- Email: [email protected]
Liberating tumor immunity
Available online at www.sciencedirect.com
Liberating tumor immunity Editorial overview Linde Meyaard and Mark J Smyth Current Opinion in Immunology 2012, 24:204–206 Available online 17th March 2012 0952-7915/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coi.2012.03.001
Linde Meyaard Department of Immunology, UMC Utrecht, Lundlaan 6, Rm KC02.085.2, Lundlaan 6, 3584 EA Utrecht, The Netherlands e-mail: [email protected] Linde Meyaard is a Professor of Immune Regulation at the University Medical Center in Utrecht. She has been working on inhibitory immune receptors since her post-doctoral stay at DNAX Research Institute in 1996– 1997, and is interested in modulation of the immune system by interference with these inhibitors. She published the first characterization of two inhibitory receptors, named LAIR-1 and SIRL-1. Her group studies the role of CD200R in the control of immune pathology of infections as well as tumor tolerance.
Mark J Smyth1,2 1
Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002, Victoria, Australia 2
Sir Peter MacCallum Department of Oncology, University of Melbourne, 3010, Victoria, Australia
Mark Smyth received his PhD at the University of Melbourne in 1988. At the National Cancer Institute (USA) he developed an interest in natural killer cells and immunity to cancer. After relocating to the Peter MacCallum Cancer Centre in 2000, He has defined three phases of cancer immune reaction, termed cancer immunoediting, and has undertaken the pre-clinical testing of combination immunotherapies in mouse models of established cancer, including approaches to understand Ig-like molecules that activate and inhibit NK and T cell function.
Current Opinion in Immunology 2012, 24:204–206
Cancer immunotherapy aims to enhance the body’s natural immune responses against tumor cells, without destroying normal tissues. Recognition of tumor cells is based on the differences between these cells and their normal counterparts. Expression of tumor antigens or danger-associated patterns (DAMPS) triggers the immune system to eliminate the tumor. Immune therapy based on monoclonal antibodies (mAbs) has shown to be highly efficient in some cases when targeting tumor-associated antigens such as Her2/Neu and CD20. A second approach to eradicate tumors making use of the body’s own cellular immune defense is vaccination with tumor antigens, especially effective against virus-induced cancers or when strong specific immune responses are primed to tumor antigens such as MAGE-3 and NY-ESO-1. A third approach is adoptive transfer of in vitro expanded, naturally arising or genetically engineered tumor-specific lymphocytes. Although these therapeutic approaches have been successful, their efficacy is only limited to a proportion of certain types of tumors (including melanoma and hematological cancers) and their targeting is antigen-specific. Cancers arise and escape elimination through a process of cancer immunoediting or because the host immune system changes in response to increased cancer-induced immunosuppression or immune system deterioration [1,2]. Thus, besides cancer therapies that focus on tumor antigens, a recently emerging approach is to target the regulatory pathways that control immune cells. Enhancing immune responses can be achieved by enforcing signals that activate, or conversely by blocking interactions that inhibit, immune cells. The immune system employs multiple restraining mechanisms to prevent over-activation or improper action of immune cells that may lead to undesired effects such as extreme lymphoproliferation, chronic inflammation, and autoimmunity. Evidence suggests that tumor cells employ these endogenous inhibitory pathways for their benefit, and thus inhibitory immune pathways have become therapeutic targets to strengthen broad anti-tumor responses and develop (adjuvant) therapeutic strategies in cancer treatment. CTLA4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, plays a central role in controlling T cell regulation in the immune system. In March of last year, the blocking CTLA4 antibody ipilimumab was FDA approved for use in advanced melanoma, being the first drug ever proven to prolong survival in stage IV melanoma [3]. CTLA4 is only the first example in a growing list of promising immune therapies that aim to break tumor tolerance and enhance tumor-specific immunity. In this issue of Current Opinion in Immunology, we have brought together seven pathways that are promising new targets for immune intervention in cancer. Five of these www.sciencedirect.com
Editorial overview Meyaard and Smyth 205
