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Published in final edited form as: Immunol Invest. 2025 Feb 21;54(5):604–622. doi: 10.1080/08820139.2025.2464055

IL-7 Immunotherapies: Current Applications and Engineering Opportunities

Emily Ariail a,b,c,e, Benjamin Biggs a,b,e, Rowan O’Flanagan c,d, Jonathan P Schneck a,b,e,f,*
PMCID: PMC12197848  NIHMSID: NIHMS2056713  PMID: 39981682

Abstract

IL-7 is a cytokine that plays a critical role in the development and proliferation of many different immune cells. IL-7 is notably important for the proper development and activity of T cells and B cells. Additionally, the cytokine plays a role in the function of natural killer cells and dendritic cells. Because of this innate biological activity, IL-7 has gained traction as a potential immunotherapy for multiple applications. Notably, IL-7 has demonstrated efficacy in adoptive cell therapy models and as a vaccine adjuvant. The cytokine has also been used as a treatment for sepsis and other chronic infections. To further enhance its therapeutic efficacy, IL-7 has been engineered by fusing the cytokine to antibody fragments or other bioactive or targeting molecules. These engineered IL-7 therapeutics seek to improve the cytokine’s pharmacokinetic and immunological properties and reduce off-target effects. IL-7 immunotherapies largely remain at the preclinical stage, but there is growing interest in IL-7’s many therapeutic applications and increasing opportunities to further engineer the molecule for future clinical translation.

Keywords: Cytokine, Immunotherapy, IL-7, Engineering

Introduction

Cytokines are small proteins that play a critical role in the immune system, acting as signaling molecules for activation, growth, inflammation, and other vital immunological functions. One class of cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, signal through the shared common gamma chain (γc) receptor (IL-2Rγ or CD132)(W. J. Leonard et al. 2019). These γc cytokines have pleiotropic effects and play critical roles in both innate and adaptive immunity. This review will focus on one important γc cytokine, IL-7, which is required for the development and proliferation of many different immune cells.

IL-7 is a small molecule, weighing only 17.4 kDa, and has a half-life between 7–23 hours in humans(Goodwin et al. 1989; Sereti et al. 2009). It is a member of the type I cytokine family, which all share a similar molecular structure made up of four α-helical bundles(Wang et al. 2009). IL-7 is notably not produced by mature immune cells and is mainly secreted by stromal cells in primary and secondary lymphoid organs. However, IL-7 has also been detected in other organs such as the liver, lung, skin, intestine, and brain(Hara et al. 2012; Moors et al. 2010; Sawa et al. 2009; Shinoda et al. 2016). The receptor for IL-7 is a heterodimer made up of the IL-7 receptor alpha subunit (IL-7Rα or CD127) and γc(Mazzucchelli & Durum 2007; Ziegler et al. 1995). The intracellular domains of these subunits are associated with janus kinase 1 (JAK-1) and janus kinase 3 (JAK-3), which phosphorylate each other during IL-7 signaling and initiate the janus kinase - signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically activating the STAT5 transcription factor (Fig. 1)(Jiang et al. 2004; Liu et al. 1997). IL-7 has also been observed toactivate the STAT1/3, PI3K, and ERK pathways (Fig. 1)(Fleming & Paige 2001; Jiang et al. 2004; Le Saout et al. 2017; Venkitaraman & Cowling 1994). Following intracellular signaling, IL-7Rα expression is down-regulated on T cells, which is not observed for other γc cytokines(J. Li et al. 2003; Schluns et al. 2000).

Figure 1.

Figure 1.

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IL-7 Signaling Cascade. IL-7 signals through the IL-7 receptor alpha (IL-7Rα) and common gamma chain (γC) complex, which initiates an internal phosphorylation cascade and activates downstream signaling pathways such as Jak/STAT, PI3K, and MAPK. These pathways have critical roles in cell proliferation, survival, and function.

Several classes of immune cells express IL-7Rα, including B cells, T cells, dendritic cells, natural killer (NK) cells, monocytes, eosinophils, and innate lymphoid cells (ILCs)(Kelly et al. 2009; Komschlies et al. 1994; Leung et al. 2019; Vogt et al. 2009; Vonarbourg & Diefenbach 2012; Vosshenrich et al. 2006). In the scope of this review, we will mainly focus on the biological effects of IL-7 on immune cells that are the common targets of immunotherapy, which include T cells, B cells, NK cells, and dendritic cells. We will discuss current uses of IL-7 as an immunotherapy and ways in which IL-7 is being engineered to advance its therapeutic translation.

