Finding a Place for Stimulatory Immune Checkpoint Antibodies

When it works, immunotherapy can dramatically outperform standard of care—for some cancer types, in ways thought unattainable a decade ago. Yet immunotherapy works in just a minority of patients, and some tumor types are particularly resistant.

Increasing the number of patients who respond has become a central focus of ongoing research. One promising avenue involves the development of immunostimulatory agonists. Like the block-buster drugs ipilimumab (Yervoy) and nivolumab (Opdivo), this strategy takes aim at the surface receptors that regulate T-cell activity—so-called immune checkpoints (Figure).¹

Whereas ipilimumab, nivolumab, and the growing number of their FDA-approved kin block inhibitory receptors, agonists are designed to activate stimulatory receptors. The endgame is the same: to reignite the antitumor immune response.

Over the past few years, a growing number of immune agonist antibodies with a variety of targets have entered clinical trials. There have been some encouraging responses, but the development of these agents has far outpaced our molecular understanding of how they work—in T cells as well as in other immune and nonimmune cells.

The T-Cell Activation Mechanism

This knowledge gap has led to disappointing outcomes and discontinuation of some clinical programs. However, clinical experience over-whelmingly demonstrates that immune agonists have great potential if the kinks can be worked out. This is particularly true of their use in rational drug combinations, in which they have the potential to prime the antitumor immune response and even help turn immunologically “cold” tumors into “hot” tumors that are more responsive to immunotherapy.T cells are the central mediators of adaptive immune protection and are endowed with potent cytotoxic capabilities. Accordingly, their activity is tightly regulated through a multistep process coordinated by a series of receptors expressed on their surface.

Figure. Immune System Presents Many Opportunities for Targeting Cancer

The first step is for T cells to become primed by foreign or altered self-antigens that are displayed on major histocompatibility complex 1 molecules on the surface of antigen-presenting cells (APCs). These antigens are recognized by the receptor on the surface of the T cell. A secondary antigen-independent signal is then generated by the interaction between numerous other receptors on the T-cell surface and their ligands on the APCs, collectively referred to as immune checkpoints. The binding of a ligand to its respective receptor propagates a signal within the T cell that is ultimately either stimulatory or inhibitory.

Step on the Gas

A stimulatory signal acts like an on switch, driving full activation of the T cell. In the absence of this signal or in the presence of an inhibitory one, T cells fail to proliferate and become unresponsive or die. This dual signal mechanism ensures that the amplitude and duration of the T cell—mediated immune response is tightly controlled, but the downside is that it can also be exploited by cancer cells to dysregulate the anti-tumor immune response.In the past decade, drugs targeting the inhibitory receptors have emerged as an important form of immunotherapy because they can help activate T cells and restore antitumor immunity. A host of immune checkpoint inhibitors are now FDA approved for a growing number of indications.

Table. Selected Clinical Trials of Immune Checkpoint Agonists Under Development

Table. Selected Clinical Trials of Immune Checkpoint Agonists Under Development (Cont.)

Despite astounding efficacy, just a minority of patients respond, and those who do respond often become refractory to treatment. In hopes of expanding the use of checkpoint therapies and other types of immunotherapy, investigators are looking at stimulatory checkpoint pathways as potential targets. To date, agonists have been developed for 7 well-characterized costimulatory receptors for T-cell activation. These drugs are designed to mimic the natural ligands so that they can increase receptor activity and boost the antitumor immune response.

Opinion is Split on OX40

The immune system is often compared to a car: Immune checkpoint inhibitors and stimulatory checkpoint agonists are said to control the gas and brake pedals on the anti-tumor immune response. The endgame is to make the immune system more effective in fighting tumors.^2-4Based on similarity in their structures, costimulatory receptors generally belong to 1 of 2 families: either the tumor necrosis factor receptor (TNFR) superfamily or the immunoglobulin G (IgG) superfamily.

