Cytokines in Cancer Immunotherapy Waldmann, Thomas A
Cold Spring Harbor perspectives in biology,
12/2018, Letnik:
10, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell leukemia, and interleukin (IL)-2 ...for the treatment of advanced melanoma and metastatic renal cancer. In addition, IL-12, IL-15, IL-21, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been evaluated in clinical trials. However, the cytokines as monotherapy have not fulfilled their early promise because cytokines administered parenterally do not achieve sufficient concentrations in the tumor, are often associated with severe toxicities, and induce humoral or cellular checkpoints. To circumvent these impediments, cytokines are being investigated clinically in combination therapy with checkpoint inhibitors, anticancer monoclonal antibodies to increase the antibody-dependent cellular cytotoxicity (ADCC) of these antibodies, antibody cytokine fusion proteins, and anti-CD40 to facilitate tumor-specific immune responses.
Interleukin-2 and interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two ...cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin-2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin-15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. As discussed in this Review, the biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
IL2 and IL15, members of the 4α-helix bundle family of cytokines, play pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor ...subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL2 through maintenance of fitness of regulatory T cells and activation-induced cell death is the elimination of self-reactive T cells to prevent autoimmunity. In contrast with IL2, IL15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. Blockade of IL2 and IL15 using monoclonal antibodies has been reported to be of value in the treatment of patients with leukemia, autoimmune disorders, and in the prevention of allograft rejection. IL2 has been approved by the FDA for the treatment of patients with malignant renal cell cancer and metastatic malignant melanoma. Clinical trials involving recombinant human IL15 given by bolus infusions have been completed, and studies assessing subcutaneous and continuous intravenous infusions are under way in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL15 with IL15Rα(+/-) IgFc.
Common gamma receptor-dependent cytokines and their JAK STAT pathways play pivotal roles in T cell immunity. Abnormal activation of this system was pervasive in diverse T cell malignancies assessed ...by pSTAT3 pSTAT5 phosphorylation. Activating mutations were described in some but not all cases. JAK1 and STAT3 were required for proliferation and survival of these T cell lines whether or not JAKs or STATs were mutated. Activating JAK and STAT mutations were not sufficient to initiate leukemic cell proliferation but rather only augmented signals from upstream in the cytokine pathway. Activation required the full pathway, including cytokine receptors acting as scaffolds and docking sites for required downstream JAK STAT proteins. JAK kinase inhibitors have depressed leukemic T cell line proliferation. The insight that JAK STAT system activation is pervasive in T cell malignancies suggests novel therapeutic approaches that include antibodies to common gamma cytokines, inhibitors of cytokine-receptor interactions, and JAK kinase inhibitors that may revolutionize therapy for T cell malignancies.
Three patients with chronic, smoldering, and acute subtypes of adult T-cell leukemia–lymphoma had rapid disease progression and increased viral replication after treatment with the anti–programmed ...death 1 antibody nivolumab.
Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated ...B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.
► Lenalidomide kills ABC DLBCLs by decreasing expression of IRF4 and SPIB ► IRF4 and SPIB maintain ABC DLBCL viability ► IRF4 and SPIB block toxic IFNβ production while enhancing prosurvival NF-κB activity ► Lenalidomide and BCR pathway drugs synergize to inhibit IRF4 and kill ABC DLBCLs
Interleukin (IL)-15 has multiple roles in innate and adaptive immunity, especially regarding CD8+ T cells and natural killer cells. However, the role of IL-15 in regulating differentiation of T ...helper cell subsets and mononuclear phagocytes (MPs) in different tissues in vivo is unknown. Here we report that IL-15 indirectly regulates Th17 but not other Th subsets in the intestinal lamina propria (LP), apparently through effects on MPs. Th17 cells in the LP were more prevalent in IL-15 KO mice than their wild-type counterparts, and less prevalent in IL-15 transgenic mice than their wild-type littermates, even co-caged. MPs from the LP of these mice were sufficient to mimic the in vivo finding in vitro by skewing of cocultured wild type OVA-specific CD4+ T cells. However, production of IL-15 or lack thereof by these MPs was not sufficient to explain the skewing, as addition or blockade of IL-15 in the cultures had no effect. Rather, a skewing of the relative proportion of CD11b+, CD103+ and double positive LP MP subsets in transgenic and KO could explain the differences in Th17 cells. Thus, IL-15 may influence MP subsets in the gut in a novel way that alters the frequency of LP Th17 cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cytokines in the Treatment of Cancer Conlon, Kevin C; Miljkovic, Milos D; Waldmann, Thomas A