Section I: Biological Effects of IL-7

T cells

Foundational experiments have established the importance of IL-7 in T cell development. Peschon et al. found that in IL-7 receptor knockout mice, thymic T cell progenitor expansion was halted(Peschon et al. 1994), illustrating the crucial role that IL-7 plays in T cell development. The precise effect of IL-7 which enables T cell development is not fully understood, but is likely due at least in part to the activation transcription factor STAT5(Pallard et al. 1999). This pathway is known to be involved in V(D)J recombination(Döbbeling 1996), although most experiments on the matter have been conducted in pre-B lymphocytes, not T cell precursors. Notably, IL-7Ra deficiency in humans has been found to cause Severe Combined Immunodeficiency (SCID) – accounting for about 10 percent of cases of the syndrome –due to a complete lack of functional T cells(Kumrah et al. 2020).This mutation has also been shown to cause rare autoimmune manifestations, including Omenn syndrome(Zago et al. 2014), although the mechanism by which the disease progression occurs is still under investigation.

In vitro and in vivo experimentation have demonstrated the importance of IL-7 in preventing the atrophy of individual T cells and maintaining the survival of whole T cell populations(Rathmell et al. 2001; Tan et al. 2001).A portion of this effect can be attributed to the fact that upon binding to IL-7, IL-7Ra stimulates PI3K and its downstream molecule Akt (Fig. 1), both of which play a role in maintaining cellular metabolism(Rathmell et al. 2001).Furthermore, downstream signaling of IL-7Raresults in increased expression of anti-apoptotic chemicals in the B cell lymphoma 2 (BCL-2) family(Chen et al. 2021), promoting survival. Naïve T cells are particularly dependent on IL-7 signaling for survival(Rathmell et al. 2001).In experiments by Tan et al, naïve T cells transplanted into an IL-7 negative host did not proliferate and disappeared over a one month period(Tan et al. 2001). This effect was not seen upon transfer to IL-4 or IL-15 deficient hosts, illustrating the unique importance of IL-7 to naïve T cell survival.

T cells also rely on IL-7 signaling to restore population homeostasis via proliferation(Guimond et al. 2009; Tan et al. 2001). Interestingly, experiments in lymphopenic mice demonstrated that while systemic IL-7 concentrations were consistently elevated, only CD8+ cells, but not CD4+’s, were observed to proliferate(Guimond et al. 2009). With further experimentation, Guimond et al.were able to conclude that systemic, high concentrations of IL-7 preferentially expand CD8+ T cells – an area of potential exploitation for therapeutic uses.

B cells

Much like T cells, B cells are significantly influenced by IL-7 signaling. The Peschon et al. study found B cell formation to be impaired in IL-7 receptor deficient mice(Peschon et al. 1994), confirming that murine B cell progenitors are non-redundantly reliant on IL-7. Interestingly, the same does not seem to be true for human B cells, as SCID patients lacking functional IL-7Ra expression have B cells present(Kumrah et al. 2020). That said, IL-7 still plays a role in humanB cell development. Pre-B lymphocyte development is mediated by both IL-7 receptor and pre-B cell receptor (pBCR) signaling, with pBCR expression correlating to the ability to proliferate in low (10–100 pg/mL) IL-7 concentrations. Fleming and Paigefound that IL-7R and pBCR binding both stimulate activation of the ERK/MAPK pathways(Fleming & Paige 2001). Increased activation levels in those pathways were observed when both signaling molecules were present compared to only one, illustrating the overlapping but complementary roles of IL-7 and pBCR.

Additionally, as seen in T cells, IL-7R binding in B cells also leads to increased expression of anti-apoptotic molecules and decreased expression of pro-apoptotic molecules, contributing to increased survival(Corfe & Paige 2012). IL-7 is also important in the creation of B cell diversity, as it assists in regulating immunoglobulin diversification.STAT5 signaling, an effect of IL-7R binding, has been demonstrated to be crucial in V(D)J recombination, as it regulates the transcriptional activation and histone acetylation of VHJ558 genes(Bertolino et al. 2005).In vivo, STAT5 deficient murine B cell progenitors and precursors showed significant impairment in the V(D)Jrecombination process(Bertolino et al. 2005),illustrating the crucial role that IL-7 signaling plays in generating a repertoire of receptors that can adequately recognize a diverse array of antigens.

