Nearly 40 years after the first cytokine-based therapy was approved for the treatment of patients with hairy cell leukemia, investigators are taking a fresh look at ways to leverage these signaling proteins to enhance immunotherapies and vaccines in other cancers.

Although most therapies in the pipeline are in the early stages of clinical development, 1 candidate is nearing the finish line. The FDA is scheduled to decide by May 23, 2023, whether to approve a biologics license application for nogapendekin alfa inbakicept (N-803; Anktiva), an IL-15 superagonist, in combination with BCG for patients with BCG–unresponsive non–muscleinvasive bladder cancer (NMIBC).

Cytokine-based immunotherapy is a promising field in cancer treatment because cytokines regulate the host immune response to cancer cells and help induce tumor cell death.

 Investigators have recognized the potential efficacy of this approach for several decades, culminating in FDA approvals for several cytokines that serve as early examples of immunotherapy.

In 1986, the FDA approved recombinant interferon (IFN)-α (Intron A) for patients with hairy cell leukemia. Subsequent indications have been added for patients with follicular lymphoma, adjuvant melanoma, metastatic renal cell carcinoma (RCC), and Kaposi sarcoma.

 High-dose IL-2 (HDIL-2; aldesleukin [Proleukin]) was approved for the treatment of patients with metastatic RCC and metastatic melanoma in 1992 and 1998, respectively.

 Other cytokines used in cancer therapy include peginterferon alfa-2b, which has been approved under several brand names, and granulocyte-macrophage colony-stimulating factor, which has several therapeutic uses, including in oncolytic virus immunotherapy.

Of the initial cytokine-based agents, IFN-α and HDIL-2 are used less frequently in current clinical practice because of the development of newer therapies, such as immune checkpoint inhibitors (ICIs) and targeted therapies, that offer superior safety and efficacy profiles.

 Now, a new generation of cytokine-based therapies, including combinations with other immune therapies, is in the works. 

The interest in exploiting cytokines for anticancer therapy stems from their central role in cellular signaling. Cytokines are soluble, low–molecular weight proteins that facilitate cell-to-cell communication and modulate immune responses at sites of inflammation, infection, and trauma.

They are grouped into several different subclasses, including IFNs, interleukins (ILs), tumor necrosis factors (TNFs), and chemokines.

Healthy cells produce cytokines to control the stimulation and priming of T cells and the differentiation of CD4-positive cells.

 In the setting of cancer, immune cells that are associated with malignancies, such as tumor-associated macrophages and cancer-associated fibroblasts, produce cytokines that promote inflammation and angiogenesis, respectively.

The relationship between cytokines and immunity relies on variables such as cytokine levels, cytokine receptor expression, and the effects of signaling pathways on corresponding immune cells.

 Cytokines exert their effects through receptor binding, which causes dimerization of the cell receptor or reorganization of the cell membrane. With IFNs and ILs, this can lead to kinase activation, frequently in the JAK/STAT network (Figure

Figure. IL-2 Mechanisms Influence Cell-Signaling Networks

In the setting of cancer, cytokine action mediates both cancer-suppressing and cancer-promoting effects. For example, proinflammatory cytokines, such as TNF-α and IL-6, stimulate antitumor effects by regulating immune interactions. Conversely, cytokines that are found in the tumor microenvironment facilitate mechanisms associated with cancer onset, such as angiogenesis, epithelial-to-mesenchymal transition, invasion, and tumor progression.

Cytokines also serve a key role in the administration of adoptive cell therapy (ACT).

 ACT includes various cellular approaches such as tumor-infiltrating lymphocyte, engineered T-cell receptor–based, chimeric antigen receptor (CAR) T-cell, and natural killer (NK) cell therapies.

 Clinically, IL-2, IL-7, and IL-15 enhance in vitro expansion and differentiation of adoptive cells and are used to augment therapeutic ACT when coadministered or genetically engineered into adoptive cells.

Another evolving area of research is genetically modifying cancer cells to express specific cytokines using nonviral vectors and gene editing technology.

 Additionally, cytokines can be employed in vaccine formulations. Granulocytemacrophage colony-stimulating factor, IFN-α, IFN-γ, IL-2, IL-12, IL-15, IL-18, and IL-21 have shown immunological efficacy when employed as a component of a vaccine adjuvant strategy.

