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Maximizing synergy and mitigating resistance: novel dual-targeted natural killer cell therapies for cancer

Cell therapies are at a crossroads. Pioneering T cell therapies have validated the concept, but a range of therapeutic and logistical shortcomings are limiting uptake. Breakthroughs are needed to bring the modality’s power to more patients.

The switch from autologous to off-the-shelf products is a key step in taking the modality into the mainstream, driving a surge in allogeneic cell therapy R&D activity. NK (natural killer) cells are creating excitement. They are highly cytotoxic, orchestrate the innate immune response, readily penetrate tumors, and have no potential to cause cytokine release syndrome or neurotoxicity, which are major safety issues for T cell therapies. Importantly for their use in off-the-shelf therapies, NK cells do not cause the graft-versus-host disease that arises when a patient receives a therapy based on unmodified T cells from a donor.

Founded in 2015 by Michael O’Dwyer of the National University of Ireland, Galway, ONK Therapeutics is developing an off-the-shelf, dual-targeted NK cell therapy platform that is clearly differentiated and represents a potential breakthrough in this fast-moving field.

As well as a chimeric antigen receptor (CAR), ONK adds a tumor necrosis factor (TNF)–related apoptosis ligand (TRAIL) variant to create dual-targeted CAR-NK cells (Fig. 1). The selection of TRAIL as the second targeting mechanism is built on evidence of the role the membrane-bound ligand plays in inducing apoptosis. The TRAIL variant activates the death receptor (DR) pathway in cancer cells to cause additional apoptosis, maximising the killing power of the NK cell therapy.

Unique dual-targeted construct

Fig. 1 | Unique dual-targeted construct. The construct is designed to maximize cytotoxicity while protecting against potential antigen escape. CAR, chimeric antigen receptor; DR, death receptor; NK, natural killer; TRAIL, tumor necrosis factor (TNF)–related apoptosis ligand.

ONK designed its optimised affinity, membrane bound TRAIL variant to be more potent and specific than the wild-type ligand. This approach ensures active delivery to the tumor, positioning ONK’s NK cell therapies to succeed despite early antibody-based approaches struggling to deliver on the promise of the target.

Enhanced cross-linking of DR5 increases activation of the death receptor pathway, tumor engagement and cytotoxicity. The ligand is expressed for the lifespan of the NK cell, enabling prolonged serial killing, and only binds to activating receptors, not decoys expressed by tumor and stromal cells. The result is increased apoptosis through sustained DR engagement that translates into greater cytotoxicity.

This second targeting mechanism confers an important additional benefit. Experience with existing cell therapies has shown cancers can develop resistance to treatment through loss of the target antigen. That process, known as antigen escape, leaves single-targeted CAR cell therapies unable to detect and kill tumor cells. Having a novel TRAIL targeting mechanism is likely to make ONK’s cell therapies less vulnerable to antigen escape.

An added advantage of targeting the DR pathway is the potential to induce important immunomodulatory effects. In cancer patients, tumor-associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDCS) are known to have increased expression of DR5. This renders them vulnerable to DR5-targeting strategies, as has previously been shown in the clinic with respect to MDSCs. Killing of these cell types could help overcome hostile conditions within the tumor microenvironment, which may be especially important in the successful targeting of solid tumors. In addition, DR5 TRAIL variant expressing NK cells may also be less susceptible to rejection as they can eliminate DR5-positive alloreactive T cells.

Validating the platform

ONK’s most advanced candidate is ONKT101, which targets CD19 and features a membrane bound DR5 TRAIL variant. First-generation CAR-T cell therapies have shown the potential of targeting CD19 to treat B cell malignancies, while also revealing the limitations of autologous, single-targeted approaches. Ongoing evaluations of allogeneic CAR-T candidates are underway, but these approaches must still overcome the previously outlined challenges inherent in the use of T cells in order to improve on the autologous approach.

ONKT101, which is partnered with Avectas, is designed to overcome those limitations through the enhanced cytotoxicity and anti-resistance attributes associated with the dual-targeted, allogeneic NK cell-based approach. The asset is made with Avectas’s SOLUPORE technology, which introduces genetic modifications through transient transfection of mRNA, rather than the electroporation used to create other cell therapies. Due to the short-lived nature of mRNA transfection, repeat infusions of off-the-shelf ONKT101 will be required.

That repeat dosing approach will enable ONK to safely assess the high affinity, membrane bound TRAIL variant for the first time in humans, with sequential dosing eliminating the need for complicated safety mechanisms such as suicide switches. If subject to no safety issues, ONK will run a larger study to assess if the use of the ligand improves on the efficacy of anti-CD19 therapies. ONK’s first-in-human study of ONKT101 will also position it to move longer-lived cell therapies into the clinic.

ONK’s subsequent NK-cell therapy, ONKT102, has a CD38 CAR with optimised affinity and a DR5 TRAIL variant. ONKT102 is designed to treat relapsed or refractory multiple myeloma (MM), a highly competitive space, but one in which ONK has the expertise to identify and carve out a differentiated approach.