chapters concern classical inhibitory receptors (PD-1, KIR, CD200R, SIRP-a and Tim-3), one discusses an activating receptor (GITR) and one deals with a family of receptors, recognizing one family of ligands (nectins) that either inhibit or induce lymphocyte activation. To optimally trigger the anti-tumor response, the inhibitory action of immunological checkpoints may need to be released at many different levels, depending on the leukocyte infiltrate within the tumor microenvironment. While CTLA4 inhibits T cells, other immunological checkpoints inhibit the immune responses at the level of myeloid cells, including the antigen presenting cells (APC). It is therefore important to investigate the therapeutic efficacy and mechanism of action of targeting various immunological checkpoints to allow for optimal (combination of) therapies to combat even less immunogenic malignancies. The pathways discussed in this issue indeed target different cell types involved in tumor tolerance. Although PD-1, Tim-3 and GITR, like CTLA4, are all expressed on subsets of T cells, they regulate these cells at different levels. As discussed by Topalian and colleagues, PD-1 and CTLA4 play distinct roles in the regulation of T cell activity, with PD-1 mainly being important to limit T cell activity during an inflammatory response [4]. Anderson clearly explains that Tim3 particularly regulates IFN-g producing CD4+ and CD8+ cells and has an important role in exhaustion [5]. Schaer and colleagues discuss GITR as a positive regulator that gives a co-stimulatory signal to CD4+ and CD8+ cells [6]. It not only enhances effector responses, but may also modulate Treg function. Indeed, the relative impact of many of these agents on effector versus regulatory T cell subsets is a contemporary subject of great debate. In contrast, SIRP-a and CD200R are mostly known as negative regulators of macrophage function. Chao et al. argue that CD47, the natural ligand for SIRP-a, enables tumor cells to escape immune surveillance by evasion of phagocytosis [7]. Indeed blocking CD47-specific antibodies enhance tumor removal in preclinical models, but the beneficial effect may also partially be due to an effect on dendritic cells. In the contribution by Rygiel and Meyaard it is discussed that release from CD200R mediated inhibition prevents outgrowth of both CD200-positive and CD200-negative tumors, most likely by modulation of dendritic or other APCs [8]. Interestingly, for both Tim-3 and CD200R there is evidence that ligation promotes the outgrowth and function of myeloid derived suppressor cells (MDCS) [5,8]. Blocking these pathways would thus have the additional benefit of preventing the suppressive effects of these cells. In addition to modulation of T cells as effector cells, or indirectly via dendritic cells, benefit may be derived from strengthening NK cell responses as anti-tumor effector cells, particularly where these innate cells may be effecwww.sciencedirect.com
tive (hematological cancers and metastatic disease). As argued by Romagne et al., a mismatch between donor killer inhibitory receptor (KIR) and recipient HLA type in allotransplantation has proven to enhance NK-cell mediated elimination of hematological cancer cells [9]. This has stimulated research towards the application of NK cell infusions and/or blocking KIR antibodies as therapy in autologous settings. To target both NK cells and effector CD8+ T cells, receptors that bind members of the nectin and nectin-like family could be targeted. As Chan and colleagues discuss, this family consists of several activating (CD226 and CRTAM) and inhibitory family members (TIGIT and CD96) [10], expressed by NK cells and T cells, which are promising targets in preclinical models of melanoma. For some of these interactions there is evidence for tumors directly hijacking these pathways for their benefit. Enhanced expression of inhibitory ligands (PD-L1 for PD-1, CD200 for CD200R and CD47 for SIRP-a) has been reported on human malignancies and in multiple cases has been associated with enhanced metastatic potential and poor clinical outcome [4,7,8]. This fits with the concept of adaptive resistance, where tumor cells may escape immune surveillance by expressing these ligands, survive, and grow out. However, not only tumor-expression of the inhibitory ligands will facilitate tumor tolerance. For instance, PD-L1 and CD200 expression on tumor-associated cells (like stroma) may create an immunosuppressive micro-environment, which will also be alleviated when these interactions are blocked [4,8]. The pathways discussed here are in different stages of clinical development. Phase 1 trials are ongoing for PD-1, KIRs, CD200R and GITR, while CD47, Tim-3 and the nectins are in the preclinical stage. The approach taken to provide agonists or antagonist for the respective pathways differs per target. For PD-1 three blocking mAbs and a B7 fusion protein have been developed, all with the goal