NK cells

In contrast to T and B cells, most NK cells can develop normally without IL-7(Vosshenrich et al. 2005).Certain NK cell phenotypes express IL-7 receptor and have been shown to respond to IL-7 binding. Systemic IL-7 promotes survival of the human CD56bright NK cell subset but does not change interferon-γ (IFN-γ) production, cytotoxicity, or activity marker expression(Michaud et al. 2010). In human NK-22 cells, named for their production and secretion of IL-22, IL-7 maintains cell survival and IL-22 production levels, but does not result in cell expansion(Cella et al. 2010). Of note and in contrast to the majority of NK cells, thymus derived NK cells are uniquely dependent on IL-7 for functionality(Vosshenrich et al. 2006). In a mouse gene knockout experiment, Vosshenrich et al. found that thymic NK cells consistently expressed IL-7Ra and depended on IL-7 signaling for homeostasis(Vosshenrich et al. 2006). This revelation disproves the idea that IL-7 is merely an accessory cytokine to NK cells - an interesting affirmation of the role of IL-7 signaling beyond B and T lymphocytes.

Dendritic cells

Dendritic cells (DCs) bridge the gap between innate and adaptive immunity through serving as antigen presenting cells (APCs). Vogt et al. investigated the relationship between dendritic cells and IL-7, finding the answer to be dependent on the specific origin and phenotype of dendritic cell(Vogt et al. 2009). DCs derived from the bone marrow were found to express IL-7 receptor, and their survival time was significantly lengthened in vitroby the presence of IL-7. Although migratory DCs also expressed IL-7 receptor, their survival was not correlated with IL-7. However, IL-7 indirectly contributed to migratory DC development via signaling in IL-7 receptor expressing lymphocytes, which interact with DC progenitors. Interestingly, DCs are known to be stimulated largely by thymic stromal lymphopoietin (TSLP), a cytokine which is remarkably similar to IL-7(Soumelis et al. 2002). The TSLP receptor is comprised of a TSLP receptor (TSLPR) chain, which resembles the common- γ chain of other receptors, andan IL-7Ra chain. Following TSLP activation, DCs induce the expansion of naïve CD4+ T cells(Soumelis et al. 2002).Despite their shared receptor subunit, TSLP plays a distinct role in DC activation and function, primarily promoting type 2 immune responses (Ebina-Shibuya & Leonard 2023).There is still no unified conclusion regarding the role that IL-7 plays in DC development and function, necessitating further research.

Section II: IL-7 as a Therapeutic

Given its multipotent role in immune homeostasis, the maturation of B cells, and the activation and differentiation of T cells, numerous studies have sought to evaluate IL-7’s therapeutic potential. The potential for IL-7 immunotherapy is highlighted by the fact that in human clinical trials, the administration of recombinant human IL-7 (rhIL-7) has demonstrated potent pro-immune effects, including robustly expanding CD4+ and CD8+ T cell populations in peripheral blood, without selective Treg expansion, and broadening the circulating T cell repertoire diversity(Sportès et al. 2008). In this section, we will discuss how pre-clinical and clinical studies of therapeutic IL-7 provide compelling evidence motivating its further use in adoptive cell therapy (ACT), for vaccine adjuvants, and against chronic infection and sepsis.

IL-7 in Adoptive Cell Therapies

Adoptive cell therapy generally refers to the process whereby an endogenous T lymphocyte population is modified, typically via genetic engineering or some other intervention, to generate a cell population with enhanced anti-tumor activity for reinfusion into the patient(Albarrán et al. 2024). This can involve the enrichment of specific tumor-reactive T cell sub-populations, engineering T cell receptors for enhanced affinity, or transducing T cells with chimeric antigen receptors (CAR-T cell therapy)(Isser & Schneck 2018; Perica et al. 2015; Sterner & Sterner 2021). However, ACT remains hampered by limitations including a lack of T-cell persistence post-reinfusion, particularly within the immune-suppressive solid tumor microenvironment (TME)(López-Cantillo et al. 2022). IL-7 offers an exciting potential method of mitigating these shortcomings. Specifically, IL-7’s aforementioned properties of helping T cells maintain a memory phenotype during activation and expansion may facilitate the enhanced persistence of adoptively transferred lymphocytes in the host(Kondrack et al. 2003; Schluns et al. 2000).