O’Dwyer, ONK’s founder and CSO, is a practicing clinician and expert in translational MM research. He has been involved in the development of several transformational drugs for blood cancers, such as imatinib, ibrutinib and daratumumab, giving him insights into how treatment paradigms will change. Even with regimens based on daratumumab, an antibody sold as Darzalex, becoming established as the first-line treatment option in MM, there remains a great need for therapies that are effective in the growing number of patients with relapsed or refractory MM after treatment with daratumumab and anti-BCMA therapies.

ONK is developing ONKT102 to address that need. Given the presence of CD38 on healthy cells, ONK is deploying an optimised affinity CAR, developed in partnership with researchers at VUMC, Amsterdam that will only bind to cells with the highest levels of CD38 expression. Preclinical studies support the effectiveness of ONK’s approach. Normal bone marrow progenitors, T cells and non-expanded NK cells are not affected by the CAR. However, since CD38 is strongly induced on NK cell expansion, there is still potential for self-killing or fratricide and ONK plans to knock out CD38 in the product. Research also suggests knocking out CD38 could improve the metabolic performance of NK cells by reducing the breakdown of nicotinamide adenine dinucleotide, as well as making NK cells more resistant to oxidative stress, a common feature of the tumor microenvironment.

Co-culturing the dual-targeted NK cells with MM patient bone marrow showed hitting both CD38 and DR5 was more effective than targeting either receptor in isolation. The expression of DR5 is increased on tumor cells from patients with relapsed and refractory MM and low doses of bortezomib, a standard of care agent, can further increase the expression of DR5, sensitising it to killing by TRAIL.

ONK is also developing ONKT104, a dual-targeted CAR-NK product targeting CLEC12A (also known as CLL-1) utilising a humanised ScFv. CLEC12A is strongly expressed by blasts in the majority of acute myeloid leukemia (AML) patients. While expressed on the leukemic stem cell, CLEC12A is absent on normal hematopoietic stem cells. This should enable safe targeting, with a reduced risk of prolonged aplasia. In AML, TRAIL preferentially kills via DR4, hence this product will employ a DR4 TRAIL variant.

Expanding into solid tumors

For ONK, hematological cancers are a proving ground for its NK platform. In targeting solid tumors, there are a variety of obstacles that have so far prevented cell therapies from making a major impact, including the absence of antigens that are truly tumor specific. The potential for on-target, off-tumor effects to render solid tumor cell therapies potentially toxic has led ONK to focus on a tumor-specific glycoform of Mucin 1 (MUC1).

Multiple solid tumor types express MUC1, including non-small cell lung cancer, breast cancer and ovarian cancer. Unfortunately, the target is also expressed by healthy tissues. ONK has designed a CAR tailored to the glycosylation pattern distinct to the version of the MUC1 protein found on cancer cells. Other cell therapy leaders have identified the glycosylation pattern as the way to unlock the potential of MUC-1 as a solid tumor target. ONK is set to bring the natural benefits of NK cells over T cells to bear on MUC-1, in a tumor-specific fashion, while also further boosting efficacy and countering resistance through its use of a DR5 TRAIL variant.

ONK’s solid tumor programs will benefit from its additional work to further optimise NK cell function in the tumor microenvironment. ONK was among the first research groups to recognise the potential to use CRISPR to enhance the natural biology of NK cells. It is now taking the concept a step further, with O’Dwyer and his colleagues exploring the effect of gene edits that may protect NK cells from exhaustion and immune evasion, such as the deletion of PD-1, CD96, TIGIT and Siglec-7, as well as the potential to use IL-15 secretion to enhance proliferation and persistence (Fig. 2).

Broad range of proprietary gene edits

Fig. 2 | Broad range of proprietary gene edits. The edits are being explored to optimize natural killer cell functionality. CD19, cluster of differentiation 19; DR, death receptor; IL, interleukin; NK, natural killer; PD1, programmed cell death protein 1; TRAIL, tumor necrosis factor (TNF)–related apoptosis ligand.

Several strategies to improve tumor homing are in development, including the enforced expression of CCR7, which is downregulated on NK cell expansion. ONK is also exploring the use of adjunctive therapies to overcome immune suppression within the tumor microenvironment. These include blockade of IL-6, which has important inhibitory effects on NK-cell function in patients with cancer.

Building a transatlantic biotech

Under the leadership of Chris Nowers, the former Head of Europe at cell therapy pioneer Kite Pharma, ONK is expanding quickly beyond its base and headquarters in Galway, Ireland. It has created a US subsidiary establishing a US R&D base at JLABS @ San Diego, joining more than 50 other resident biotech companies in the heart of the Torrey Pines Mesa at the flagship facility of Johnson & Johnson Innovation. The cluster provides a ready talent pool as a global hotspot for NK-cell therapy companies.

ONK is also expanding its business development and partnering outreach. Once ONK has proof-of-concept data, it will have a validated, highly differentiated, proprietary dual-targeted platform suitable for application to a wide range of targets. Biopharma companies with strong interest in cell therapy or simply optimised and differentiated binders are potential partners for ONK as it seeks to unlock the full value of its NK-cell therapy platform.

ONK’s recognition of the breadth of opportunities on the horizon is testament to O’Dwyer’s novel skillset and the years spent studying engineered NK-cell therapies. Nowers brings additional corporate experience in building small companies from the ground up. As it grows rapidly on those solid foundations, ONK will turn its rich pipeline of ideas into breakthrough therapies, improving outcomes for patients with a range of hematological and solid cancers.

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