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Homeostasis of normal CD8 memory cells is impaired in mixed knockout chimeras. OT-I memory CD8 T cells were CFSE labeled and transferred into the indicated bone marrow chimeric mice. Spleens cells were analyzed at 6 wk for CFSE intensity and numbers of OT-I cells (detected by OVA/K b tetramer binding). A, CFSE intensity among OVA/K b tetramer CD8 T cells (R represents the percentage of cells that proliferated). B, Absolute numbers of splenic OVA/K b tetramer CD8 T cells recovered from indicated groups of chimeras.
Source publication
IL-15 is critical for generation of multiple lymphoid subsets. Recent data have demonstrated a unique aspect of responses to IL-15, in that cells bearing the IL-15Ralpha chain can bind soluble IL-15 and "transpresent" the cytokine to other cells, allowing the latter to respond to IL-15. However, it is unclear whether IL-15 is normally secreted and...
Contexts in source publication
Context 1
... C57BL/6 (B6), B6.SJL, B6.PL, and B6.129 IL-15R / mice (The Jack- son Laboratory, Bar Harbor, ME) and C57BL/6 IL-15 / (Taconic Farms, Germantown, NY) were used. In Fig. 4, IL-15 / and IL-15R / ani- mals were 10 generations backcrossed to B6 and were derived from mice provided by J. Peschon (Immunex, Seattle, WA) and A. Ma (University of California, San Francisco, CA), respectively. OT-I TCR transgenic mice (9) were originally obtained from F. Carbone (University of Melbourne, Mel- bourne, Australia) and ...
Context 2
... marrow cells from B6.PL (or B6.SJL), IL-15 / , and IL-15R / mice were depleted of T cells by culture, in the presence of complement, with anti- Thy1.2 (30H12) or anti-Thy1.1 (1A14) (for Figs. 1-3), or with anti-Thyl (T24; for Fig. 4). Mixed bone marrows (see Fig. 1) were injected into the tail vain of lethally irradiated (900 -1000 cGy) IL-15R / mice. Chimeras were used 9 -12 wk later for analysis or as recipients for cell ...
Context 3
... T cells is due to their basal proliferation in response to IL-15 (14, 15); therefore, we tested whether Ag-specific memory T cells could proliferate in mixed knockout chimeras. CFSE-labeled memory OT-I CD8 T cells were transferred into either group 1 or group 3 chimeric host mice, and their maintenance and proliferation was ana- lyzed 6 wk later (Fig. 4). Memory CD8 T cell proliferation oc- curred in the control (group 1) chimeras indicated by the loss of CFSE; however, significantly fewer divisions occurred in the mixed knockout (group 3) chimeras (Fig. 4A). Furthermore, greater numbers of memory OT-I T cells persisted in group 1 vs group 3 chimeric hosts (Fig. 4B). Thus, these data ...
Context 4
... T cells were transferred into either group 1 or group 3 chimeric host mice, and their maintenance and proliferation was ana- lyzed 6 wk later (Fig. 4). Memory CD8 T cell proliferation oc- curred in the control (group 1) chimeras indicated by the loss of CFSE; however, significantly fewer divisions occurred in the mixed knockout (group 3) chimeras (Fig. 4A). Furthermore, greater numbers of memory OT-I T cells persisted in group 1 vs group 3 chimeric hosts (Fig. 4B). Thus, these data reinforce the interpretation that the IL-15 / plus IL-15Ra / mixed chi- meras cannot support maintenance of IL-15-dependant cell ...
Context 5
... was ana- lyzed 6 wk later (Fig. 4). Memory CD8 T cell proliferation oc- curred in the control (group 1) chimeras indicated by the loss of CFSE; however, significantly fewer divisions occurred in the mixed knockout (group 3) chimeras (Fig. 4A). Furthermore, greater numbers of memory OT-I T cells persisted in group 1 vs group 3 chimeric hosts (Fig. 4B). Thus, these data reinforce the interpretation that the IL-15 / plus IL-15Ra / mixed chi- meras cannot support maintenance of IL-15-dependant cell ...
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Citations
... Microenvironment in Response to CD40 Agonism. IL-15 is known to be coexpressed in trans with IL-15Rα by myeloid cells, including by DCs, where IL-15Rα binds to IL-15 intracellularly and functions as a chaperone protein on the cell surface (17)(18)(19)(20)(21)(22). Surface IL-15/IL-15Rα complexes are transpresented to opposing lymphocytes during cell-cell interactions, serving as the primary mechanism by which physiologic IL-15 signals are delivered in vivo (23). ...