to release cells from PD-1 mediated inhibition [4]. As in the case of CTLA4, the blocking mAb is recognizing the inhibitory receptor. However, the ligand PD-L1, overexpressed by many tumor types, is also being targeted for blockade with mAbs. Similarly, the methods proposed for intervention with CD200R and SIRP-a inhibition, are based on blocking mAbs to the ligands rather than the receptors [7,8]. To release NK cell inhibition by KIRs, trials so far have been with KIR-mismatched NK cells, an approach that obviously comes with more costs and safety issues than mAb therapy. A blocking KIR antibody, representing half of the NK cell population in most individuals is now in phase I trials [9]. Since for GITR, an agonist rather than an antagonist will lead to the desired outcome, both GITR-L and agonistic antibodies have been tested in preclinical models and a humanized agonistic anti-GITR antibody is now in phase I trials [6]. Current Opinion in Immunology 2012, 24:204–206
206 Tumour immunology
As expected, these non-specific immune modulatory therapies will also affect healthy tissue and result in side effects. The autoimmune toxicity of CTLA4 therapy was somewhat predicted from mouse studies and is quite significant, albeit manageable with immunosuppressive agents such as corticosteroids. Lessons can be drawn from knockout mice; CTLA4 mice have a very severe spontaneous lymphoproliferative phenotype, while mice lacking some of the other pathways are comparatively healthy, unless challenged. Interestingly, agonists for GITR seem to preserve peripheral Treg function, which may prevent autoimmune side effects [6]. Another concern is the balance between inflammatory responses that benefit the anti-tumor response versus inflammatory responses that promote tumor outgrowth, as raised by Rygiel and Meyaard [8]. The question arises whether these new immunotherapies may result in less or similar toxicities to anti-CTLA4, and certainly while synergistic antitumor activities will likely be obtained by combining these approaches, awareness of parallel immunopathology and autoimmunity will be paramount to clinical development. Will the most effective therapy(ies) in the end be the one(s) that result(s) in most side-effects? This is an important question to be tackled and fertile ground for immunologists. The more straightforward clinical path is to combine immune modulation with other existing approaches such as surgery, chemotherapy and radiotherapy. Some of these appear amenable to combination with mAbs that target the host immune system [11,12]. One consideration is that following ipilimumab treatment, prolonged periods of stable disease followed by tumor regression have been observed in some patients. This indicates that for studies including immunotherapy agents, longer periods of time may be required before clinical benefit can be detected by imaging. In addition, CTLA4 and PD-1 block both have been proposed to enhance the beneficial effects of tumor vaccination [4]. Likewise, CD47 block therapy facilitates classical antibody-mediated immune therapy [7], but his concept cannot be applied to all pathways. GITR agonists can be detrimental when given at the same time as tumor vaccines and only enhance responses if given after and not at the same time as the vaccination [6]. This indicates that method and timing of immune modulation can dramatically influence the outcome. Lastly, immune modulation therapies may work very efficiently in concert. For instance, Tim-3 and PD-1 are often co-expressed and mark the most functionally exhausted population of CD8+ T cells; therefore coblockade may be very efficient in restoring function of these cells and controlling tumor growth [5]. In recent years, increasing numbers of previously illusive ligands for inhibitory receptors have been identified,
Current Opinion in Immunology 2012, 24:204–206
many of which are expressed on tumor cells [13]. The family of inhibitory immune receptors is still expanding; as revealed by in silico analyses the full spectrum of inhibitory receptors, let alone their ligands is currently far from complete [14]. In addition, novel co-stimulators are still being identified, as illustrated by the nectinreceptors [10]. The efficacy of modulators of these pathways in cancer therapy will depend on the tumor type, the progression of disease and the combination of therapies given. The overviews presented in this issue illustrate the multiple successful efforts developing novel targets in this area. In addition to evaluating combination therapies to improve clinical benefit, the next steps appear to be to develop immune-monitoring strategies (in blood and tumor tissue) for the identification of relevant biomarkers and to establish guidelines for the assessment of clinical end points.
