SEARCH

SEARCH BY CITATION

Keywords:

  • Cancer;
  • IL-7;
  • Immunity;
  • Infection

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

The complexity that the immune system faces in distinguishing pathogens from self is manifested by the intricate immunological networks involved in initiation, promotion and abrogation of immunity. A substantially more complex algorithm is required to distinguish normal from aberrant self (e.g. in the form of cancers), and this is reflected by the apparent inefficiency of our immune system to eradicate tumors; however, with our expanding insights into the molecular networks that govern immunity, we can now consider therapies that transiently promote immunity and/or antagonize immune inhibitory networks. Cytokines that normally function to regulate immune responses hold much therapeutic promise in this regard. Translating this promise to tangible outcomes will require a thorough analysis of how, when and in what way these cytokines should be used to take advantage of synergistic and complementary effects of current cancer therapeutics. In this review, we focus on IL-7, as much data are emerging on the ability of this unique homeostatic cytokine to augment various anti-tumor immunotherapeutic modalities.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

Despite every person being chronically infected with three or more viruses, our immune system efficiently prevents overt disease 1. Indeed, we are continually exposed to a plethora of pathogens and our immune system prevents or clears many of these infections. We have exploited the relative success of our immune system in the development of the most successful medical intervention – vaccination. Hence, why then have we not been able to exploit the system one step further in promoting immune clearance of cancer? The answer lies in the evolutionary mechanisms that on the one hand promote immunity to pathogens and on the other hand prevent autoimmunity. Our knowledge of these opposing molecular pathways has expanded recently with the identification of numerous immune inhibitory networks 2.

Notwithstanding the impediment of these inhibitory pathways, our immune system does play an indisputable role in preventing some tumors caused by infections 3. Pathogens may be directly tumorigenic; alternatively, persistent infection may create an inflammatory milieu conducive to tumor formation 4. In both instances, immune-mediated control or eradication of the infectious agent is able to abrogate cancer development. In cancers that do not have an infectious etiology, our immune system may still play some role, albeit less successful, in antagonizing disease progression 5. In these instances, perhaps the lessons we have learnt from the relative success of immunity in fighting infections and our understanding of the immune inhibitory networks that function to prevent autoimmunity will aid us in therapeutically promoting anti-tumor immunity.

We begin by defining some of the immune inhibitory networks that limit immunity in the absence of overt infection. We discuss how these immune inhibitory networks can be rationally antagonized to promote anti-tumor immune responses with a particular emphasis on adaptive immune responses that can adjust to tumor mutations. We highlight the role of the one homeostatic cytokine, IL-7, in regulating many aspects of immunity from development and homeostasis to the formation of immunological memory. In view of its critical immunological functions, IL-7 may hold much promise as a potential immunotherapeutic agent and we discuss how these may be applied in the treatment of cancer.

Immune inhibitory networks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

Our immune system is constantly poised at the edge of immune activation in order to respond to any infectious threats. To prevent spurious activation and autoimmunity, the system is regulated by numerous inhibitory networks that, for the most part, can distinguish between unwanted immune responses directed against self- and bona fide responses directed against infectious organisms. It is critical to understand how these immune inhibitory networks function and how they are antagonized during infection to promote immunity. Only with such knowledge, can we rationally approach the design of anti-tumor immunotherapeutics 6, 7. Some of the immune inhibitory networks are detailed in the following subsections and also shown in Fig. 1.

thumbnail image

Figure 1. Multiple factors collaborate in limiting anti-tumor immunity. Obstacles occur at many levels including tumor antigen expression, stromal and vascular barriers that prevent immune-cell migration, antagonistic tumor microenvironment and intrinsic T-cell inhibitory networks that are not adequately reversed due to the lack of costimulatory signals.