... Activity in Humanized Mouse Models of Bladder Cancer. The above data and prior literature (17)(18)(19)(20)(21)(22) thus support the hypothesis that exogenous IL-15 might provide an opportunity to further enhance CD40 agonist therapeutic activity. We tested this hypothesis using a CD40-and FcγR-humanized C57BL/6J mouse and the fullyhuman anti-CD40 agonist antibody 2141-V11, an antibody Fcengineered for enhanced FcγRIIB binding necessary for optimal CD40 agonist activity (26) that is under active clinical evaluation for the intravesical treatment of NMIBC (NCT05126472). ...
CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclini-cal rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose- limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40- targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL- 15 pathway in contributing to the therapeutic activity of CD40 agonism in ortho-topic bladder tumors, with upregulation of transpresented IL- 15/IL- 15Rα surface com-plexes, particularly by cross- presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL- 15, although they lack high levels of IL- 15Rαat baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through com-bined treatment with anti- CD40 agonist antibodies and exogenous IL- 15, including the fully- human Fc- optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL- 15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof- of- concept for combined use of Fc- optimized anti- CD40 agonist antibodies and agents targeting the IL- 15 pathway. These data support expansion of ongoing clinical studies evaluating anti- CD40 agonist antibodies and IL- 15- based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.
... It can signal through IL-2Rb/gc heterodimer either alone with poor affinity or through transpresentation via IL-15Ra with high affinity. The latter consists in IL-15 binding to IL-15Ra expressed at the surface of presenting cells (dendritic cells, macrophages, stromal cells…) and being transpresented to IL-2Rb/gc-expressing NK cells (47)(48)(49). The importance of this mechanism was demonstrated with adoptive transfer experiments where the injected NK cell pool was not maintained in IL-15Ra-deficient hosts while IL-15Ra-deficient NK cells transferred in wild-type (WT) mice were able to survive (50). ...
NK cells are innate lymphocytes involved in a large variety of contexts and are crucial in the immunity to intracellular pathogens as well as cancer due to their ability to kill infected or malignant cells. Thus, they harbor a strong potential for clinical and therapeutic use. NK cells do not require antigen exposure to get activated; their functional response is rather based on a balance between inhibitory/activating signals and on the diversity of germline-encoded receptors they express. In order to reach optimal functional status, NK cells go through a step-wise development in the bone marrow before their egress, and dissemination into peripheral organs via the circulation. In this review, we summarize bone marrow NK cell developmental stages and list key factors involved in their differentiation before presenting newly discovered and emerging factors that regulate NK cell central and peripheral maturation. Lastly, we focus on the impact inflammatory contexts themselves can have on NK cell development and functional maturation.
... Numerous groups have shown that various γ C family cytokines can be used to induce proliferation and expansion of the circulating memory CD8 + T cell pool and that this response can be maximized using cytokine complexes (composed of cytokines bound to antibodies or cytokine receptor chains) (15,16,28,29). IL-15 signals through IL-2Rβ and γ C , while the high affinity receptor for IL-15, IL-15Rα, is not required by cells responding to IL-15; instead, IL-15Rα is used to "transpresent" IL-15 from the IL-15-synthesizing cell to another and can also form soluble complexes with IL-15 that increase during inflammation (30)(31)(32)(33)(34)(35)(36). Hence, IL-15/IL-15Rα-Fc complexes (IL-15c), as well as IL-2 complexes and IL-2 muteins designed to selectively engage IL-2Rβ/γ C , have been used to drive expansion of memory CD8 + T cells (15,16,28,37,38), with potential therapeutic applications in the control of infectious diseases and cancer (39)(40)(41)(42). ...
... Whether IL-15c treatment also mediates indirect effects remains to be determined. While IL-15Rα is typically dispensable on circulating memory CD8 + T cells during homeostasis (and is not required for IL-15 complex signaling) (30)(31)(32)(33)(34)(35), it has been found on circulating memory CD8 + T cells and, when overexpressed in naive CD8 + T cells, promotes proliferation (14,57). Whether T cell-associated IL-15Rα is required by memory CD8 + T cells in homeostatic or inflammatory contexts in specific tissues should be considered in future studies. ...