Several factors have limited the efficacy of cytokine immune therapy—namely, their short half-life, high toxicity, and low efficacy. High doses of cytokines required for therapeutic intratumoral concentrations may lead to systemic adverse events (AEs) such as hypotension, acute renal insufficiency, respiratory failure, and neuropsychiatric symptoms.

For example, HDIL-2 therapy is associated with toxicities such as pulmonary edema and hypotension.

 Likewise, systemic administration of recombinant IFN-α is poorly tolerated by patients.

Low efficacy observed with cytokine therapy originates from the mechanism of action of cytokines themselves. Pleiotropic effects are characteristic of cytokine signaling.

 These effects may limit the utility of HDIL-2 because IL-2 is an activator of both cytotoxic T cells and immunosuppressive T regulatory (Treg) cells. These effects are dependent upon the dose and timing of IL-2 administration.

At high doses, Il-2 promotes CD8-positive effector T-cell and NK cytolytic activity.

 At low doses, IL-2 expands Treg populations and inhibits the formation of TH17 cells, which are involved in autoimmunity.

Redundancy is critical for cytokine signaling; however, this creates a challenge for therapeutic application because the changes in cytokine effect can be compensated by other cytokines.

Emerging Approaches in Cytokine Immunotherapy

Despite these limitations, the potential to combine cytokines with other therapeutic agents in addition to advances in genetic engineering and cellular and immune therapy have led to a renewed interest in exploiting the anticancer properties of cytokines.

State-of-the-art cytokines are engineered to increase half-life and tumor targeting via polyethylene glycol conjugation, fusion to tumor-targeting antibodies, and modulation of cytokine/cell receptor-binding affinity.

 Novel approaches aim to improve traditional cytokine therapies, notably IFN and IL-2, and are intended to mitigate the undesirable effects associated with these cytokines (Table

Table. Select Cytokines Investigated in Cancer Immunotherapy

IFN-α regulates tumor development by modulating genes that control tumor cell growth and multiplication, cell death, and immune checkpoint–mediated immune suppression.

 Recombinant IFN-α formulations exist in 3 isoforms (alfa-2a, alfa-2b, and alfa-2c) as well as pegylated formulations that are conjugated with a polyethylene glycol moiety.

Modakafusp alfa (TAK-573) is an immunocytokine designed to deliver IFNα2b to CD38-positive cells.

 The therapy comprises 2 attenuated IFNα2b molecules that are genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody. This strategy is intended to reduce toxicity and off-target binding.

Modakafusp alfa has been evaluated in a phase 1/2 study (NCT03215030) in patients with relapsed/refractory multiple myeloma.21 In 30 patients treated with modakafusp, the objective response rate (ORR) was 43% and the median progression-free survival was 5.7 months (95% CI 1.2-15.9).

Likewise, a phase 1/2b dose-escalation study (NCT04157517) is evaluating the safety, pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy of modakafusp alfa in patients with metastatic solid tumors.

 In the escalation phase, treatment-related AEs (TRAEs) occurred in 81% of patients (N = 21) and included infusion- related reactions (52.4%), chills (47.6%), and nausea (33.3%). Data from the study support a dose of 1.0 mg/kg every 3 weeks, which will be assessed in the phase 2 component of the trial in combination with pembrolizumab (Keytruda), a PD-1 inhibitor, in patients with metastatic melanoma.

The exploration of therapies that target various ILs is a robust area of development. Clinical findings for several of these novel agents are accumulating, with recent developments demonstrating both the potential and the pitfalls of this therapeutic approach. 

Nogapendekin alfa inbakicept is a novel IL-15 superagonist complex constructed with an IL-15 variant that is attached to an IL-15Rα sushi domain/IgG1 Fc fusion protein. It directly stimulates CD8-positive T cells and NK cells through β/γT-cell receptor binding and avoids Treg stimulation.

The therapy has been evaluated in combination with intravesical BCG in QUILT-3.032 (NCT03022825), an open-label, phase 2/3 study in patients with BCG-unresponsive high-grade NMIBC.

 Results from the study form the basis of the pending biologics license application.

Trial findings demonstrated that 71% of patients who had not responded to previous therapies showed a complete response, with a median duration of 26.6 months. Bladder cancer–specific overall survival at 2 years was 100%. The most common grade 1 and grade 2 treatment-emergent AEs (TEAEs) were dysuria (30%), pollakiuria (25%), hematuria (25%), urinary tract infection (19%) fatigue (19%), and urgency (18%). TEAEs of grade 3 severity were dysuria and pollakiuria (1% each), and hematuria and urinary tract infection (2% each).