Previously, research groups leveraged IL-7’s properties to generate human CAR-T cells engineered for transgenic constitutive expression and secretion of IL-7. Using CAR-T cells targeting CD19 (the most commonly CAR-targeted antigen) with a CD28 co-stimulatory domain and a transgene encoding secreted IL-7, researchers utilized these 28z/IL-7-CAR-T cells to probe IL-7’s role in phenotypic exhaustion and cell-mediated killing(L. Li et al. 2022).28z/IL-7-CAR-T cells demonstrated comparable cytotoxicity compared with conventional 28z-CAR-T cells, as well as unaltered cytokine secretion profiles(L. Li et al. 2022). However, assessing expression levels of CCR7 and CD45RA (traditional differentiation markers), CXCR3 (a stem cell-like memory marker), and PD-1, CTLA-4, TIM-3 and LAG3 (exhaustion markers), researchers demonstrated that CD4+ 28z/IL-7-CAR-T cells maintained a greater fraction of naïve and central memory phenotype subsets after activation and expansion, as well as reduced exhaustion markers compared to CD4+ 28z-CAR-T cells(L. Li et al. 2022). In vitro, 28z/IL-7-CAR-T cells demonstrated improved persistence over 28z CAR-T cells against a long-term tumor challenge model(L. Li et al. 2022). These findings translated in vivo, where adoptively transferred T cells in a xenograft lymphoma murine model demonstrated improved survival and persistence among 28z/IL-7-CAR-T cell groups(L. Li et al. 2022). Notably, 28z/IL-7-CAR-T cell groups maintained a higher frequency of CD4+ T cells, and cytokine analysis suggested that IL-7 biased towards a T helper 1 (Th1)(L. Li et al. 2022).Withthe recent paradigm shift highlighting the critical role of CD4+ T cells, and Th1-biased subsets, in enhancing ACT efficacy through various mechanisms, these studies provide further support for the future use of IL-7 in ACT(K. Li et al. 2017; L. Li et al. 2022).

Similarly, another group investigated IL-7-expressing CAR-T cells in the context of bone tumors. Here, T lymphocytes were engineered to both target the chordoma-specific antigen B7–H3 and express IL-7, and subsequently evaluated in a patient-derived, B7–H3-expressing chordoma organoid model(Wu et al. 2024). Again, IL-7-secreting CAR-T cell-treated groups outperformed B7–H3 CAR-T cell and non-transfected T cell groups, exhibiting superior tumor control and enhanced killing in vitro(Wu et al. 2024). Together, these studies indicate the potential benefit of including secreted IL-7 in CAR-T cell therapy for targeting a range of different cancers.

Furthermore, numerous investigations support the use of IL-7 in combination with CCL19 in ACT. One group engineered CAR-T cells with a tandem construct encoding a CAR specific for human CD20, along with expression of both IL-7 and CCL19 (7 × 19 CAR-T cells)(Adachi et al. 2018). In murine solid tumor models, 7 × 19 CAR-T cells outperformed control groups to achieve superior anti-tumor activity and complete tumor regression(Adachi et al. 2018). Notably, histopathology analysis of tumor resections at 21 days revealed that 7 × 19 CAR-T cell treatment groups exhibited substantially greater T cell infiltration of both endogenous and adoptively transferred T cells among the 7 × 19 CAR-T cell group, as well as being the only group to demonstrate infiltration of dendritic cells into the tumor(Adachi et al. 2018).

Additionally, the therapeutic benefit of IL-7 in combination with CCL19 has been established in ACT-contexts outside of CAR-T cell therapy. In a different study, the same research group utilized a murine model of P815 mastocytoma, a tumor expressing the P1A antigen, to investigate the potential of IL-7/CCL19 co-secretion in enhancing T cell therapy. P1A-specific T cells, derived from TCR-transgenic mice, were genetically modified to express IL-7 and CCL19 (referred to as 7 × 19 P1A T cells)(Tokunaga et al. 2022). These engineered cells were evaluated in DBA/2 mice preconditioned with sublethal irradiation, then challenged with P815 tumor cells. Similar to previous studies, the cytokine-secreting 7 × 19 P1A T cell treatment groups outperformed regular P1A-specific T cell and control groups, promoting prolonged survival and complete tumor regression in 50% of treated mice(Tokunaga et al. 2022). Furthermore, combining 7 × 19 P1A T cells with anti–PD-1 antibody treatment resulted in a synergistic effect, leading to complete tumor regression in 80% of the animals(Tokunaga et al. 2022). Overall, these results provide strong support for the compatibility of IL-7 with many current ACT-based treatment approaches to achieve improved outcomes.

