Biochemist offers hope for leukaemia treatment

20 August 2019

Biochemist Dr Alice Cheung has been fascinated by the mechanism of cells – how they divide and function – since high school and her undergraduate days at the University of Hong Kong (HKU).

Today, the Senior Research Fellow in the Department of Haematology at Singapore General Hospital can take pride in her research that could transform the clinical treatment of acute myeloid leukaemia (AML) and other cancers.

Her breakthrough involves the use of human cord stem cells for treating the disease and includes the development of a protocol that would ensure there is a ready supply through expansion of the T cells involved. “We are now trying to file a patent and are in discussion with agencies about conducting pre-clinical trials,” Dr Alice Cheung (Butterfield Croucher Studentship 2007, Croucher Foundation Fellowship 2009) said.

The development has attracted widespread international attention, reflected in her winning the American Society of Hematology (ASH) Global Research Award (2018).

It was the opportunity to undertake her PhD under the supervision of eminent haematologist Anskar Leung Yu-hung, currently a Clinical Professor in the Department of Medicine at HKU, that first allowed Cheung to direct her interest in cell biology towards AML. “I’m still intrigued now,” she said.

There is no cure for AML, and the total number of patients worldwide stood at 351,965, with mortality of 265,461, according to 2012 figures from the World Health Organisation.

Current standard treatment for AML starts with induction chemotherapy, and most patients do respond to this. However, the relapse rate is 60-70 per cent while the survival rate of those who relapse is low. Those patients experience the emergence of leukemic cells that are therapy-resistant, and the patient can die, either of their disease or the toxicity of repeated but ineffective treatment.

Research has therefore been focused on post-relapse and treatment-resistant AML. Stem cell research has been extensive in this area since the existence of stem cells linked to the propagation of AML was established. The implication has been that if you could target the AML stem cell, you could eradicate the disease. The challenge has been identifying it and specifically targeting it, without causing excessive side effects.

“Initial notions in stem cell research were focused on characterising this very rare population of cells so we can target them,” said Cheung, who explained that these leukemic stem cells also constantly evolve and change their biology as the disease progresses.

Despite significant advances in the understanding of the cellular and molecular biology of AML, treatment strategies used worldwide have remained largely static and inefficacious for decades. At present, allogeneic hematopoietic stem cell transplantation (HSCT) (often in the form of a bone marrow or peripheral blood transplant) post-induction chemotherapy is the only treatment regime for AML that is associated with significantly improved overall prognosis.

The belief is that while the normal stem cells present in the transplant graft are able to regenerate the patient’s blood system (damaged by induction chemotherapy), T cells in the same graft can mount an immune reaction to kill any residual leukemic cells (that survived through the chemotherapy) through what is known as an alloreactive graft-versus-leukaemia (GvL) reaction.

This treatment is often augmented by follow-up rounds of donor leukocyte infusions (DLIs) where a donor’s lymphocytes (the subtype of white blood cells that comprise a major portion of the human immune system, including T cells) are taken from blood from the same bone marrow donor and introduced into the patient’s body.

Both allogeneic HSCT and DLI have been available for many years but are normally accompanied by a high risk of treatment-related mortality and graft-versus-host disease (GvHD), which can be lethal. Donor-derived T cells also see the recipient cells in the body as foreign entities so try to destroy them in addition to the leukemic cells.

Nevertheless, there are ways to get around the GvHD issue. Clinical observations in the 1990s already showed that patients who had undergone allogeneic HSCT with grafts specifically depleted of alpha beta (αβ) T cells (the major type of T cells in adults) not only fare better in long-term disease control, but also display reduced incidence of severe GvHD symptoms. As a result, the majority of these patients have shown long-term, disease-free, survival. Follow-up studies found that these patients have a common characteristic of exhibiting a high level of donor-derived gamma delta T cells (γδ T cells) post-transplant.

Gamma delta T cells (γδ T cells) are a minor subset of T cells that are well known for their rapid response in fighting against viral infections. Coincidently, these cells have also been known to induce minimal, if not no, GvHD – a stark contrast to the αβ (alpha beta) T cells.

These casual correlative observations suggested to Cheung the ability of γδ T cells in eliciting good GvL effect without inducing GvHD. This was the catalyst of her interest in utilising γδ T cells for cancer immunotherapy.

“If we can harness the specialised property of allogeneic gamma delta T cells so they can recognise cancer cells but not induce GvHD, we can solve the problem,” she said.

Cheung’s team now focuses on studying γδ T cells derived from human cord blood because it has a very different γδ T cell subtype composition compared with adult blood.

“More work is needed to confirm it, but we believe the type of γδ T cells found in cord blood are much more effective at killing cancer cells compared to those found in adult blood. That is why we are focusing our research on cord blood,” she said. However, that presented Cheung’s team with a practical obstacle that required a ground-breaking solution.

For clinical applications, there simply isn’t enough cord blood for it to be clinically relevant, so most clinical research has focused on γδ T cells from adult human blood.

To overcome this, Cheung’s team looked to develop an in vitro expansion method of γδ T cells from cord blood, with the challenge of not just achieving expansion but to do so without the γδ T cells losing their critical cancer killing properties.

The outcomes so far are promising, to the point that the team is now seeking to file a patent and discussing pre-clinical trials. “The data supports that in vitro expanded cord blood derived γδ T cells is a promising alternative cell source for immunotherapy,” Cheung said.

She also believes her team’s approach could enhance other novel techniques, such as Chimeric Antigen Receptor T-Cell Therapy (CAR T-Cell Therapy). This nascent immunology treatment extracts T cells from the patient’s blood and genetically engineers them in the laboratory before being re-introduced to the patient.

However, the requirement to isolate the patient’s own cells for CAR-T generation means an extended time lag for treatment to be administered and may not be applicable to many patients.

“Our plan is to generate allogeneic ‘off-the-shelf’ gamma delta-based CAR-T cells to improve the efficacy as well as the applicability of the treatment,” she said.

While Cheung is not yet ready to talk of a potential cure for AML she is confident about the positive impact this research will make to the future treatment of the disease.

“We do believe this is a superior and far more effective form of treatment than is currently available,” she said.

Dr Alice Cheung completed her BSc (Hons) and MPhil in the Department of Biochemistry, University of Hong Kong (HKU), in 2002 and 2004 respectively. She received a Butterfield Croucher Studentship (2007) for her PhD studies on acute myeloid leukaemia in the Department of Medicine (Division of Haematology), HKU. She undertook post-doctoral training in Dr Connie Eaves’ laboratory at the Terry Fox Laboratory (TFL), BC Cancer Agency, Canada, during which she was awarded a Croucher Fellowship in 2009. In 2014, Cheung moved to Singapore, where she is Senior Research Fellow in the Department of Haematology at Singapore General Hospital, specialising in cellular immunotherapy. Dr Alice Cheung received a Croucher Fellowship in 2009 and a Butterfield Croucher Studentship in 2007.

To view Cheung’s Croucher profile, please click here.