References 1.
Schreiber RD, Old LJ, Smyth MJ: Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011, 331:1565-1570.
2.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ: Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011, 29:235-271.
3.
Sharma P, Wagner K, Wolchok JD, Allison JP: Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer 2011, 11:805-812.
4.
Topalian SL, Drake CG, Pardoll DM: Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012, 24:207-212.
5.
Anderson AC: Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol 2012, 24:213-216.
6.
Schaer DA, Murphy JT, Wolchok JD: Modulation of GITR for cancer immunotherapy. Curr Opin Immunol 2012, 24:217-224.
7.
Chao MP, Weissman IL, Majeti R: The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012, 24:225-232.
8.
Rygiel TP, Meyaard L: CD200R signaling in tumor tolerance and inflammation: as tricky balance. Curr Opin Immunol 2012, 24:233-238.
9.
Romagne F, Thielens A, Vivier E: NK MHC-class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol 2012, 24:239-245.
10. Chan CJ, Andrews DM, Smyth MJ: Receptors that interact with nectin and nectin-like proteins in the immunesurveillance and immunotherapy of cancer. Curr Opin Immunol 2012, 24:246-251. 11. Zitvogel L, Kepp O, Kroemer G: Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 2011, 8:151-160. 12. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM et al.: Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol 2010, 22:113-124. 13. Lebbink RJ, Meyaard L: Non-MHC ligands for inhibitory immune receptors: novel insights and implications for immune regulation. Mol Immunol 2007, 44:2153-2164. 14. Daeron M, Jaeger S, Du Pasquier L, Vivier E: Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol Rev 2008, 224:11-43.
www.sciencedirect.com
Liberating tumor immunity Editorial overview Linde Meyaard and Mark J Smyth Current Opinion in Immunology 2012, 24:204–206 Available online 17th March 2012 0952-7915/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.coi.2012.03.001
Linde Meyaard Department of Immunology, UMC Utrecht, Lundlaan 6, Rm KC02.085.2, Lundlaan 6, 3584 EA Utrecht, The Netherlands e-mail: [email protected] Linde Meyaard is a Professor of Immune Regulation at the University Medical Center in Utrecht. She has been working on inhibitory immune receptors since her post-doctoral stay at DNAX Research Institute in 1996– 1997, and is interested in modulation of the immune system by interference with these inhibitors. She published the first characterization of two inhibitory receptors, named LAIR-1 and SIRL-1. Her group studies the role of CD200R in the control of immune pathology of infections as well as tumor tolerance.
Mark J Smyth1,2 1
Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002, Victoria, Australia 2
Sir Peter MacCallum Department of Oncology, University of Melbourne, 3010, Victoria, Australia
Mark Smyth received his PhD at the University of Melbourne in 1988. At the National Cancer Institute (USA) he developed an interest in natural killer cells and immunity to cancer. After relocating to the Peter MacCallum Cancer Centre in 2000, He has defined three phases of cancer immune reaction, termed cancer immunoediting, and has undertaken the pre-clinical testing of combination immunotherapies in mouse models of established cancer, including approaches to understand Ig-like molecules that activate and inhibit NK and T cell function.