Download figure to PowerPoint

A disguised and silent beast

The innate immune system distinguishes self from pathogens through PRR including TLR, C-type lectin receptors, Nod-like receptors and RIG-1-like receptors 8. NK cells additionally use self-MHC to distinguish self from aberrant cells, expressing a foreign MHC or no MHC at all 9. T cells in the adaptive immune system are subject to thymic negative selection and peripheral deletion. These processes delete T cells that recognize self-antigens with high avidity without limiting the diversity of cells that can recognize foreign antigens 10. Additionally, an effective adaptive immune response requires costimulatory signals from DC, which themselves, require activation through PRR-mediated signaling 11. Hence, with the apparent lack of TLR ligands, the predominant expression of self-antigens and self-MHC, how can cancers be recognized and targeted as aberrant by our immune system? Evidence suggests that cancers may provide innate immune activating signals 12, 13. Also, some cancers downregulate self-MHC making them targets for NK cells 9, 14. Finally, tumors may express aberrant forms of self antigens or antigens that have limited tissue expression or antigens that were only transiently expressed during development 15. Given that not all T cells recognizing self are deleted, some are ignored and some are tolerized, these T cells could be induced to respond to these tumor antigens, perhaps through the provision of costimulatory factors such as cytokines 16–18. Furthermore, although technically demanding, the adoptive transfer of in vitro-expanded tumor-specific immune cells, particularly T cells, may overcome some of the limitations of an endogenous immune response 19.

A “bad” environment

Several aspects of the tumor microenvironment limit immune responses. Physical obstacles include stromal barriers and aberrant vasculature that impede migration of immune cells into the tumor site 13. These physical barriers can be compromised by radiotherapy and chemotherapy. Additionally, as these therapies cause massive tumor destruction, it is likely that abundant immune-activating signals will be released. It would therefore be logical that immunotherapy, aimed at boosting anti-tumor immunity, should be initiated around the time of radiotherapy or chemotherapy, depending on the immune toxicity of these agent 13.

In the tumor environment, where immunostimulatory signals may be less than optimal, both at the level of antigenicity and at the level of costimulatory factors, it is likely that Treg and myeloid-derived suppressors cells impede T-cell responses more effectively 20–23. With the provision of additional stimulatory factors, such as pro-inflammatory cytokines, it may be possible to render anti-tumor T effector cells more refractory to the effects of these regulatory and suppressive cells 18, 24, 25. Although some of these cytokines may actually increase Treg numbers, the more critical phenomenon appears to be the ability of the pro-inflammatory cytokine to induce a refractory state in effector cells making them resistant to suppression 23. Nonetheless, depletion of Treg using mAb therapies further promotes the anti-tumor efficacy of cytokines 26.

Competing effects between immunostimulatory and inhibitory signals also occurs at the level of tumor-secreted molecules and tumor-associated ligands 2, 27, 28. Although tumors can provide immunostimulatory signals that activate DC, such as heat shock proteins, high-mobility group box 1 protein and uric acid, the overwhelming signals appear to be inhibitory. These inhibitory molecules, which are secreted within the tumor microenvironment by tumor cells, Treg, myeloid-derived suppressors cells and stromal cells, include TGF-β, IL-10 and indoleamine 2,3-dioxygenase 28–30. All of these molecules antagonize activated immune cells and additional TGF-β may favor expansion and recruitment of Treg 23. In this milieu, ineffective killer T-cell responses may actually become counterproductive. Inflammatory cells incapable of killing cancer cells may contribute to the activation and growth of tumor cells by secreting cytokines and factors that promote activation of STAT3 and NF-κB within cancer cells 31. Activation of these pathways can then directly or indirectly augment the inhibitory environment. Tumor cells also express numerous surface ligands, including PD-L1, that antagonize immunity by binding to their cognate receptors on immune cells 2.

If the balance between immunostimulatory and inhibitory signals determines the effectiveness of an immune response, then it should be possible to favor activation of an efficient anti-tumor immune response by provision of stimulatory signals 27, 32. This may be achieved with the administration of pro-inflammatory or homeostatic cytokines 33; however, given that these cytokines function to shift the immune-balance, they are best utilized as adjuvant treatments. In isolation, cytokine treatment may not have sufficient efficacy to overcome the overwhelming inhibitory factors.

Decisions within

In addition to exogenous factors that provide inhibitory signals to immune cells, T cells are endowed with many cell surface and intrinsic molecules that ensure a quiescent state in the absence of sufficient immunostimulatory signals 2. The immune system evolved primarily to deal with pathogens, which for the most part provide their own immunostimulatory signals in the form of pattern recognition ligands such as TLR activators. These pathogen-associated ligands are able to overcome the inhibited immune state and initiate an immune response 11. In this way, our immune system is able to distinguish between pathogen-induced immune activation and spurious activation. In the former case, immunity is promoted and in the latter, inhibitory networks function successfully to impede immunity. Activated T cells express CTLA-4, a surface molecule that antagonizes costimulatory signaling 34. Cell-intrinsic inhibitory molecules, such as Cbl-b, are able to alter the threshold of TCR and costimulatory signaling 35. Numerous ubiquitin ligases, such as TRAF6 and Itch, antagonize NF-κB and PI3 kinase activation pathways 35. Similarly, SOCS proteins negatively regulate cytokine signaling 36. Other molecules that intrinsically antagonize immune-cell activation or function include Homer proteins, diacylglycerol kinase α and Egr proteins 37–39. Although the array of inhibitory molecules appears daunting, the evolutionary drive was to create sufficient crosschecks to control an immune system poised to respond to pathogens but is also capable of causing autoimmune disease. Again, elements of these inhibitory networks can be disarmed with the use of exogenous cytokines. For example, IL-7 is capable of repressing Cbl-b, antagonizing p27Kip1 (a cell cycle inhibitor), and antagonizing the activity of Foxo transcription factors that inhibit activation and cell cycling 18, 40. Given the delicate balance, any exploitation of the immune response to promote anti-tumor immunity must be tempered by the possibility of causing overt autoimmunity 41.