Journal of interferon & cytokine research,
01/2019, Letnik:
39, Številka:
1
Journal Article
Recenzirano
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Cytokines are major regulators of innate and adaptive immunity that enable cells of the immune system to communicate over short distances. Cytokine therapy to activate the immune system of cancer ...patients has been an important treatment modality and continues to be a key contributor to current clinical cancer research. Interferon alpha (IFNα) is approved for adjuvant treatment of completely resected high-risk melanoma patients and several refractory malignancies. High-dose interleukin-2 (HDIL-2) is approved for treatment of metastatic renal cell cancer and melanoma, but both agents are currently less commonly used with the development of newer agents. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN gamma (IFNγ), IL-7, IL-12, and IL-21 were evaluated in clinical trials and remain part of certain investigational trials. The initial single-agent clinical trials with the long-awaited IL-15 have been completed and combination trials with antitumor antibodies or checkpoint inhibitors (CPIs) have been initiated. However, cytokines in monotherapy have not fulfilled the promise of efficacy seen in preclinical experiments. They are often associated with severe dose-limiting toxicities that are manageable with appropriate dosing and are now better understood to induce immune-suppressive humoral factors, suppressive cells, and cellular checkpoints, without consistently inducing a tumor-specific response. To circumvent these impediments, cytokines are being investigated clinically with new engineered cytokine mutants (superkines), chimeric antibody-cytokine fusion proteins (immunokines), anticancer vaccines, CPIs, and cancer-directed monoclonal antibodies to increase their antibody-dependent cellular cytotoxicity or sustain cellular responses and anticancer efficacy. In this review, we summarize current knowledge and clinical application of cytokines either as monotherapy or in combination with other biological agents. We emphasize a discussion of future directions for research on these cytokines, to bring them to fruition as major contributors for the treatment of metastatic malignancy.
Cancer immunotherapy is designed to stimulate the immune system to reject and destroy tumors. Recently, interleukin-15 (IL-15), a member of the four α-helix bundle family of cytokines, has emerged as ...a candidate immunomodulator for the treatment of cancer. IL-15 acts through its specific receptor, IL-15Rα, which is expressed on antigen-presenting dendritic cells, monocytes and macrophages. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. It also enhances the cytolytic activity of CD8+ T cells and induces long-lasting antigen-experienced CD8+ CD44hi memory T cells. IL-15 stimulates differentiation and immunoglobulin synthesis by B cells and induces maturation of dendritic cells. It does not stimulate immunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15 activity could enhance innate and specific immunity and fight tumors. Here we review aspects of IL-15 biology that make it a promising agent for anticancer therapy. We also discuss preclinical models in which IL-15 has demonstrated antitumor activity and highlight ongoing clinical trials of IL-15 in patients with cancer and HIV infection.
We completed clinical trials of rhIL-15 by bolus, subcutaneous, and continuous intravenous infusions (CIV). IL-15 administered by CIV at 2 mcg/kg/day yielded a 38-fold increase in 10- day number of ...circulating NK cells, a 358-fold increase in CD56
NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circumvent checkpoints, trials of IL-15 in combination with other anticancer agents were initiated. Tumor-bearing mice receiving IL-15 with antibodies to CTLA-4 and PD-L1 manifested marked prolongation of survival compared to mice receiving IL-15 with either agent alone. In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632). In rhesus macaques CIV IL-15 at 20 μg/kg/day for 10 days led to an 80-fold increase in number of circulating effector memory CD8 T cells. However, administration of γc cytokines such as IL-15 led to paralysis/depression of CD4 T-cells that was mediated through transient expression of SOCS3 that inhibited the STAT5 signaling pathway. This lost CD4 helper role could be restored alternatively by CD40 agonists. In the TRAMP-C2 prostate tumor model the combination of IL-15 with agonistic anti-CD40 produced additive effects in terms of numbers of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells expressed and tumor responses. A clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15. To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL). IL-15 enhanced the ADCC and therapeutic efficacy of both antibodies. These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.
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