New frontiers in cancer therapy: from blood cancers to solid tumours

“Scientists have made great progress in developing new cancer treatments, including immunotherapies like monoclonal antibodies and CAR-T cell therapy,” says Mitsunobu Tanimoto, executive vice president at ONO PHARMA USA in Cambridge, Massachusetts. “But many patients, especially those with rare cancers, are still waiting for effective treatments.”

Many significant advances in treating cancer arise from a better understanding of its molecular landscape and how drugs interact with it. By digging deep into the molecular machinery at work, scientists can improve the effectiveness and safety of cancer therapy, especially for hard-to-treat cancers, such as rare lymphomas and solid tumours.

“When developing new treatments, we focus on mechanisms of action that differ from existing drugs,” says Tanimoto. “This puts ONO scientists in unexplored territory.”

The growth of cancer — and battling it — depends much on the cancer’s interaction with the immune system. A person’s natural defenses can fight the disease, but also be modified by it to fuel cancer growth. Many cancers can also hide from the immune system or weaken the immune response against it.

After developing the world’s first programmed cell death protein 1 (PD-1) inhibitor¹, nivolumab — a type of immune checkpoint inhibitor that helps the body recognize and attack cancer cells — ONO continues its ambition to help create therapies for patients with limited treatment options.

In 1717, Ichibei Fushimiya founded ONO PHARMACEUTICAL, which was originally set up as an apothecary in Osaka, Japan. In 1998, ONO PHARMA opened its first office in the United States, expanding its reach to a global audience with the same drive commitment to deliver novel medicines to patients, especially those battling cancer.

“Our work in oncology is founded on respect, perseverance, and out-of-the-box thinking, such as exploiting new mechanisms of action,” says Kunihiko Ito, president and CEO of ONO PHARMA USA.

The company employs top researchers and collaborates with others around the world to help new approaches to treating cancer. This work ranges from molecular biology to technologies driven by artificial intelligence. Part of that work involves digging deeper into the causes of cancer.

“We will bring innovative medicines to patients that aim to target the underlying diseases processes,” says Tanimoto.

New immunotherapy treatments, emerging technologies and ongoing research are giving physicians more tools to help the immune system do the job it was meant to: fight back against threats like cancer.

Unleashing the immune system

To keep the immune system under control, the surfaces of T and B cells have checkpoint inhibitors, such as PD-1. In normal conditions, these proteins keep the immune system from overreacting and attacking healthy cells. But some cancers co-opt this system and use it to prevent T-cell attacks on itself.

In 2002, scientists at ONO started looking for ways to make treatments that target checkpoint inhibitors. “At the time, the notion of treating cancer by intercepting the immune system was not supported by the scientific community,” says Ito. “We encouraged our R&D team to think differently, and we supported them to explore new theories.”

After almost a decade, ONO’s work spawned nivolumab — a monoclonal antibody initially approved in Japan in July 2014 for unresectable melanoma. By blocking cancer’s control of PD-1 proteins, this antibody liberates T cells to attack various forms of cancer, including non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma and more.

ONO is now looking beyond PD-1 inhibitors at a host of other immunological treatment targets.

Attacking two targets

One area of emerging significance is the potential value of bispecific antibodies in the treatment of refractory or resistant forms of cancer — a growing challenge in this space. Instead of targeting just one molecule, bispecific antibodies bind to two. As a result, such antibodies can impact more than one element of cancer development. At ONO’s Research Center of Immunology, scientists design and develop these bispecific antibodies.

The company is running a phase I study of the bispecific antibody ONO-4685 as a monotreatment for patients with relapsed or refractory (R/R) T-cell lymphoma². T-cell lymphomas are rare types of cancer, which are categorized as tumours of mature T-cell or natural killer cell origin.

Like nivolumab, ONO-4685 targets PD-1, but it also designed to bind to CD3 antigens on the surface of T cells. CD3 plays a role in activating T cells during an immune response. Because ONO-4685 binds both targets in T cells, plus some cancerous T cells, the clinical study will explore whether it helps improve the ability of immune cells to fight cancer and inhibit cancer growth by suppressing malignant T cells.