Immune escape

Tumors are far from static and their labile genetic states may allow for the emergence of cancer clones that have altered target antigens with either a complete loss of antigen expression or a loss of MHC expression 42. In the appropriate inflammatory milieu T cells specific for diverse, and in some cases subdominant, tumor antigens can contribute to tumor killing 18, 43, 44. Furthermore, with adequate inflammatory signals, NK cells may be able to kill cancer cells that lack surface MHC expression 45. Some of these escape mechanisms, particularly the downregulation of MHC, are due to epigenetic changes in tumor cells, which may be reversible with the therapeutic use of histone deactylase inhibitors and DNA methyltransferase inhibitors 46. Additionally, radiotherapy and type I interferons can upregulate MHC expression and antigen presentation 42, 47.

Immunotherapy modalities

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

Despite the many mechanisms opposing naturally acquired endogenous anti-tumor immunity, it is possible to exploit the numerous components of our immune system in promoting an anti-tumor response (Fig. 2). The advances in tumor immune therapy are discussed in the following sections.

thumbnail image

Figure 2. Promoting anti-tumor immunity. The numerous inhibitory networks that abrogate anti-tumor immunity can be antagonized with the provision of cytokines, costimulatory signals and mAb that block inhibitory signals. Additionally, conventional radiotherapy and chemotherapy can promote tumor destruction and immune-cell accessibility to the cancer site and small molecule inhibitors, such as histone deactylase antagonists, can promote tumor antigen expression.

Download figure to PowerPoint

Monoclonal antibodies

The production of humanized or chimeric mAb has allowed for the successful development of several anti-tumor therapies. These highly specific Ab can be passively delivered to antagonize receptor-mediated signaling in tumor cells, induce apoptosis or cell death, promote immune activation by targeting costimulatory molecules on T cells and antagonize immunosuppressive molecules. The therapeutic potential of mAb in cancer treatment has been comprehensively reviewed 48. Numerous studies have demonstrated complementary effects when mAb and cytokines are combined. mAb can be used to complex and promote the activity of exogenously administered cytokines48. Reciprocally, cytokines can promote Ab-dependent cellular cytotoxicity mediated by mAb that target tumor antigens 49.

Cytokines

Exogenously administered cytokines offer the therapeutic potential of shifting the immune regulatory milieu in the cancer microenvironment to favor the promotion of anti-tumor immune responses. Cytokines that signal through the common γ-chain (γc) receptor, particularly IL-2, IL-15, IL-21 and IL-7, have received much attention as potential immunotherapeutics in promoting anti-tumor immune responses (Fig. 3) 33, 50, 51. In preclinical studies, each of these cytokines alone or in combination has shown efficacy in enhancing tumor immunity 33.

thumbnail image

Figure 3. The γc cytokine receptors that promote anti-tumor immunity. The heterodimeric receptor complexes utilize the same γc together with unique cytokine-specific receptor chains. In the case of IL-15, IL-15Rα captures IL-15, which is then transpresented to target cells expressing the IL-2Rβ and γc heterodimeric complex. IL-2 mediates most of its physiological effects by binding to a heterotrimeric receptor complex composed of IL-2Rβ, γc and IL-2Rα. IL-2Rα lacks a cytoplasmic domain and hence its primary function is to increase the affinity of the heterotrimeric complex for its cognate cytokine.