IL-7’s therapeutic role in ACT is also not limited to transfection-induced secretion. In a study aimed at elucidating the role of IL-7 bioavailability in inducing and maintaining polyfunctional CD4+ T cells, researchers administered injections of rhIL-7 to mice three days after administering adoptive cell therapy. After the adoptive transfer of naïve T cells, the subsequent IL-7 administration led to enhanced expansion and maintenance of polyfunctional CD4+ effector cells in vivo(Ding et al. 2017). Overall, the collective results of these studies provide strong support for the utility and compatibility of incorporating IL-7 into future ACT approaches.

IL-7 as a Vaccine Adjuvant

Interest in IL-7’s use extends beyond just cellular therapies. IL-7 can also have a role as an adjuvant, which are substances that serve as critical vaccine components by enhancing the immunogenicity against vaccine antigens via a number of different immunostimulatory and uptake mechanisms(T. Zhao et al. 2023). Accordingly, there is growing interest in IL-7 as a potential vaccine adjuvant by leveraging its potent immunostimulatory properties.

Recently, researchers have evaluated the potential therapeutic application of IL-7 as a low-toxicity adjuvant to facilitate a long-term viral vaccine-induced antitumor response. Within a pancreatic tumor-bearing mouse model, after alymphocytic choriomeningitis virus (LCMV)vaccine-induced immune response,adjuvant IL-7 was found to promote and sustain antitumor responses and improve overall survival, while enhancing the survival of activated endogenous T cells (Pellegrini et al. 2009). This activation extended across multiple effector responses, notably altering the immune response for increased numbers of IL-2–producing cells, IL-17–producing CD4+ T cells, and Th17 cells, as well as increased infiltration of NK cells and NKT cells in thepancreas of tumor-bearing mice (Pellegrini et al. 2009). Mechanistically, transcription factor analysis indicatesthe IL-7 effect is driven by downregulation of TGF-βthrough enhancing expression of TGF-βantagonist pathways (Pellegrini et al. 2009).The study also utilized IL-7 in other clinically-relevant vaccination approaches, including vaccinia virus immunization and dendritic cell vaccination in mouse models of spontaneous pancreatic tumors (Pellegrini et al. 2009). Again, IL-7 - treated groups exhibited enhanced tumor control, further supporting its future use as an antitumorvaccine adjuvant (Pellegrini et al. 2009).

IL-7 also has demonstrated strong efficacy as an adjuvant for vaccines against viral pathogens. In a study of diphtheria toxoid (DT) vaccination in non-human primates, IL-7 was successfully formulated to support vaccination via non-traumatic mucosal antigenic stimulation(Logerot et al. 2021). Notably, macaques pre-treated with recombinant glycosylated simian IL-7 exhibited significantly increased levels of anti-DT antibody compared to macaques without IL- 7 pre-treatment for up to 15 weeks(Logerot et al. 2021). Additionally, IL-7 treatment led to increased expression of multiple chemokines and cytokines, as well as increased immune cell recruitment, in local mucosa tissues(Logerot et al. 2021). Consequently, as IL-7 demonstrates strong efficacy as an adjuvant, there is growing interest in exploring broader use, including in adenovirus-based, subunit, inactivated, or other vaccines for immunization against pathogens like SARS-CoV-2(Bekele et al. 2021).

Beyond these studies, other researchers are successfully implementing IL-7 as an adjuvant via novel platforms, including transfecting cancer cells or bacteria cells to express IL-7, administering rhIL-7 via other administration routes, and administering IL-7 fused with an antibody crystallizable fragment (Fc) region(Y. Zhao et al. 2022).The encouraging results of these studiescompel future vaccine strategies to consider IL-7 as a potent, readily incorporated adjuvant that provides enduring immune effects.

IL-7 against Chronic Infection and Sepsis

In chronic infections, including those caused by human immunodeficiency virus (HIV), rubella virus, measles virus, hepatitis B virus (HBV) and hepatitis C virus (HCV), a patient’s virus-specific CD4+ and CD8+ T cells often exhibit various degrees of phenotypic exhaustion, contributing to substantial variance of antiviral T cell responses(Virgin et al. 2009). As such, IL-7’s capacity to restore and enhance immune function has prompted multiple studies evaluating its use in combatting chronic infections(Nanjappa et al. 2011).

For example, a recent study evaluated IL-7’s therapeutic application in mouse models infected with LCMV, inducing chronic infection(Nanjappa et al. 2011). Notably, it was observed that periodic administration of IL-7 can enhance viral clearance while sustaining high numbers of cytokine-producing cells, as well as memory-like, non-exhausted, and virus-specific CD8+ T cells(Nanjappa et al. 2011). However, the most pronounced increase in LCMV-specific CD8+ T cells and enhanced viral clearance was observed when IL-7 treatment was administered for a period of at least three weeks, indicating that ideal IL-7 dosing strategies must be elucidated to achieve optimal therapeutic benefit(Nanjappa et al. 2011).