Interleukin-15 (IL-15) is often considered a central regulator of memory CD8 ⁺ T cells, based primarily on studies of recirculating subsets. However, recent work identified IL-15–independent CD8 ⁺ T cell memory populations, including tissue-resident memory CD8 ⁺ T cells (T RM ) in some nonlymphoid tissues (NLTs). Whether this reflects the existence of IL-15–insensitive memory CD8 ⁺ T cells is unclear. We report that IL-15 complexes (IL-15c) stimulate rapid proliferation and expansion of both tissue-resident and circulating memory CD8 ⁺ T cell subsets across lymphoid and nonlymphoid tissues with varying magnitude by tissue and memory subset, in some sites correlating with differing levels of the IL-2Rβ. This was conserved for memory CD8 ⁺ T cells recognizing distinct antigens and elicited by different pathogens. Following IL-15c–induced expansion, divided cells contracted to baseline numbers and only slowly returned to basal proliferation, suggesting a mechanism to transiently amplify memory populations. Through parabiosis, we showed that IL-15c drive local proliferation of T RM , with a degree of recruitment of circulating cells to some NLTs. Hence, irrespective of homeostatic IL-15 dependence, IL-15 sensitivity is a defining feature of memory CD8 ⁺ T cell populations, with therapeutic potential for expansion of T RM and other memory subsets in an antigen-agnostic and temporally controlled fashion.
... Another strategy to limit the radius of action is that certain cytokines can act anchored to the membrane, as in the case of transforming growth factor beta (TGFβ) (Yang et al., 2013) or IL-15. In this case, anchoring occurs through binding to one of the receptor chains, a phenomenon known as transpresentation (Sandau et al., 2004). However, some cytokines can have an endocrine effect through circulation in vesicles such as exosomes (Braicu et al., 2015). ...
Cancer is a heterogeneous disease, requiring treatment tailored to the unique phenotype of the patient's tumor. Monoclonal antibodies (mAbs) and variants thereof have enabled targeted therapies to selectively target cancer cells. Cancer cell-specific mAbs have been used for image-guided surgery and targeted delivery of radionuclides or toxic agents, improving classical treatment strategies. Cancer cell-specific mAbs can further inhibit tumor cell growth or can stimulate immune-mediated destruction of cancer cells, a feature that has also been achieved through mAb-mediated manipulation of immune cells and pathways. Drawbacks of mAbs and their variants, together with the discovery of camelid heavy chain-only antibodies and the many advantageous features of their variable domains, referred to as VHHs, single domain antibodies or nanobodies (Nbs), resulted in the exploration of Nbs as an alternative targeting moiety. We therefore review the state-of-the-art as well as novel exploitation strategies of Nbs for targeted cancer therapy.
... IL-15 immunomodulatory properties are being explored alone or in combination with other agents to potentiate anti-tumor responses. IL-15 is frequently found associated to the receptor IL-15Ra on dendritic cells (127). It has been shown that soluble IL-15/ recombinant IL-15Ra complexes elicit a rapid and strong expansion and activation of CD8+ T cells and NK cells, improving immune activation in vivo (128). ...
In 1975 two independent groups noticed the presence of immune cells with a unique ability to recognize and eliminate transformed hematopoietic cells without any prior sensitization or expansion of specific clones. Since then, NK cells have been the axis of thousands of studies that have resulted until June 2021, in more than 70 000 publications indexed in PubMed. As result of this work, which include approaches in vitro, in vivo, and in natura, it has been possible to appreciate the role played by the NK cells, not only as effectors against specific pathogens, but also as regulators of the immune response. Recent advances have revealed previous unidentified attributes of NK cells including the ability to adapt to new conditions under the context of chronic infections, or their ability to develop some memory-like characteristics. In this review, we will discuss significant findings that have rule our understanding of the NK cell biology, the developing of these findings into new concepts in immunology, and how these conceptual platforms are being used in the design of strategies for cancer immunotherapy.
... IL15 signals through a heterotrimeric receptor including the common gamma chain (gc) shared with IL2, IL4, IL7, IL9, and IL21, the IL2Rb chain shared with IL2 and the unique IL15Ra chain. IL15 and IL15Ra are produced in a coordinated fashion predominantly by dendritic cells (DC), monocytes and macrophages stimulated with Toll-like receptors, type I or II IFN and through agonistic CD40 ligands (9,10). IL15 is only secreted in small quantities and is mainly membrane bound under physiologic conditions (11,12). ...