The majority are TNFRs; their downstream signaling for activation relies upon adaptor proteins, including the TNF-α receptor—associated factors (TRAFs). Cellular outcomes are ultimately influenced by the induction of the transcription factor nuclear factor–кB.

Not all costimulatory receptors are found on the surface of the T cell. The expression of some is induced upon antigen priming or following activation of other costimula-tory receptors. One example from the TNFR superfamily is OX40, also known as CD134.

OX40 is one of the oldest targets for immu-nostimulatory agonists and a few years ago was lauded among the new immunotherapy targets. However, subsequent clinical trial data have been underwhelming, and the jury is still out on whether OX40 agonists are ideal anticancer drugs.⁵ Roche in mid-2017 discontinued development of its OX40 agonist RG7888, despite promising preliminary results from a phase I study in patients with locally advanced or metastatic solid tumors.⁶

AstraZeneca had 3 OX40-targeting assets in development but also has scaled back its investment in these agents. The humanized monoclonal antibody (mAb) MEDI0562 is the only agent listed in AstraZeneca’s pipeline. Updated data from a phase I study in patients with advanced solid tumors were presented at this year’s European Society for Medical Oncology (ESMO) 2018 Congress.

A total of 55 patients were treated across 6 dose cohorts. No dose-limiting toxicities (DLTs) were observed. Treatment-related adverse events (TRAEs) were reported in 67% of patients—most frequently, fatigue and infusion-related reactions (IRRs).

Among 50 patients evaluable for response, 2 had immune-related partial responses (irPRs) and 22 experienced stable disease. The 2 irPRs were observed in a patient with squamous cell carcinoma of the larynx treated at 0.03mg/kg once every 2 weeks and a patient with bladder cancer at the 3mg/kg dose, also every 2 weeks.⁷

MEDI6469, a mouse mAb, and MEDI6383, an OX40 ligand fusion protein, are still listed in ongoing clinical trials, according to clinicaltrials.gov. Furthermore, the results of a phase IB clinical trial of MEDI6469 as neoadjuvant therapy in patients with head and neck squamous cell carcinoma were presented at last year’s American Society of Clinical Oncology Annual Meeting (ASCO 2018).

MEDI6469 was well tolerated among 17 patients with resectable disease, who received 3 doses of 0.4mg/kg, followed by surgical excision and neck dissection. Surgery was not delayed, and there were no grade 3/4 AEs. Over a median follow-up of 20 months, 13 patients were still alive and without disease and 4 had evidence of immu-nological response to treatment.⁸

Pfizer, GlaxoSmithKline, and Incyte also have OX40 agonists in development (Table), although limited data have been presented at this time. For the most part, OX40 agonists as monotherapy have proved disappointing; therefore, investigators turned to combination therapy.

Recent data highlight the potential for unexpected consequences of combination therapy. Two preclinical studies demon-strated that concurrent administration of OX40 agonists and PD-1 inhibitors in mice had neither a synergistic nor even an additive effect but instead was detrimental, producing poorer outcomes and lower survival rates than with either agent alone.

CD40 Turns Cold Tumors Hot?

However, when an OX40 agonist was administered first, followed by PD-1 inhibitor treatment—but not in the reverse order—there was significantly improved efficacy in mice refrac-tory to anti-PD1 therapy.^9,10The orientation of CD40 and its ligand CD154 is unique among the costimulatory receptors, with the ligand located on the surface of activated T cells, whereas CD40 itself is found predominantly on APCs and B cells.

Owing to this arrangement, it is thought that CD40 plays a unique role in T-cell priming. Upon interaction with its ligand, CD40 triggers APC “licensing”—a state in which it can activate T cells. CD40 signaling enhances the expression of the ligands of other costimulatory molecules on the surface of APCs.^2,11

A host of CD40-targeting agonists have been developed and are being evaluated in ongoing clin-ical trials, although none have progressed to the later stages. Several strategies for improving effi-cacy are being examined, including intratumoral administration and antibody engineering.