Current Opinion in Immunology 2012, 24:204–206
Cancer immunotherapy aims to enhance the body’s natural immune responses against tumor cells, without destroying normal tissues. Recognition of tumor cells is based on the differences between these cells and their normal counterparts. Expression of tumor antigens or danger-associated patterns (DAMPS) triggers the immune system to eliminate the tumor. Immune therapy based on monoclonal antibodies (mAbs) has shown to be highly efficient in some cases when targeting tumor-associated antigens such as Her2/Neu and CD20. A second approach to eradicate tumors making use of the body’s own cellular immune defense is vaccination with tumor antigens, especially effective against virus-induced cancers or when strong specific immune responses are primed to tumor antigens such as MAGE-3 and NY-ESO-1. A third approach is adoptive transfer of in vitro expanded, naturally arising or genetically engineered tumor-specific lymphocytes. Although these therapeutic approaches have been successful, their efficacy is only limited to a proportion of certain types of tumors (including melanoma and hematological cancers) and their targeting is antigen-specific. Cancers arise and escape elimination through a process of cancer immunoediting or because the host immune system changes in response to increased cancer-induced immunosuppression or immune system deterioration [1,2]. Thus, besides cancer therapies that focus on tumor antigens, a recently emerging approach is to target the regulatory pathways that control immune cells. Enhancing immune responses can be achieved by enforcing signals that activate, or conversely by blocking interactions that inhibit, immune cells. The immune system employs multiple restraining mechanisms to prevent over-activation or improper action of immune cells that may lead to undesired effects such as extreme lymphoproliferation, chronic inflammation, and autoimmunity. Evidence suggests that tumor cells employ these endogenous inhibitory pathways for their benefit, and thus inhibitory immune pathways have become therapeutic targets to strengthen broad anti-tumor responses and develop (adjuvant) therapeutic strategies in cancer treatment. CTLA4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, plays a central role in controlling T cell regulation in the immune system. In March of last year, the blocking CTLA4 antibody ipilimumab was FDA approved for use in advanced melanoma, being the first drug ever proven to prolong survival in stage IV melanoma [3]. CTLA4 is only the first example in a growing list of promising immune therapies that aim to break tumor tolerance and enhance tumor-specific immunity. In this issue of Current Opinion in Immunology, we have brought together seven pathways that are promising new targets for immune intervention in cancer. Five of these www.sciencedirect.com
Editorial overview Meyaard and Smyth 205
chapters concern classical inhibitory receptors (PD-1, KIR, CD200R, SIRP-a and Tim-3), one discusses an activating receptor (GITR) and one deals with a family of receptors, recognizing one family of ligands (nectins) that either inhibit or induce lymphocyte activation. To optimally trigger the anti-tumor response, the inhibitory action of immunological checkpoints may need to be released at many different levels, depending on the leukocyte infiltrate within the tumor microenvironment. While CTLA4 inhibits T cells, other immunological checkpoints inhibit the immune responses at the level of myeloid cells, including the antigen presenting cells (APC). It is therefore important to investigate the therapeutic efficacy and mechanism of action of targeting various immunological checkpoints to allow for optimal (combination of) therapies to combat even less immunogenic malignancies. The pathways discussed in this issue indeed target different cell types involved in tumor tolerance. Although PD-1, Tim-3 and GITR, like CTLA4, are all expressed on subsets of T cells, they regulate these cells at different levels. As discussed by Topalian and colleagues, PD-1 and CTLA4 play distinct roles in the regulation of T cell activity, with PD-1 mainly being important to limit T cell activity during an inflammatory response [4]. Anderson clearly explains that Tim3 particularly regulates IFN-g producing CD4+ and CD8+ cells and has an important role in exhaustion [5]. Schaer and colleagues discuss GITR as a positive regulator that gives a co-stimulatory signal to CD4+ and CD8+ cells [6]. It not only enhances effector responses, but may also modulate Treg function. Indeed, the relative impact of many of these agents on effector versus regulatory T cell subsets is a contemporary subject of great debate. In contrast, SIRP-a and CD200R are mostly known as negative regulators of macrophage function. Chao