The search for new small molecules

In hope of combining precision oncology with immunotherapy, ONO is exploring the protease mucosa-associated lymphoid tissue protein 1 (MALT1) as a target to treat several types of blood cancer.

“MALT1 is involved in an intracellular signaling pathway in lymphocytic blood cells,” says Tanimoto. “Activation of this protease is reported to play an important role in the survival of lymphocyte malignancies.”

ONO is running a phase I trial on ONO-7018 as a treatment for R/R NHL and chronic lymphocytic leukemia (CLL)³ both of which are difficult to treat if the cancer comes back. This study is enrolling patients and expected to be completed at the end of 2027.

MALT1 proteolytic activity has also gained additional attention through reports describing its tumour-promoting roles in several types of non-hematological solid cancer, such as breast cancer and glioblastoma⁴. ONO is hopeful that its small-molecule therapy will exhibit antitumour activity in NHL and CLL.

Tumours: increasing accessibility

Many modern immunotherapies focus on blood-based cancers, like the leukemias and lymphomas that ONO researcher’s study, but solid tumours could also benefit from these treatments. In part, solid tumours resist many immunotherapies by preventing entry into the tumour. Success of treatments will depend on finding the targets that can overcome the cancer’s defences.

One route ONO scientists are exploring is EP4 — one of four subtypes of the EP prostanoid receptor. Prostanoids are lipids that help to control inflammatory responses. Among a variety of biochemical roles, EP4 plays a part in increasing the ability of immune cells to enter tumours. An EP4 antagonist is in the works: ONO-4578. Scientists hope that this therapy will make tumours more accessible to cancer treatments.

In an ongoing phase I trial, ONO is evaluating ONO-4578 when given alone or with nivolumab⁵. This study involves patients with advanced or metastatic solid tumours. If successful, the results of this work could lead to researchers exploring the effects in more tumour types.

The location of a cancer significantly impacts the ability to treat it, which often makes cancers in the central nervous system (CNS) particularly challenging. One example is primary central nervous system lymphoma (PCNSL) — a rare type of non-Hodgkin lymphoma (NHL) that primarily develops in brain, spinal cord, or eyes, and it accounts for 4% of intracranial tumours and 4–6% of extranodal lymphoma⁶.

“PCNSL is a B-cell malignancy that manifests primarily in the CNS and afflicts around 1,500 new patients a year in the United States,” says Thomas Lechner, vice president medical affairs at ONO PHARMA USA. The FDA has not yet approved any immunotherapy for PCNSL. So, patient's options in the United States are limited. Although first and second-line chemotherapies — also known as induction and consolidation therapies — show meaningful clinical outcomes in some patients, the cancer can return. Furthermore, R/R PCNSL has a poor prognosis⁶.

But ONO is working hard, in hope to bring new treatment options to these patients. In March 2023, the FDA granted orphan drug designation to tirabrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, being studied in the United States by ONO.

“BTK is a key regulator of the B-cell receptor (BCR) pathway, and aberrant BCR signaling has been implicated in the survival of malignant B-cells,” says Tanimoto. “Tirabrutinib is a highly selective inhibitor.”

ONO’s tirabrutinib is currently approved for treating R/R PCNSL in only Japan, South Korea, and Taiwan. In the United States, ONO is running the PROSPECT Study⁷ Parts A and B of the phase II study in adult patients with R/R PCNSL are open and enrolling: part A will investigate tirabrutinib as monotherapy in R/R PCNSL, while part B will investigate tirabrutinib in combination with the most-used, high-dose methotrexate regimes in newly diagnosed PCNSL.

“We hope that part A of the trial will be fully recruited by the end of 2023,” Lechner says.

“We are extremely pleased that tirabrutinib has been granted orphan drug status for the treatment of PCNSL,” says Ito. “We hope to bring a new treatment option to patients in the United States in the near future.”

From immunotherapies, to small molecule inhibitors and targeted tumour treatments, scientists at ONO PHARMA USA plan to continue their innovative work on lymphomas and beyond.

“As a pioneer in cancer immunotherapy,” says Ito, “we will continue to empower our scientists to discover first-in-class products that meet high unmet medical needs.”