Preliminary data from a first-in-human trial of intratumoral administration of ADC-1013 were reported at the 2017 Society for Immunotherapy of Cancer Annual Meeting. Twenty-three patients were treated with doses ranging from 22.5 mcg/kg to 400 mcg/kg or intravenous dosing at 75 mcg/kg. Intratumoral injection into nonhepatic lesions was well tolerated. AEs included fatigue, pyrexia, nausea, and vomiting and were mostly grade 1/2 and transient.¹²

SEA-CD40 is an afucosylated humanized IgG1 mAb produced by technology that Seattle Genetics reports removes 100% of the fucose compared with 60% to 70% by previous technologies.

Interim results from a phase I study in metastatic solid tumors were presented at ASCO 2018. To date, 48 patients have been treated with escalating doses. DLTs, all of which were IRRs, occurred in 5 patients. TRAEs included IRRs, chills, fatigue, nausea, vomiting, dyspnea, and headache. Thirty-four patients were evaluable for efficacy; 1 with basal cell carcinoma experienced a partial response (PR) and 10 others experienced stable disease (SD).¹³

The current emphasis for CD40 agonists is on combination therapy. Researchers at the University of Pennsylvania in Philadelphia recently demonstrated that CD40 is an important switch for boosting T-cell activity in tumors.

CD27-CD70: A Pair of Targets

It is thought that CD40 agonists, by promoting ADC licensing, can help recruit T cells to the tumor microenvironment and activate them once they are there. This has the potential to render immunotherapy more effective in tumor types that are unresponsive.CD27 is another member of the TNFR superfamily that functions as a costimulatory receptor, binding to its ligand CD70. Interestingly, CD70 has been found to be highly expressed in many tumor types and in some is associated with poorer prognosis. Both CD27 and CD70 are therefore being pursued as immunotherapeutic targets.^5,14,15

Just 1 CD27-targeting mAb is in clinical development. Data from the dose-expansion portion of a phase I/II study of varlilumab (CDX-1127) in combination with nivolumab in patients with advanced solid tumors were presented at ASCO 2018.

Patients with colorectal cancer (CRC; n = 42) received varlilumab at a dose of 3 mg/kg every 2 weeks, and those with ovarian cancer (n = 66) received 3 mg/kg every 2 weeks or every 12 weeks, or 0.3 mg/kg every 4 weeks in combination with nivolumab 240 mg every 2 weeks. AEs were consistent with the safety profile of the individual drugs. Among the 49 ovarian cancer patients evaluable for response, there were 5 PRs and 19 SDs; for 41 CRC patients, there were 2 PRs and 7 SDs.¹⁶

The fully human mAb cusatuzumab (ARGX-110) is the sole CD70 inhibitor offering. Results from 2 trials were presented recently. Twelve patients with newly diagnosed acute myeloid leukemia (AML) have so far been treated with escalating doses once every 2 weeks in combination with a standard dose of azacitidine (Vidaza), following a 2-week lead-in with cusatuzumab monotherapy in a phase I/II clinical trial.

The combination was well tolerated, and the overall response rate (ORR) was 92%, with a complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate of 82%.¹⁷

GITR Agonists

Data from a phase I/II trial in patients with advanced cutaneous T-cell lymphoma demonstrated that ARGX-110 administered intravenously at 1 or 5 mg/kg every 3 weeks was safe and well tolerated, with an ORR of 23% in 26 patients evaluable for response.¹⁸The glucocorticoid-induced TNF receptor familyrelated protein (GITR) is also being targeted, with a number of agonists in phase I/II clinical trials. GITR expression is upregulated upon T-cell activation, but it is also continually expressed on regulatory T cells. There is some debate about whether GITR has both an inhibitory and a stimulatory role and if the antitumor effects of GITR agonists depend on their ability to costimulate effector T cells or suppress regulatory T cell function.^5,14,19