Download figure to PowerPoint

High-dose IL-2 therapy is an established treatment modality for the management of advanced metastatic melanoma and metastatic renal cell carcinoma, producing overall response rates of approximately 15% in these groups 52. IL-2 is capable of expanding activated T cells in vitro. In vivo, IL-2 is required for the development and secondary expansion of memory T cells 53. IL-2 is critical for the development of Treg 54, 55. Indeed, mice deficient in IL-2 or its receptor develop overt autoimmune inflammatory disease due to the absence of Treg. This attribute of IL-2 has been exploited with the use of specific mAb that complex IL-2 and promote its ability to expand Treg and abrogate autoimmunity in vivo56. Interestingly, alternate mAb have been used to complex IL-2 for in vivo animal administration and these Ab–IL-2 complexes potently promote CD8+ T-cell and NK-cell expansion without causing excessive Treg expansion 57. Exogenous administration of IL-2 can be deleterious presumably secondary to cytokine storms, which abrogate immunity rather than promote it 58. However, in the setting of adoptive immune therapies, with preconditioning and immune depletion of recipient hosts, IL-2 promotes and maintains the function and number of transferred tumor reactive T cells 58.

IL-15 shows much promise in animal studies but progression to clinical trials has been slow. IL-15 physiology is complicated by the requirement for transpresentation 59. The cytokine must be captured by IL-15Rα and then transpresented to target cells that bind the cytokine and signal through the γc/IL-2Rβ receptor complex. Animal studies have established the importance of IL-15 in the homeostasis of CD8+ memory T cells, NK, NKT cells, γδ intestinal intraepithelial T cells and killer DC 60–63. Administration of IL-15 to mice induces a proliferative T-cell response predominantly in the CD8+ memory T-cell compartment. IL-15 also has a proliferative effect on murine NK cells. In these preclinical studies, IL-15 appears to be less toxic than IL-2 16, 64–67.

IL-21 is not required for the development of the immune system. Mice deficient in IL-21 do have minor changes in the representation of immunoglobulin isotypes 68. In vitro, IL-21 shows limited capacity to induce proliferation of T cells, however, IL-21 is important in effector T-cell and NK-cell function, although these effects appear to be mediated through IL-21's synergistic activity with other γc cytokines 58, 69–74. Mice deficient in IL-21 have poor immune responses to chronic viruses 75–77. Preclinical studies also highlight the functional attributes of this cytokine with increased CD8+ T-cell and NK-cell anti-tumor activity 72, 78–80. IL-21 has also been shown to favor the differentiation of Th cells that secrete IL-17 (Th17) at the expense of Treg differentiation 81, 82. These Th17 cells have been shown to promote anti-tumor immunity 18, 83, 84. Several phase I/II clinical trials in patients with melanoma and renal cell carcinoma have demonstrated that IL-21 can be administered safely and have given insight into IL-21's therapeutic potential 85–87. Further studies are required to establish whether IL-21 has significant therapeutic value in anti-tumor immune therapy.

IL-7 is a critical nonredundant cytokine required for immune development and homeostasis. IL-7's physiological and therapeutic roles are discussed in detail in the The role of IL-7 in immunity section.

Vaccination

Various approaches have been used to vaccinate against tumor antigens. Anti-tumor vaccines can take the form of peptide vaccines coadministered with immunostimulatory molecules, transfer of tumor antigen-loaded and matured or gene-modified DC, and injection of gene modified tumor cells that express cytokines such as GM-CSF 88–90. In preclinical trials, these approaches have had mixed success. Phase I and II clinical trials using GM-CSF-secreting tumor cell vaccines have provided data supporting the rationale for these immunotherapeutic approaches 91. Indeed, the US Food and Drug Administration have recently approved a vaccine consisting of autologous peripheral blood mononuclear cells pulsed and activated with recombinant prostatic acid phosphatase antigen linked to GM-CSF for the treatment of metastatic prostate cancer that is refractory to hormone manipulation 92. This again highlights the adjuvant effects of cytokines that can complement other anti-tumor immunotherapeutic modalities.

Adoptive cell therapies

Promising anti-tumor responses have been reported with the use of adoptive cell therapies (ACT) 19, 93. Autologous tumor-infiltrating or circulating anti-tumor T cells are recovered from patients and then expanded ex vivo for transfer back into immune-depleted hosts together with IL-2 therapy. The success of these therapies is partly dependent on host lymphodepletion that induces endogenous homeostatic cytokine secretion, which in turn promotes the activity of ACT 19. Treatment efficacy has only been shown in patients with melanoma and its therapeutic applicability to other tumor types has not been determined. ACT has recently been adapted such that autologous T cells are gene-modified to code for a tumor-specific T-cell receptor 94.