Moreover, during sepsis, an inflammatory response to severe infection often associated with systemic inflammation, depletion of both adaptive and innate immune cells occur and ultimatelysepsis results in multi-system organ failure leading to death(Angus et al. 2001; Chung et al. 2003; Hotchkiss et al. 1999; Oberholzer et al. 2001). In a study using a cecal ligation and puncture (CLP) model to induce intra-abdominal peritonitis in mice, IL-7 has demonstrated a capacity to mitigate sepsis. Specifically, dosing with rhIL-7 shortly after CLP was shown to preserve counts of both adaptive and innate immune cells, including CD4+ T cells, CD8+ T cells, NK cells, B cells, and dendritic cells(Unsinger et al. 2010). Additionally, rhIL-7 preserved naïve, central memory, and effector memory T cells in secondary lymphoid tissues, and overall improved long-term survival(Unsinger et al. 2010). As such, IL-7 has clear, broad utility in the treatment chronic infection and sepsis, supporting immune function and extending survival.

Beyond pre-clinical research, IL-7 has also been used successfully in clinical studies to address chronic infection. Notably, in the first in-human trial of IL-7 administration for chronically lymphopenic HIV infection, 13 patients were treated with combination antiretroviral therapy (c-ART) and rhIL-7. Patients receiving rhIL-7 demonstrated significant improvements in immune function, with rhIL-7 in combination with c-ART treatment inducing higher numbers of functional CD4+ and CD8+ T cells capable of responding in vitro to TCR stimulation(Levy et al. 2009). Remarkably, CD4+ T cell count remained significantly increased in chronically lymphopenic HIV-infected patients for more than 45 weeks after rhIL-7 administration had ceased(Levy et al. 2009). Hence, the utility of IL-7 in mitigating chronic infection can translate from pre-clinical research into successful clinical trials. Together, the results of these pre-clinical and clinical studies provide validation and encouragement of therapeutic IL-7’s use as a therapy for mitigating chronic infection and septic shock.

Section III: Engineered IL-7 immunotherapies

Cytokines are critical modulators of the immune system, which makes them attractive therapeutic agents. However, the path to clinical translation of cytokines is generally challenging because of their poor pharmacokinetic properties and low specificity, resulting inoff-target effects.To overcome these challenges,engineers have genetically linked cytokines to other proteins, which can increase serum persistence and better control biodistribution. Cytokines are often genetically fused to antibodies or antibody fragments, which was first introduced near the end of the 20th century with IL-2 and IL-12 cytokine/antibody fusion proteins(Harvill & Morrison 1995; Peng et al. 1999).Antibodies arecommonly used because they have both targeting capabilities and favorable pharmacokinetics, but cytokines can also be genetically linked to other proteins for directed biodistribution or enhanced bioactivity. For example, pro-inflammatory cytokines have been fused to collagen-binding proteins for increased retention in the tumor microenvironment(Momin et al. 2019).In this section, we will specifically discuss how IL-7 is being engineered using these principles to further advance its therapeutic potential.

IL-7 / Antibody Fusions

One commonly employed cytokine engineering technique is fusing cytokines with the crystallizable fragment (Fc) domain of antibodies (Fig. 2) to increase their half-life through neonatal Fc-receptor (FcRn)-mediated recycling, which was first introduced with IL-10 and IL-2(Zheng et al. 1995, 1999). IL-7-Fc fusions have increased proliferation of CD8+ T cells and enhanced adoptive cell therapy under lymphopenic conditions in mouse models(Nam et al. 2010; Yu et al. 2021). Investigators have constructed a further engineered version of IL-7-Fc (hIL-7-hyFc) in which IL-7 is fused to the hybridizing IgD/IgG4 immunoglobulin domain(S. W. Lee et al. 2020). This hyFc platform increases half-life while avoiding complement activation(M. Y. Kim et al. 2022). When delivered in combination with CAR-T cells in mouse models of cancer, hIL-7-hyFc enhanced engineered T cell expansion and antitumor efficacy while maintaining T cell persistence(M. Y. Kim et al. 2022). Investigators have followed up on these studies by testing the hIL-7-hyFc and CAR-T cells combination for the treatment of solid tumors. Multiple cancer models were tested in mice, including neuroblastoma and pancreatic cancer, and treated with hIL-7-hyFc in combination with CAR-T cells(D. Li et al. 2024). In each cancer model, investigators observed solid tumor regression, and the hIL-7-hyFc also enhanced T cell expansion and reduced markers of exhaustion(D. Li et al. 2024). The hIL-7-hyFc has also been used in combination with other immunotherapies. Lee et al. demonstrated that hIL-7-hyFc enhanced the antitumor efficacy of bispecific T cell engagers (BiTEs) by activation of bystander CD8+ T cells in mouse models(K.-J. Lee et al. 2024).BiTEsare an emerging cancer immunotherapythat leverage bispecific antibody technology to co-localize cytotoxic T cells and targetcells for effective elimination(Tian et al. 2021).Additionally, Kwon et al. observed antiviral effects of hIL-7-hyFc in mice infected with different respiratory viruses(Kwon et al. 2024), demonstrating additional applications for Fc-fused IL-7 other than cancer immunotherapies.