Bristol-Myers Squibb is testing BMS-986156 and reported preliminary results of a phase I/II study in advanced solid tumors at the 2017 ASCO Annual Meeting. Patients (n = 66) were treated with escalating doses alone or in combination with nivolumab. No DLTs were reported, and the most common TRAEs were pyrexia, chills, and fatigue.²⁰

Novel Designs for 4-1BB Agonists

Results from an ongoing phase I study of MEDI1873 were presented at the ESMO 2018 Congress. In the 40 patients who had been dosed, the maximum tolerated dose had not yet been reached, but 3 DLTs had been reported at 250, 500, and 750 mg. TRAEs most frequently involved headache and IRRs. The best response was SD in 42.5% of patients; 17.5% had SD for 24 weeks or longer.²¹4-1BB (CD137) is an activation-induced costimulatory molecule that, when engaged by its ligand 4-1BBL, drives T-cell proliferation and cytokine production and protects cells from activation-induced cell death by upregulation of antiapoptotic genes.²²

Two 4-1BB agonists are in clinical trials: urelumab and utomilumab. The initial development of urelumab, which began in 2008, was hampered by issues of on-target, dose-dependent inflammatory liver toxicity. Clinical trials were halted but then resumed in 2012, using lower doses of urelumab to avoid these toxicities; however, efficacy was limited.²²

Utomilumab development, on the other hand, has been less impeded by safety concerns, but it is a less potent agonist of 4-1BB. Both drugs continue to be evaluated in a range of clinical trials, with a focus on combination therapy.

The results of the first-in-human study of utomilumab were published in 2018. Patients (n = 55) were treated with escalating doses of utomilumab, ranging from 0.006 to 10 mg/kg. There were no DLTs, and the most common TRAEs included fatigue, vomiting, abdominal pain, decreased appetite, and nausea. The ORR was 3.8% in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including 1 CR and 1 PR.²³

In a separate trial, the combination of utomilumab and pembrolizumab (Keytruda) demonstrated an ORR of 26.1%, including 2 CRs in patients with small cell lung cancer and renal cell carcinoma and 4 PRs.²⁴

ICOS and CD28

Researchers are also attempting to develop next-generation 4-1BB agonists that don’t compromise either safety or efficacy by more specifically directing agonist activity to the tumor. There are 3 main strategies: intratumoral administration, bispecific antibodies that target 4-1BB and a tumor-specific antigen, and “masked” antibodies that are unmasked by tumor-specific proteases. PRS-343, a bispecific antibody targeting 4-1BB and HER2, is currently in phase I clinical trials.Inducible costimulatory (ICOS) and CD28 are the 2 costimulatory receptors that belong to the IgG superfamily, with ICOS being the newest entrant into clinical development. ICOS is thought to be involved in the immunosuppressive functions of regulatory T cells. As a result, both agonists and antagonists of ICOS are of interest, and 2 agonists and 1 antagonist are being evaluated in clinical trials.

Jounce Therapeutics’ humanized mAb agonist is being evaluated in the ongoing ICONIC trial. Preliminary results from 164 heavily pretreated patients with advanced cancer were presented at ASCO 2018. Patients received escalating doses of JTX-2011 as monotherapy or in combination with nivolumab. The drug was well tolerated, and there were reports of PRs in patients with gastric cancer and triple negative breast cancer.²⁵

GSK3359609 is a humanized IgG4 mAb agonist being developed by GlaxoSmithKline. Updated results from the first-in-human INDUCE-1 trial were presented at the ESMO 2018 Congress. To date, 79 patients have been treated with GSK3359609 alone (part 1) or in combination with pembrolizumab (part 2). Clinical activity was observed in both parts, and both monotherapy and the combination were well tolerated.²⁶

There is just a single CD28 agonist in clinical development. Theralizumab was initially under development in 2006, but a phase I clinical trial was halted due to the development of cytokine release syndrome in 6 healthy volunteers who became critically ill with immune-related multiorgan failure. Clinical development resumed in 2011 after researchers were able to show that the toxicity was limited to the highest dose used.²⁷

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Gainesville, Florida.

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