Similar mechanisms that operate to promote the efficacy of ACT may also be responsible for a graft-versus-leukemia effect that is observed in cases of allogeneic hemopoietic stem cell transplants used in the treatment of leukemias. Indeed, this effect has been exploited with the use of donor lymphocyte infusions containing T cells that are capable of producing sustainable remissions in patients with CML 95. The utility of NK cells in promoting anti-tumor responses is best exemplified by the graft-versus-leukemia effects of NK cells 96. Patients receiving allogenic haemopoietic stem cell grafts, after lymphoablation therapy for the treatment of AML, had a better outcome if the grafts had a minor mismatch compared with the recipient. The graft-versus-leukemia effect in these cases is attributed to NK-cell alloreactivity. Adoptive transfer of mature allogenic NK cells appears to be less successful 97, 98. Further studies addressing the added benefit of using exogenous cytokines to promote NK activity are required.

The role of IL-7 in immunity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

The ability of cytokines to promote certain aspects of innate immunity and augment adaptive T-cell responses distinguishes them as therapeutics that may hold much promise in immune mediated anti-tumor responses. An understanding of cytokine physiology and function would greatly aid in the assessment of their utility in immune therapy. Indeed, such knowledge is essential in determining how, when and in what combination should cytokines be administered to promote anti-tumor immunity. We focus on IL-7 because of its critical nonredundant role in immune development, which may be reflected in its therapeutic potential 99.

Humans deficient in IL-7 or its receptor have a severe-combined immunodeficiency due to the absence of T cells. Mice deficient in IL-7 or its receptor additionally lack B cells. This highlights the importance of this cytokine in immune development and homeostasis 99. Recently, IL-7 was shown to be required for the development of thymic-derived NK cells that express the IL-7 receptor (CD127) 100. These NK cells are found in the periphery, particularly lymph nodes, but their function is yet to be fully characterized. IL-7 is also required for the development and homeostasis of a group of intestinal lymphocytes that produce IL-22 and are believed to be important in pathogen defense in the gut 101. These lymphoid tissue inducer (LTi)-like cells express CD127 and the natural cytotoxic receptor NKp46 but not NK1.1 nor CD3, and they require the activity of several transcription factors, including RORc and Id2. Additionally, studies have shown that IL-7 is important in the maintenance of adult LTi cells 102. Indeed, IL-7 is critically required for the formation of Peyer's patches. This may be related to the requirement for IL-7 in promoting survival of fetal LTi and their precursors 103. IL-7 also plays a significant role in DC development 104.

IL-7 signaling results in the activation of numerous pathways including JAK/STAT and PI3K-AKT pathways along with activation of the src family of kinases 99. This results in induction of cell cycling through the repression of Foxo transcription factors and the repression of cell cycle inhibitors 40, 105. IL-7 also promotes T-cell survival and the upregulation of the anti-apoptotic molecules such as Bcl-2 and Mcl-1 99.

IL-7 and other cytokines as immunotherapeutics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

Promotion of T-cell survival is an important element in ACT and other immune therapies targeting adaptive immune responses to tumors. IL-7 is a potent pro-survival cytokine that acts primarily on naïve and memory T cells that express high levels of CD127. IL-7 also promotes the survival of effector T cells. IL-2 and IL-15 also greatly enhance survival of effector T cells and similar to IL-7, IL-15 also promotes CD8+ memory T-cell survival 33, 51.

Survival of tumor-specific T cells must also be accompanied by the reversal of anergy and promotion of functional activity. Exogenous γc cytokines can promote cell cycle entry. Indeed, IL-7 potently downregulates the cell cycle inhibitor p27Kip1. Through these mechanisms, the anergic T-cell state can be reversed 106, 107. IL-7 is able to promote CD4+ and CD8+ T-cell function. It augments T-cell-mediated secretion of cytokines and upregulates granzyme B expression in cytolytic T cells 18. IL-15 and IL-21 also upregulate the expression of granzyme B in T cells and NK cells, respectively 74, 108. Th17 cells appear to be particularly effective at killing tumor cells 18, 83, 84. Although IL-7 itself does not contribute to the generation of Th17 cells, the inflammatory milieu created by exogenous IL-7, and in some cases endogenous IL-7, promotes Th17 differentiation 18, 109.

A peculiar attribute of IL-7, reflecting its role in immune developmental and homeostasis, is its ability to increase the diversity of T cells recognizing different antigens 44. This may be an important phenomenon in broadening anti-tumor immune responses, especially if tumor antigens mutate under immunological pressure 43.