Nogapendekin alfa inbakicept also is being tested in patients with BCG-naïve, high-grade NMIBC in the phase 1/2 QUILT-2.005 study (NCT02138734). Additionally, the therapy is being evaluated in combination with pembrolizumab with and without chemotherapy as a frontline treatment for patients with stage III or IV non–small cell lung cancer in the phase 3 QUILT2.023 trial (NCT03520686). The study, which is active but no longer recruiting participants, has a target enrollment of approximately 1500 patients.

SOT101 is a fusion protein of IL-15 and the IL-15 receptor α sushi-positive domain, which is a glycoprotein motif that facilitates interactions.

 The sushi domain of IL-15Rα enables binding of IL-15 and diminishes inflammation.

In early findings, SOT101 exhibited a favorable safety profile and promising preliminary efficacy signals in the phase 1 AURELIO-3 study (NCT04234113).

 The trial evaluated subcutaneous SOT101 in patients with advanced and metastatic solid tumors as monotherapy and in combination with intravenous pembrolizumab every 3 weeks. Interim data from 51 patients revealed the clinical benefit rate of SOT101 monotherapy was 38% among 13 patients who received doses of 6 μg/kg to 12 μg/kg, whereas the observed clinical benefit rate in patients receiving the pembrolizumab combination was 63% across all SOT101 doses. Pyrexia, chills, lymphopenia, anemia, transaminase elevation, and vomiting were the most common TEAEs.

The efficacy, as measured by the ORR, and safety of combining SOT101 with pembrolizumab will be further evaluated in the phase 2 AURELIO-04 study (NCT05256381).

Data from preclinical studies suggest that NKTR-255, a polymer-conjugated IL-15 agonist, triggers the proliferation and activation of NK cells and CD8-positive T cells as well as memory CD8-positive T cells. Clinical testing has shown that the population of CD8-positive T cells expanded when NKTR-255 monotherapy was administered to patients with multiple myeloma and non-Hodgkin lymphoma, including in participants previously treated with CAR T-cell therapy.

In December 2022, investigators launched a phase 2/3 trial (NCT05664217) to explore the safety and efficacy of NKTR-255 vs placebo following CD19-directed CAR T-cell therapy in patients with CD19-positive relapse/refractory large B-cell lymphoma.

In stage 1 of the study (phase 2), plans call for treating approximately 56 participants with a 1-time dose of CD19-directed CAR T-cell therapy. After approximately 14 days, patients will be randomly assigned to receive NKTR-255 in 1 of 3 cohorts or placebo every 3 weeks for up to 7 cycles or 5 months. NKTR will be dosed at 1.5 μg/kg, 3.0 μg/kg, or an initial dose of 3.0 μg/kg followed by 6.0 μg/kg in subsequent cycles.

 In stage 2 (phase 3), patients will receive CD-19-directed CAR T-cell therapy and then be randomly assigned 3:2 to receive NKTR-255 at the recommended stage 1 dose or placebo. The primary end points of the study, which has a target enrollment of 400 patients, are the complete response rate at 6 months and event-free survival at 3 years. Initial primary end point data are expected to be available in the second half of 2024.

The therapeutic potential of IL-2 also continues to be explored. TransCon IL-2 β/γ is a novel, long-acting prodrug that provides sustained release of a receptor-selective IL-2 variant (IL-2 β/γ) analogue. TransCon IL-2 β/γ contains a small polymer, methoxy PEG, that blocks IL-2Rα binding, thus eliminating the unfavorable effect that occurs with HDIL-2, increased immunosuppressive Treg activity.

Dosing, safety, and preliminary efficacy of TransCon IL-2 β/γ are under investigation in the phase 1/2 IL Believe trial (NCT05081609) as monotherapy and in combination with pembrolizumab in adult patients with locally advanced or metastatic solid tumors.

Masking technology also represents a novel strategy to facilitate more specific tumor targeting. XTX202 is a masked, tumor-selective IL-2 agent that is inactive in nontumor tissues; its therapeutic action is released when it is unmasked by matrix metalloproteases in the tumor microenvironment.32 The modified IL-2 domain of the XTX202 molecule is designed to reduce binding to high-affinity IL-2 receptor. Simultaneously, it binds to the intermediate-affinity IL-2 receptor, thereby decreasing Treg activation while activating effector T cells.