... Recently there has been a dramatic increase in these studies in murine models and in clinical trials of patients leading in some cases to approval by the FDA. It has been used in many disease systems using diverse agents including BCG, STING signaling, pattern recognition agents (TLR 3,4,7,8,9), cytokines (IL2, IL7, IL12, IFNg, IFNa/b), monoclonal antibodies (anti-CTLA-4, anti-CD40), and oncolytic viruses. Tumor types involved included B-cell lymphoma, malignant melanoma, and hepatocellular carcinoma. ...
Purpose:
IL-15 promotes activation and maintenance of natural killer (NK) and CD8+ T-effector memory (TEM) cells making it a potential immunotherapeutic agent for the treatment of cancer. However, monotherapy with IL-15 was ineffective in cancer patients, indicating that it would have to be used in combination with other anticancer agents. The administration of high doses of common gamma chain (γc) cytokines, such as IL-15, is associated with the generation of "helpless" antigen-nonspecific CD8 T-cells. The generation of the tumor-specific cytotoxic T-cells (CTLs) can be mediated by CD40 signaling via agonistic anti-CD40 antibodies. Nevertheless, parenteral administration of anti-CD40 antibodies is associated with unacceptable side effects, such as thrombocytopenia and hepatic toxicity, which can be avoided by intratumoral administration.
Experimental design:
We investigated the combination of IL-15 with an intratumoral anti-CD40 monoclonal antibody (mAb) in a dual tumor TRAMP-C2 murine prostate cancer model and expanded the regimen to include an anti-PD-1 mAb.
Results:
Here we demonstrated that anti-CD40 given intratumorally not only showed significant antitumor activity in treated tumors, but also uninjected contralateral tumors, indicative of abscopal efficacy. The combination of IL-15 with intratumoral anti-CD40 showed an additive immune response with an increase in the number of tumor-specific tetramer-positive CD8 T-cells. Furthermore, the addition anti-PD-1 further improved efficacy mediated by the anti-CD40/IL-15 combination.
Conclusion:
These studies support the initiation of a clinical trial in patients with cancer utilizing IL-15 in association with the checkpoint inhibitor, anti-PD-1, and intratumoral optimized anti-CD40.
... The finding that IL-15 is trans-presented to neighboring cells by IL-15Ra (15), the strikingly similar impact of genetically ablating IL-15 or IL-15Ra on innate and adaptive immune cell compartments (6,24) and the dispensability of IL-15Ra on memory CD8 T cells to respond to IL-15 (49) have firmly established the concept that IL-15Ra is essential for IL-15 signaling. However, soluble IL-15 can bind the IL-15Rbgc heterodimeric receptor complex albeit with less affinity than when IL-15 is presented by IL-15Ra (15,16). ...
Interleukin-15, produced by hematopoietic and parenchymal cells, maintains immune cell homeostasis and facilitates activation of lymphoid and myeloid cell subsets. IL-15 interacts with the ligand-binding receptor chain IL-15Rα during biosynthesis, and the IL-15:IL-15Rα complex is trans-presented to responder cells that express the IL-2/15Rβγc complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαβγc complex is considered the functional IL-15 receptor. However, studies on the pathogenic role of IL-15 in inflammatory and autoimmune diseases indicate that IL-15 can signal independently of IL-15Rα via the IL-15Rβγc dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control Listeria monocytogenes infection. We show that IL-15-deficient mice succumb to infection whereas IL-15Rα-deficient mice clear the pathogen as efficiently as wildtype mice. IL-15-deficient macrophages did not show any defect in bacterial uptake or iNOS expression in vitro. In vivo, IL-15 deficiency impaired the accumulation of inflammatory monocytes in infected spleens without affecting chemokine and pro-inflammatory cytokine production. The inability of IL-15-deficient mice to clear L. monocytogenes results from impaired early IFNγ production, which was not affected in IL-15Rα-deficient mice. Administration of IFNγ partially enabled IL-15-deficient mice to control the infection. Bone marrow chimeras revealed that IL-15 needed for early bacterial control can originate from both hematopoietic and non-hematopoietic cells. Overall, our findings indicate that IL-15-dependent IL-15Rα-independent signaling via the IL-15Rβγc dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.