et al. argue that CD47, the natural ligand for SIRP-a, enables tumor cells to escape immune surveillance by evasion of phagocytosis [7]. Indeed blocking CD47-specific antibodies enhance tumor removal in preclinical models, but the beneficial effect may also partially be due to an effect on dendritic cells. In the contribution by Rygiel and Meyaard it is discussed that release from CD200R mediated inhibition prevents outgrowth of both CD200-positive and CD200-negative tumors, most likely by modulation of dendritic or other APCs [8]. Interestingly, for both Tim-3 and CD200R there is evidence that ligation promotes the outgrowth and function of myeloid derived suppressor cells (MDCS) [5,8]. Blocking these pathways would thus have the additional benefit of preventing the suppressive effects of these cells. In addition to modulation of T cells as effector cells, or indirectly via dendritic cells, benefit may be derived from strengthening NK cell responses as anti-tumor effector cells, particularly where these innate cells may be effecwww.sciencedirect.com
tive (hematological cancers and metastatic disease). As argued by Romagne et al., a mismatch between donor killer inhibitory receptor (KIR) and recipient HLA type in allotransplantation has proven to enhance NK-cell mediated elimination of hematological cancer cells [9]. This has stimulated research towards the application of NK cell infusions and/or blocking KIR antibodies as therapy in autologous settings. To target both NK cells and effector CD8+ T cells, receptors that bind members of the nectin and nectin-like family could be targeted. As Chan and colleagues discuss, this family consists of several activating (CD226 and CRTAM) and inhibitory family members (TIGIT and CD96) [10], expressed by NK cells and T cells, which are promising targets in preclinical models of melanoma. For some of these interactions there is evidence for tumors directly hijacking these pathways for their benefit. Enhanced expression of inhibitory ligands (PD-L1 for PD-1, CD200 for CD200R and CD47 for SIRP-a) has been reported on human malignancies and in multiple cases has been associated with enhanced metastatic potential and poor clinical outcome [4,7,8]. This fits with the concept of adaptive resistance, where tumor cells may escape immune surveillance by expressing these ligands, survive, and grow out. However, not only tumor-expression of the inhibitory ligands will facilitate tumor tolerance. For instance, PD-L1 and CD200 expression on tumor-associated cells (like stroma) may create an immunosuppressive micro-environment, which will also be alleviated when these interactions are blocked [4,8]. The pathways discussed here are in different stages of clinical development. Phase 1 trials are ongoing for PD-1, KIRs, CD200R and GITR, while CD47, Tim-3 and the nectins are in the preclinical stage. The approach taken to provide agonists or antagonist for the respective pathways differs per target. For PD-1 three blocking mAbs and a B7 fusion protein have been developed, all with the goal to release cells from PD-1 mediated inhibition [4]. As in the case of CTLA4, the blocking mAb is recognizing the inhibitory receptor. However, the ligand PD-L1, overexpressed by many tumor types, is also being targeted for blockade with mAbs. Similarly, the methods proposed for intervention with CD200R and SIRP-a inhibition, are based on blocking mAbs to the ligands rather than the receptors [7,8]. To release NK cell inhibition by KIRs, trials so far have been with KIR-mismatched NK cells, an approach that obviously comes with more costs and safety issues than mAb therapy. A blocking KIR antibody, representing half of the NK cell population in most individuals is now in phase I trials [9]. Since for GITR, an agonist rather than an antagonist will lead to the desired outcome, both GITR-L and agonistic antibodies have been tested in preclinical models and a humanized agonistic anti-GITR antibody is now in phase I trials [6]. Current Opinion in Immunology 2012, 24:204–206
206 Tumour immunology
As expected, these non-specific immune modulatory therapies will also affect healthy tissue and result in side effects. The autoimmune toxicity of CTLA4 therapy was somewhat predicted from mouse studies and is quite significant, albeit manageable with immunosuppressive agents such as corticosteroids. Lessons can be drawn from knockout mice; CTLA4 mice have a very severe spontaneous lymphoproliferative phenotype, while mice lacking some of the other pathways are comparatively healthy, unless challenged. Interestingly, agonists for GITR seem to preserve peripheral Treg function, which may prevent autoimmune side effects [6]. Another concern is the balance between inflammatory responses that benefit the anti-tumor response versus inflammatory responses that