In the phase 1/2 XTX202-01 trial (NCT05052268), investigators are seeking to determine appropriate dosing and preliminary efficacy of XTX202 monotherapy in patients with metastatic RCC and unresectable or metastatic melanoma.

AU-007 is a monoclonal antibody that binds to IL-2 on its CD25-binding epitope and is designed to redirect IL-2 to activate immune-stimulating T-effector and NK cells while simultaneously decreasing Treg cell activation.

 Because Tregs express CD25, blocking the interaction between IL-2 and the CD25 subunit on the Treg receptor may reduce immunosuppressive effects.

 The mechanism of AU-007 is unique in that it converts a Treg-mediated autoinhibitory loop into an immune-stimulating loop by binding and redirecting newly secreted endogenous IL-2.

A phase 1/2 study (NCT05267626) was recently initiated to assess the safety, tolerability, and initial efficacy of AU-007 alone or combined with HDIL-2 in patients with advanced solid tumors. In early results, 2 of 3 evaluable patients who received AU-007 had a best response of stable disease, and the only drug-related toxicity was grade 1 diarrhea in 1 patient.

A long-acting formulation of IL-7, efineptakin alfa (NT-17), was developed to enhance T-cell infiltration. It is currently under investigation in combination with pembrolizumab in the phase 1b/2a KEYNOTE A60 trial (NCT04332653) in patients with various types of cancer. In the phase 2a dose-expansion phase, there are separate cohorts for patients with microsatellite-stable colorectal cancer and pancreatic cancer who have not previously received prior ICI therapy, and for patients with triple-negative breast cancer, non–small cell lung cancer, or small cell lung cancer who have received ICIs.

Findings for patients with ICI-naïve colorectal or pancreatic cancer demonstrated that combination therapy was associated with a higher ORR and disease control rate (DCR) in 13 patients without liver metastases than in 37 participants with liver metastases.

The ORR for patients without metastases was 15.4% and 30.8% by RECIST 1.1 and iRECIST criteria, respectively. In patients with metastases, the ORR was 0.0% and 2.7%, by RECIST 1.1 criteria and 30.8%, iRECIST criteria, respectively. The DCR was 53.9% with RECIST 1.1 criteria and 69.2% with iRECIST criteria in those without liver metastasis. In patients with liver metastasis, the DCR was 21.6% using RECIST 1.1 criteria and 24.3% with iRECIST criteria.

SRF388 is a human IgG1-blocking antibody that targets IL-27, preventing it from upregulating inhibitory immune checkpoint receptors and downregulating proinflammatory cytokines.

 SRF388 was evaluated as monotherapy or combination therapy with pembrolizumab in a phase 1 dose-escalation study (NCT04374877) involving 29 patients with advanced treatment-refractory solid tumors.

A confirmed partial response was observed in 1 patient with highly treatment-refractory NSCLC at 8 weeks; the partial response was durable for 20 weeks. Stable disease occurred in 9 patients (31%) at 8 weeks, with 6 of 9 maintaining durable disease control at 6 months. TRAEs occurred in 21% of patients, with most designated low-grade events.

Although major pharmaceutical companies were pursuing IL-12–based therapies, 3 leading drug makers have retreated from clinical programs for once-promising candidates in the past several months. AstraZeneca halted its involvement with 2 candidates, MEDI1191 and MEDI9253; Bristol Myers Squibb bowed out of developing DF6002; and Merck KGaA sold off M9241. Industry observers note that smaller biotech companies are now dominating the IL-12 field.

Meanwhile, the National Cancer Institute continues to evaluate M9241, a fusion protein also known as NHS-IL12,39 in several phase 1/2 clinical studies. NHS-IL12 is being tested in combination with entinostat, a histone deacetylase inhibitor, with and without bintrafusp alfa, a bifunctional fusion protein directed at PD-L1 and TGF-β, in advanced cancers including human papillomavirus–associated malignancies or microsatellite-stable small bowel or colorectal cancer (NCT04708470) and in combination with docetaxel in metastatic castration-resistant prostate cancer (NCT04633252).

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Yardlee Kauffman, PharmD, MPH

Articles

A New Generation of Cytokine-Based Immunotherapy Takes Shape