Figure 2.

Figure 2.

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IL-7 Fusion Proteins. To improve the pharmacokinetic and functional properties of IL-7, the cytokine isoftenengineeredas a fusion protein withanother molecule. Most commonly, IL-7 is fused with either an antibody fragment, such as a single-chain variable fragment (scFv) or crystallizable fragment (FC); a full-length antibody; or another bioactive protein that can alter IL-7’s bioactivity or biodistribution.

To improve the pharmacokinetic and targeting properties of IL-7, the cytokine can also be combined with a single chain variable fragment (scFv) or full-length antibody (Fig. 2), but this has been explored less frequently than Fc-fusions. An early iteration of an scFv-IL-7 fusion protein linked IL-7 to an scFv targeting a tumor-associated isoform of fibronectin(Pasche et al. 2011). This fusion protein preferentially accumulated at the tumor site and inhibited tumor growth in immunocompetent mice, but was not able to fully eradicate tumors(Pasche et al. 2011). A more recent attempt at an scFv-IL-7 fusion protein also targeted a domain of fibronectin but used two linked scFv domains attached to IL-7, also known as a single-chain diabody (scDb) format(Nitto et al. 2024). This scDb-IL-7 effectively eradicated mouse models of sarcoma in combination with PD-1 blockaded and increased an important transcription factor, T Cell Factor 1 (TCF-1), on CD8+ T cells(Nitto et al. 2024), which is critical for T cell development and has been associated with durable immune responses(X. Zhao et al. 2022).IL-7 has not yet been fused to a full-length antibody, but it has been investigated in combination with anti-IL-7 antibodies. Boyman et al. discovered that IL-7 complexed with the anti-IL-7 antibody M25 exhibits augmented bioactivity in vivo compared to free IL-7 and greatly enhances the expansion of T and B lymphocytes(Boyman et al. 2008). Martin et al. further investigated this IL-7/anti-IL-7 antibody complex and revealed that the enhanced bioactivity of IL-7 is partially due to half-life extension from the Fc domain, but they also discovered a half-life independent contribution from the antigen-binding fragment (Fab) that remains to be elucidated(Martin et al. 2013).This intramolecular interaction between cytokine and anti-cytokine antibody has been leveraged for other cytokines, such as IL-2, to modulate downstream effects and specifically target immune cell subsets(Boyman et al. 2006; E. K. Leonard et al. 2024; VanDyke et al. 2022).

Other IL-7 Fusion Proteins

Additional emerging approaches fuse IL-7 with another protein to improve targeted delivery or immune modulation (Fig. 2). Early work by Henson et al. fused IL-7 to the N-terminal domain of CCR9, which is a chemokine receptor expressed in thymic tissue. In aged mice, the IL-7/CCR9 fusion protein was able to completely restore thymic architecture and also better restored thymopoiesis, with notably higher levels of CD4+ T cells(Henson et al. 2005). The fusion protein also increased the number of activated CD8+ T cells in a mouse model of influenza and resulted in reduced disease progression. As another targeting strategy, Kang et al. linked IL-7 to a collagen-binding domain (CBD), which was derived from von Willebrand factor and binds preferentially to tumor stroma(Kang et al. 2023). This approach was also used to create a CBD-IL-12 fusion protein. The investigators found that intravenously co-delivering IL-7-CBD and CBD-IL-12 had synergistic antitumor effects and did not increase systemic toxicity in mice(Kang et al. 2023). This is likely due to their ability to specifically target collagenous tumor tissue and offers a potential engineering strategy to decrease the off-target effects of current cytokine therapeutics.