... 8 IL-15 is co-expressed with an IL-15 binding protein, IL-15 receptor alpha (IL-15Rα), a membrane anchored, stabilizing polypeptide crucial to the natural biosynthesis of the cytokine. [9][10][11][12] The two polypeptide chains form a complex in the endoplasmic reticulum, and undergo glycosylation and traffic through the Golgi to the plasma membrane. [13][14][15] The membrane-anchored IL-15Rα is responsible for IL-15 retention on the cell surface, where it is trans-presented to adjacent responding cells expressing the IL-2/IL-15 βγ receptor. ...
Background
NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.
Methods
Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1).
Results
As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1–77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8 ⁺ T cells), increased CD16 ⁺ monocytes, and increased CD163 ⁺ macrophages at injection sites.
Conclusions
Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy.
Trial registration number
NCT02452268 .
... With the aid of IL-15Ra, IL-15 is protected from degradation, accumulates on the membrane and in the circulation of mice, and exhibits increased biological activity (65). Accordingly, IL-15-expressing cells must simultaneously express IL-15Ra to supply IL-15 to IL-15responsive NK cells bearing IL-15Rb and gc (66,67). The distinct requirement is further unveiled by the discovery that IL-15 is preassembled with IL-15Ra in a complex in the endoplasmic reticulum/Golgi and subsequently shuttled to the cell surface (8,68). ...
Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras–MEK–MAPK, JAK–STAT5, and PI3K–ATK–mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.
... Dubois et al. [28] showed that IL-15 acts on the surface of producing cells in complex with the membrane-anchored IL-15Rα to engage the IL-2/IL-15 receptor β/γ complex in nearby cells, a process termed trans-presentation. Furthermore, in physiological conditions, IL-15 and IL-15Rα expression from the same cells is required in order to achieve biological activity; bone marrow from chimeric mice repopulated with a mixture of IL-15-/-and IL-15Rα-/-cells failed to generate memory CD8 + T cells and mature NK cells [29][30][31]. An additional observation was that IL-15 and IL-15Rα genes present similarities in their promoter function and are co-transcribed in different cell types [19,28,[32][33][34]. ...
... Cancers 2021, 13, x FOR PEER REVIEW 3 of 20 a mixture of IL-15-/-and IL-15Rα-/-cells failed to generate memory CD8 + T cells and mature NK cells. [29][30][31]. An additional observation was that IL-15 and IL-15Rα genes present similarities in their promoter function and are co-transcribed in different cell types [19,28,[32][33][34]. ...
Simple Summary
The rapidly expanding field of cancer immunotherapy uses diverse technologies, including cytokines, T cells, and antibody administration, with the aim to induce effective immune responses leading to tumor control. Interleukin-15 (IL-15), a cytokine discovered in 1994, supports the homeostasis of cytotoxic immune cells and shows promise as an anti-tumor agent. Many studies have elucidated IL-15 synthesis, regulation and biological function and explored its therapeutic efficacy in preclinical cancer models. Escherichia coli-derived single-chain IL-15 was tested in the first in-human trial in cancer patients. Its effects were limited by the biology of IL-15, which in vivo comprises a complex of the IL-15 chain with the IL-15 receptor alpha (IL-15Rα) chain, together forming the IL-15 heterodimer (hetIL-15). Currently, single-chain IL-15 and several heterodimeric IL-15:IL-15Rα variants (hetIL-15, N-803 and RLI) are being tested in clinical trials. This review presents a summary of contemporary preclinical and clinical research on IL-15.
Abstract
Immunotherapy has emerged as a valuable strategy for the treatment of many cancer types. Interleukin-15 (IL-15) promotes the growth and function of cytotoxic CD8⁺ T and natural killer (NK) cells. It also enhances leukocyte trafficking and stimulates tumor-infiltrating lymphocytes expansion and activity. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and the so-called IL-15 receptor alpha chain that are together termed “heterodimeric IL-15” (hetIL-15). hetIL-15, closely resembling the natural form of the cytokine produced in vivo, and IL-15:IL-15Rα complex variants, such as hetIL-15Fc, N-803 and RLI, are the currently available IL-15 agents. These molecules have showed favorable pharmacokinetics and biological function in vivo in comparison to single-chain recombinant IL-15. Preclinical animal studies have supported their anti-tumor activity, suggesting IL-15 as a general method to convert “cold” tumors into “hot”, by promoting tumor lymphocyte infiltration. In clinical trials, IL-15-based therapies are overall well-tolerated and result in the expansion and activation of NK and memory CD8⁺ T cells. Combinations with other immunotherapies are being investigated to improve the anti-tumor efficacy of IL-15 agents in the clinic.