promote tumor outgrowth, as raised by Rygiel and Meyaard [8]. The question arises whether these new immunotherapies may result in less or similar toxicities to anti-CTLA4, and certainly while synergistic antitumor activities will likely be obtained by combining these approaches, awareness of parallel immunopathology and autoimmunity will be paramount to clinical development. Will the most effective therapy(ies) in the end be the one(s) that result(s) in most side-effects? This is an important question to be tackled and fertile ground for immunologists. The more straightforward clinical path is to combine immune modulation with other existing approaches such as surgery, chemotherapy and radiotherapy. Some of these appear amenable to combination with mAbs that target the host immune system [11,12]. One consideration is that following ipilimumab treatment, prolonged periods of stable disease followed by tumor regression have been observed in some patients. This indicates that for studies including immunotherapy agents, longer periods of time may be required before clinical benefit can be detected by imaging. In addition, CTLA4 and PD-1 block both have been proposed to enhance the beneficial effects of tumor vaccination [4]. Likewise, CD47 block therapy facilitates classical antibody-mediated immune therapy [7], but his concept cannot be applied to all pathways. GITR agonists can be detrimental when given at the same time as tumor vaccines and only enhance responses if given after and not at the same time as the vaccination [6]. This indicates that method and timing of immune modulation can dramatically influence the outcome. Lastly, immune modulation therapies may work very efficiently in concert. For instance, Tim-3 and PD-1 are often co-expressed and mark the most functionally exhausted population of CD8+ T cells; therefore coblockade may be very efficient in restoring function of these cells and controlling tumor growth [5]. In recent years, increasing numbers of previously illusive ligands for inhibitory receptors have been identified,
Current Opinion in Immunology 2012, 24:204–206
many of which are expressed on tumor cells [13]. The family of inhibitory immune receptors is still expanding; as revealed by in silico analyses the full spectrum of inhibitory receptors, let alone their ligands is currently far from complete [14]. In addition, novel co-stimulators are still being identified, as illustrated by the nectinreceptors [10]. The efficacy of modulators of these pathways in cancer therapy will depend on the tumor type, the progression of disease and the combination of therapies given. The overviews presented in this issue illustrate the multiple successful efforts developing novel targets in this area. In addition to evaluating combination therapies to improve clinical benefit, the next steps appear to be to develop immune-monitoring strategies (in blood and tumor tissue) for the identification of relevant biomarkers and to establish guidelines for the assessment of clinical end points.
References 1.
Schreiber RD, Old LJ, Smyth MJ: Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011, 331:1565-1570.
2.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ: Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011, 29:235-271.
3.
Sharma P, Wagner K, Wolchok JD, Allison JP: Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer 2011, 11:805-812.
4.
Topalian SL, Drake CG, Pardoll DM: Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012, 24:207-212.
5.
Anderson AC: Tim-3, a negative regulator of anti-tumor immunity. Curr Opin Immunol 2012, 24:213-216.
6.
Schaer DA, Murphy JT, Wolchok JD: Modulation of GITR for cancer immunotherapy. Curr Opin Immunol 2012, 24:217-224.
7.
Chao MP, Weissman IL, Majeti R: The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012, 24:225-232.
8.
Rygiel TP, Meyaard L: CD200R signaling in tumor tolerance and inflammation: as tricky balance. Curr Opin Immunol 2012, 24:233-238.
9.
Romagne F, Thielens A, Vivier E: NK MHC-class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol 2012, 24:239-245.
10. Chan CJ, Andrews DM, Smyth MJ: Receptors that interact with nectin and nectin-like proteins in the immunesurveillance and immunotherapy of cancer. Curr Opin Immunol 2012, 24:246-251. 11. Zitvogel L, Kepp O, Kroemer G: Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 2011, 8:151-160. 12. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM et al.: Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol 2010, 22:113-124. 13. Lebbink RJ, Meyaard L: Non-MHC ligands for inhibitory immune receptors: novel insights and implications for immune regulation. Mol Immunol 2007, 44:2153-2164. 14. Daeron M, Jaeger S, Du Pasquier L, Vivier E: Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol Rev 2008, 224:11-43.
www.sciencedirect.com