Similar to the co-delivery of both IL-7 and IL-12-based molecules by Kang et al., another technique for engineering IL-7 therapies involves fusing the cytokine to another bioactive protein. To improve the proliferation and development of immune cells, Lai et al. used a flexible linker to connect IL-7 to the β-chain of hepatocyte growth factor (HGFβ)(Lai et al. 2006). When injected intratumorally, the IL-7/HGFβ construct inhibited local tumor growth in mice and improved dendritic and T cell infiltration(Lai et al. 2011). IL-7/HGFβ also inhibited metastases formation in murine models of colon cancer and melanoma(Lai et al. 2011). This research group also investigated the antitumor effects of linking IL-7 to another common gamma chain cytokine, IL-15. The IL-7/IL-15 fusion protein similarly inhibited local tumor growth in mice and increased the infiltration of multiple inflammatory immune cells, while notably decreasing the infiltration of regulatory T cells(Song et al. 2016). This fusion protein was also able to inhibit cancer metastases in mice and significantly increased the serum half-life of these molecules(Song et al. 2016). Shireman et al. also combined IL-7 with an additional cytokine, creating a therapeutic, GIFT-7, consisting of granulocyte-macrophage colony stimulating factor (GMCSF) fused to the N-terminus of IL-7(Hsieh et al. 2015). In aged mice, GIFT-7 was able to restore an antiviral T cell response after administration of cytomegalovirus(Hsieh et al. 2015). This led investigators to later utilize GIFT-7 as a cancer vaccine, which increased intratumoral T cells, reduced T cell exhaustion, and enhanced the clonality of the TCR repertoire(Shireman et al. 2023). The GIFT-7 vaccine also increased survival of aged mice with glioma(Shireman et al. 2023). Overall, engineering IL-7 through fusion to targeting molecules or other bioactive cytokines and growth factors presents an opportunity to enhance therapeutic efficacy.

Discussion

IL-7 plays an important role in the development, proliferation, and function of immune cells. In lymphocytes, IL-7 is critical for normal B and T cell growth from progenitor cells. IL-7 also acts on mature T cells by expanding activated T cells and maintaining their memory function. For dendritic cells, IL-7 has been implicated in their development and regulatory function. IL-7 has also been observed as an essential mediator of development in NK cells. Because of these innate biological effects, IL-7 has been delivered as an immunotherapy for chronic infections or sepsis, as an adjuvant for vaccines, and in combination with adoptive cell therapies for cancer. The benefits of utilizing IL-7 as an immunotherapy include its broad applications and safety profile, as IL-7 has been well tolerated in clinical trials thus far(J.-H. Kim et al. 2021; Trédan et al. 2015). This is in contrast with other cytokines previously investigated as immunotherapies, such as IL-2, which have deleterious side effects(J.-H. Kim et al. 2021; Panelli et al. 2004). The safety of IL-7 is likely due to its ability to act as a negative regulator of its own receptor expression. However, there are also challenges to clinical translation of IL-7-based therapies, including its poor pharmacokinetic properties and potential off-target effects, as IL-7Rα is widely expressed.

To address the challenges with therapeutic translation, IL-7 is being increasingly engineered to improve its efficacy, serum persistence, and targeted delivery. Multiple strategies have been employed to further engineer IL-7, but the most common approach, as summarized here, is fusing the cytokine to antibody fragments or other targeting moieties or growth factorsvia an amino acid linker. These engineered IL-7 molecules have demonstrated efficacy in models of cancer and infection. Other emerging applications of IL-7 are currently being investigated, such as IL-7 being used to enhance translation of mRNA post gene delivery in T cells(Tilsed et al. 2024). Therefore, there is increasing interest in the application of improved IL-7 therapeutics. Furthermore, the previously described IL-7 fusion proteins have only been investigated pre-clinically, emphasizing the need for continued advancement of novel IL-7-based therapeutics and the opportunity to make a lasting impact on this field.

Acknowledgements

This work was supported by the National Institutes of Health(R01EB029341; R21CA185819; P41EB028239; R33CA229042; and R33CA278429). We also acknowledge funding from the Troper Wojcicki Foundation and Thalheimer Foundation.B.B. is supported by the Quad Fellowship and the American Australian Association Graduate Education Scholarship.Figures were created with Biorender.com.

Footnotes

Declaration of Interest Statement

No potential conflict of interest was reported by the author(s).

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