The inhibitory networks that limit adaptive immunity must also be antagonized for effective immune responses. Both IL-7 and IL-15 are capable of rendering effector T cells refractory to the inhibitory effects of Treg 18, 24, 25. Additionally, IL-7 is able to antagonize inhibitory TGF-β signaling and it also antagonizes many T-cell intrinsic factors that inhibit activation 18. The ubiquitin ligase Cbl-b and Foxo transcription factors are both negatively regulated by IL-7 signaling events 18. In preclinical studies, the milieu created by IL-7 administration together with Treg depletion dramatically improves the efficacy of ACT 26.

The innate immune response can also be augmented with cytokine therapy. IL-15 enhances NK function and cytolytic activity 110, 111. Some of the observed effects of IL-15 on NK cells may be mediated via DC that transpresent the cytokine to prime and promote survival of the NK cells 112, 113. IL-21 can synergize with IL-2 to promote the activity of γδ T cells and it may also promote NK activity by upregulating the expression of numerous receptors including FcγRIIIa. This latter attribute may explain the observation that NK cells have greater lytic activity against mAb-targeted tumor cells in the presence of IL-21 49.

IL-7 clinical trials

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

Three studies have utilized IL-7 in clinical cancer trials. All the studies demonstrated that IL-7 was well tolerated at the administered doses. In two of the phase I trials, with 12 and 16 patients, respectively, no anti-tumor effects were reported 44, 114. One of these trials utilized IL-7 as adjuvant treatment along with a suboptimal melanoma vaccine in metastatic melanoma patients 114. The other trial, in patients with refractory malignancies, utilized IL-7 as a single agent 44. Both trials showed expansion of CD4+ and CD8+ T cells. IL-7 also promoted an increase in the diversity of the T-cell repertoire and enhanced the output or cycling of recent thymic emigrants 44. In contrast to IL-2, which promotes Treg expansion, in both of these trials 44, 114 Treg numbers were not increased.

Another phase I trial, which was conducted with six patients, assessed the efficacy of a vaccine consisting of melanoma cells that ectopically expressed IL-7 115. Surrogate makers of anti-tumor immunity were detected but nominal anti-tumor efficacy was observed. These studies are encouraging in developing IL-7 as a therapeutic in view of its safety profile and immunological effects. Further studies are required to address the clinical utility of IL-7 administered for longer time courses and together with other anti-tumor therapies.

Limitations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

The delicate balance between indispensable immunity required for the control of infections and potential deleterious responses against “self” is clearly evident by the gamut of pathologies seen in the immunodeficiency syndromes and, at the other end of the spectrum, autoimmune diseases. Furthermore, this fragile state is unmistakably manifest when immunosuppressive drugs are used to treat autoimmunity and the inevitable infectious consequences of immunodeficiency become evident. Our experience in manipulating immunity has grown exponentially in recent times and as with all treatments, therapeutic windows need to be determined. With specific regard to cytokine therapies there is the potential to promote autoimmunity 41 and indeed polymorphisms in the IL-7 signaling pathway have been associated with multiple sclerosis 116–118. As with immunosuppressive therapies, immune-augmenting therapies such as cytokine administration, will need to be titrated, tailored, and importantly, be transient and reversible.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

Considerable work needs to be done to define the timing, duration and best combinations of cytokine therapies. The synergistic effects of IL-21 and its ability to upregulate CD127 may make it a promising cytokine to use in combination with IL-7. Furthermore, the efficacy of combining cytokine therapies with conventional anti-tumor therapies to promote innate and adaptive clearance of residual tumor burden needs to be explored. The efficacy of many current modalities of immune therapy including mAb treatments, vaccination and ACT may be increased with the use of cytokines as adjuvant. Our expanded knowledge of the physiological role and function of IL-7 and other cytokines will assist us in developing rational therapies incorporating adjuvant cytokine treatments.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References

The Canadian Institute for Health Research and the Terry Fox Cancer Foundation of the National Cancer Institute of Canada support the work of T. W. M. The Cancer Research Institute (New York, NY), the Walter and Eliza Hall Institute of Medical Research and the National Health and Medical Research Council of Australia support the work of M. P.

Conflict of interest: The authors declare no financial or commercial conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Immune inhibitory networks
  5. Immunotherapy modalities
  6. The role of IL-7 in immunity
  7. IL-7 and other cytokines as immunotherapeutics
  8. IL-7 clinical trials
  9. Limitations
  10. Concluding remarks
  11. Acknowledgements
  12. References