibitors
This is a contribution to the special issue edited by Johanna Olweus, Cancer Immunotherapy.
1892
M O L E C U L A R O N C O L O G Y 9 ( 2 0 1 5 ) 1 8 9 1 e1 8 9 3
targeting CTLA-4 and PD-1 (Sledzinska et al, this issue). Moreover, they share new insights into the mechanism of action of a number of co-inhibitory molecules that might be targets of future immunotherapies. Several other reviews in this issue discuss the opportunity of combination therapies including checkpoint inhibition. An alternative approach to enhance a systemic anti-tumor T-cell response in patients is to evoke inflammation locally in the tumor and facilitate efficient presentation of the antigens that are at hand to T cells. Such “in situ vaccination” strategies are reviewed by Brody and colleagues (Hammerich et al, this issue). The described strategies to induce or augment cellular immunity are to a large extent “shot-gun” approaches. By contrast, therapeutic antibodies represent the ultimate targeted therapy. It took more than 20 years to translate Kohler and Milstein’s method for producing monoclonal antibodies into an FDA-approved therapeutic agent. However, persistence in this research area was generously rewarded, and today therapeutic antibodies represent one of the fastest growing areas in oncology. Current antibodies target wildtype surface proteins with cell type-restricted expression. In this issue, Ferrone and colleagues challenge this dogma and review strategies to extend the targets of antibodies to intracellular proteins (Wang et al, this issue). The success of therapeutic antibodies spurred research on targeted cell-based therapy. New and robust techniques for gene transfer to human T lymphocytes open a wide range of new opportunities to arm T cells with receptors that have defined specificity. The first major breakthrough came from genetic transfer of engineered antibodies. Chimeric Antigen Receptors (CARs) are fusion constructs consisting of the antigen-binding moiety of antibodies and transmembrane signaling proteins from T cells. As reviewed by Whilding and Maher, a cell-based effector arm led to a tremendous increase in antibody efficacy in leukemia (Whilding and Maher, this issue). The authors also discuss opportunities to extend the use of CARs to treatment of solid tumors. Karpanen and Olweus review the next challenge, which is to develop high-throughput systems for identification of safe targets, and of safe and effective tumor-targeted T-cell receptors (Karpanen and Olweus, this issue). Success in this area will greatly increase the number of therapeutic targets since Tcell receptors can recognize peptides from intracellular proteins. In the era of personalized medicine, cancer immunotherapy adds a new level of complexity to the term. In addition to delivering the anti-cancer drug with optimal dose and scheduling for each individual, the optimal anti-cancer drug may have to be derived from components of the patient’s own immune system, or from a donor selected to match each patient. Personalized immunotherapy raises important questions related to pre-clinical screening systems and the design of clinical trials. For example, the importance of mouse models in testing of small molecule drugs is unquestionable, but the relevance of such models is doubtful for preclinical safety evaluation of immunotherapeutic strategies where human immune cells are part of the effector arm. Thus, concerted efforts are required to standardize preclinical screening approaches in silico and in vitro, as discussed in this issue. Furthermore, the scarcity of relevant
animal models put even more emphasis on innovative and stepwise clinical trials that challenge traditional protocol design. It is not known why some patients successfully respond to therapy while others progress on the same regime. Combinatorial approaches might in such cases be required rather than a switch of strategy, and Sathyanarayanan and Neelapu discuss how we can maneuver in the jungle of therapeutic possibilities that arise (Sathyanarayanan and Neelapu, this issue). Selecting the right patient for the right treatment is one important component of such trials. In fact, the degree of lymphocyte-infiltration in tumor is in many cases the best prognostic marker of response to therapy, but the significance varies with cancer type and molecular subtype, as reviewed by Quigley and Kristensen (Quigley and Kristensen, this issue). High-throughput sequencing technologies furthermore provide a new tool for the precise identification of T-cell clones that respond to immunotherapy, as reviewed by Robins and colleagues (Kirsch et al, this issue). In addition to the potential therapeutic utility of this information, the possibility to accurately and quantitatively follow T-cell repertoires by parallel tracking in tumor, blood and other tissues over time represent valuable biomarkers to predict response. The ultimate aim in oncology is to target molecules that are altered as a result of cancer-specific gene mutations. With high-throughput DNA sequencing it is now feasible to perform exome sequencing of any given tumor and map mutations as part of routine diagnostics. A disappointing fact is, however, that most mutations are patient-specific, and the mutated protein may not be druggable with existing inhibitors. The prospect of mutation-directed immunotherapy could change the situation dramatically. DNA and RNA sequence information from tumors can be combined with computer algorithms to predict peptides encoded by mutated genes that can evoke an immune response. The patient can be monitored for presence of T cells responding to the mutations. Out of several alternative future immunotherapeutic applications of this information, such T cells could be selected and expanded in vitro for re-infusion into the patient, their T-cell receptors used in gene therapy and/or the peptides synthesized and used for vaccination purposes. The rapid technological development, in terms of turn-around times for exome sequencing, bioinformatic prediction, and T-cell receptor sequencing, hold promise to make such personalized approaches a reality for certain patient groups in relatively few years. The search for immunotherapy targets might therefore end up being the most important rationale for both exome and RNA sequencing of tumors where the aim is to develop truly personalized medicine. The scientific challenges are accompanied by a number of non-scientific challenges not reviewed in the current issue. These include logistic, regulatory and financial obstacles, many of which are similar to those faced by other personalized medicine strategies. However, the efficacy of immunotherapy is likely to pave the way for new solutions to overcome these hurdles as the application of immunotherapy becomes more widespread. The recent commercial interest of large pharmaceutical companies in adoptive cell therapy approaches, boosted by the promising results with CAR- and TCR-based gene therapies, is one example. It is our hope
M O L E C U L A R O N C O L O G Y 9 ( 2 0 1 5 ) 1 8 9 1 e1 8 9 3
that the current issue will educate a broader community about the realities and potentials of cancer immunotherapy, and inspire research leading to new insights in how we can convert even more immune failures into clinical responses.
1893
Johanna Olweus Oslo University Hospital Radiumhospitalet, Department of Cancer Immunology, Institute for Cancer Research, Ullernchausseen 70, N-0310 Oslo, Norway E-mail address: [email protected]
R E F E R E N C E S
Klebanoff, C.A., Acquavella, N., Yu, Z., Restifo, N.P., 2011. Therapeutic cancer vaccines: are we there yet? Immunol. Rev. 239, 27e44. Rosenberg, S.A., Yang, J.C., Restifo, N.P., 2004. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909e915. Thomas, E.D., Lochte Jr., H.L., Lu, W.C., Ferrebee, J.W., 1957. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 257, 491e496.
Johanna Olweus received her M.D. and her Ph.D. from the University of Bergen, Norway. She is a specialist in Immunology and Transfusion medicine and since 2008 Full Professor at the University of Oslo and Head of Department of Cancer Immunology at the Institute for Cancer Research, Oslo University Hospital Radiumhospitalet. Since 2013 she is the Director of K.G. Jebsen Center for Cancer Immunotherapy. Olweus and her research group are focused on the development of new strategies for T-cell based cancer immunotherapy and in-depth mechanistic analyses of the immune responses in clinical immunotherapy trials.
http://dx.doi.org/10.1016/j.molonc.2015.10.017 1574-7891/ª 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
