In brief

A*STAR scholar Samantha Wong provides personal insights on her journey in biomedical research, as well as the potential of antibody based drugs and new cancer immunotherapies.

© A*STAR Research

Training the body’s defenders

4 May 2023

By tapping into the strengths of the innate immune system, Samantha Wong aims to develop safer, more potent cancer treatments.

We know the basics of how cancers form; when errors crop up in our genetic code, they can mislead our cells into duplicating endlessly. But if a cell’s mistakes are how tumours appear, why not train cells to fix them too? That’s the idea behind cancer immunotherapy—treatments that harness our immune system to seek and destroy malignant cells.

Since the 2010s, immunotherapies have led to incredible outcomes for patients with cancer. However, they’re still no silver bullet; not only are they still ineffective against most solid cancers, but they’re costly to produce and can trigger dangerous side effects such as cytokine storms.

At A*STAR’s Experimental Drug Development Centre (EDDC), A*STAR scholar Samantha Wong and her colleagues aim to address these challenges with the help of human antibodies. Known for their specificity, antibodies may provide a safer immunotherapeutic option and also be customised for a wide range of cancers.

In this interview with A*STAR Research, Wong shares some highlights from her scientific journey, her work as assay lead of the Antibody Innate Modulators (AIM) platform, and her experiences in bringing drugs from the lab to the clinic.

What inspired you to enter biomedicine?

Funnily enough, I started junior college as a humanities student, but then I became obsessed with a certain medical drama series. I joked with my former biology teacher about becoming a doctor, which led to surprisingly serious discussions. With his support, I decided to restart junior college as a science student.

In junior college and a subsequent 4-month stint in Bruno Reversade’s lab at A*STAR, I found myself unexpectedly enjoying the research process. I realised that, despite what television portrays, there’s still so much to discover about human health and how to improve it. This led me to apply for A*STAR’s National Science Scholarship, and here I am today—a different type of doctor, but I regret nothing!

How has the A*STAR scholarship supported your scientific journey?

It gave me crucial support to grow as a scientist and a person. The academic opportunities it gave me at world-class institutions, like Imperial College London and Harvard University, kickstarted my scientific career.

I was also exposed to diverse perspectives that greatly shaped my worldview. Harvard was electrifying both in its cutting-edge research and the sheer variety of its people. Till today, the networks I built there still help me keep up with the latest developments in biotech.

How does your role at EDDC relate to drug discovery?

In a nutshell, the AIM platform team is looking at how to harness the innate immune system—specifically, natural killer (NK) cells—to target solid tumours.

You can broadly divide the immune system into two branches: the innate, comprising first-line, less-specific defenders; and the adaptive, comprising highly-specific, long-lived defenders. Most approved immunotherapies target T cells from the latter. This can be a double-edged sword: while they’re effective tumour killers, T cells can proliferate and secrete cytokines excessively, causing unpleasant side effects.

Compared to T cells, NK cells are a smaller but still potent immune cell population, making them relatively safer. They’re also naturally involved in cancer surveillance. Using them, we aim to build a customisable antibody platform that combines their safety with the specificity needed to recognise cancer antigens. If we succeed, it could support significant future drug development; other teams could effectively replace its antigen-targeting component as needed for different cancers.

Could you share about your work with antibody-based drugs?

I’ve been interested in antibodies since my PhD work on small molecule inhibitors for prolyl hydroxylase domain 3 (PHD3). While it was an exciting target to treat dysregulated fat metabolism, PHD3 has two other structurally similar isoforms, which kept causing cross-reactivity issues and consequent toxicities.

Hence, I decided to work on antibodies; they’re known for their specificity! Humans can have over a trillion unique antibodies, each of which can lock on to a specific cell surface protein, then signal our immune system to eliminate its target. Currently, I work with artificially-designed antibodies that not only target surface proteins specific to cancer cells, but also bind those specific to NK cells, bringing the killers and targets together.

However, antibodies have their pros and cons as therapeutics. They’re incredibly specific, but too large to enter cells and target intracellular proteins; unlike small molecules, which are also easier to manufacture. We might eventually harness the best of both.

What are some common challenges in drug discovery and development?

Simply put, drug discovery is hard and costly. Unless a drug candidate targets a disease with no existing treatments, it needs to show significantly greater safety or efficacy—ideally both—than the current standard of care to have a chance at commercial success.

The general process starts with discovering a druggable target responsible for a disease, then designing or screening for a drug. That drug is tested in cells, then animals, then finally humans. If the drug works as expected, a business plan can be devised to commercialise it.

There’s no easy phase at any point. What works in cells might not in animals, and what works in animals might not in humans, or create adverse side effects only in the latter. Even a successful drug trial doesn’t guarantee commercial success; investors and patients will compare your drug against the standard of care, and it must be convincing enough for prescribers to administer it and insurers to cover it, especially if other options already exist.

What does a researcher need to tackle those challenges?

While it’s currently uncommon, I hope academic scientists get more chances for formalised exposure to drug development’s business aspects, as it’s critical to take a cross-disciplinary approach to the process. It’s easy to think of drug discovery and subsequent business development as sequential, independent stages, but such an approach during the former may smooth out the latter.

For instance, a scientist aware of a scientifically-savvy investor’s concerns would design their experiments to preemptively address potential questions on safety, efficacy and superiority over other options. They would identify problems that may trip up future development efforts and address them early.

What encouragement would you give to young talents (especially women) in STEM?

It’s difficult, but not impossible. In research, failure is inevitable; it takes conscious effort to accept this. Several times after months of failed experiments, I declared I would quit graduate school. However, if you persist, you’ll develop a grit mindset that serves you well both in science and life in general.

Don’t be afraid to seize opportunities and ask for things, but have something to offer in exchange. It can be as simple as buying coffee in exchange for a chat about someone’s work; the worst they can say is “no”. Also, keep an open mind and stay curious. In discussions with people holding conflicting views, it’s worth trying to understand the roots of their beliefs—you may learn surprising new things along the way.

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This article was made for A*STAR Research by Wildtype Media Group