An immunofluorescence image of immunotherapy treatment, with tumour cells (blue) under attack by T cells (green). Immune checkpoint inhibitors can be effective against triple-negative breast cancer, but work is underway to improve response rates.Credit: Nicola Ferrari / Alamy
In the fight against triple-negative breast cancer, something needs to change. These tumours, which are diagnosed in 10–15% of breast cancer patients, are typically more aggressive, have fewer treatment options and are more likely to recur than hormone receptor-positive or human epidermal growth factor receptor (HER)-positive breast cancers. The prognosis for this disease subtype, which disproportionately affects younger women and Black women, is extremely poor.1
“Effective new treatment options are urgently needed to improve the outlook for these patients,” says Pavani Chalasani, a medical oncologist at George Washington University (GW) Cancer Center in Washington DC.
In the past few years, a handful of novel targeted therapies have been approved by the US Food and Drug Administration (FDA) to treat triple-negative breast cancers. Among these, immunotherapies called immune checkpoint inhibitors have emerged as a promising avenue. These drugs are intended to harness the patient’s immune cells to seek out and destroy cancer cells.
“The immune checkpoint inhibitors are a very exciting development,” says Rong Li, an expert in breast cancer biology at GW Cancer Center. “However, despite their promise, the response rate is relatively low.”
Understanding the underlying reasons for this resistance could hold the key to expanding the benefits of these cutting-edge treatments to a broader spectrum of patients. Promisingly, the insights generated at GW Cancer Center have informed the development of an experimental antibody treatment designed to break down a resistance mechanism observed in triple-negative breast cancer and other solid tumours.
Exclusion zone
In solid tumours, cancer cells don’t exist in isolation. They live within a complex ecosystem that includes a variety of other types of cell and structural components. Recent investigations into the distribution of cancer-killing immune cells within this microenvironment have yielded a fascinating revelation. “In around 50% of triple-negative breast cancers, you find a lot of these immune cells at the boundary of the tumour — but there are very few at the core,” Li says.
This phenomenon, known as immune exclusion2, may provide a glimpse into why some tumours resist immunotherapy: while cancer-killing immune cells rally at the tumour’s periphery, they often encounter difficulties infiltrating the core.
Emerging research has put a spotlight on collagen fibres — an integral component of the extracellular matrix surrounding cells — as potential culprits in facilitating immune exclusion. A dense collagen-based structure, akin to a ‘defence line’, has been observed surrounding the edges of various solid tumours, including triple-negative breast cancers.
“This kind of structure could act as a physical barrier that blocks immune cells from coming into the tumour to interact with and kill cancer cells,” Li emphasizes.
Furthermore, the make-up, architecture and organization of tumour collagen have been directly linked with the ability of cancer cells to invade neighbouring tissues and spread to other parts of the body3. However, the underlying mechanisms governing the arrangement of these collagen fibres have so far remained elusive.
Therapeutic opportunity
Discoidin domain receptor 1 (DDR1) is a collagen-binding receptor that is often expressed at very high levels in solid tumours, correlating with cancer progression4. Traditionally, it was understood that DDR1 influences cancer-cell invasiveness upon binding to collagen in the extracellular matrix. But Li’s research has unearthed a previously unknown role for tumour DDR1, casting it as a key player in promoting immune exclusion5.
“In our mouse models, inactivating DDR1 in tumour cells leads to a breakdown of the architecture of collagen fibres,” he says. “At the same time, we see significant flooding of cancer-killing immune cells into the tumour.”
Piecing together the evidence, Li has proposed a model in which DDR1 interaction with collagen plays a pivotal role in enabling tumours to erect an effective defence line against immune-cell infiltration. Blocking this function of DDR1 could provide an effective way to break down this protective barrier, opening the floodgates for cancer-killing immune cells to enter the tumour and wreak havoc.
This discovery paved the way for a collaboration with Texas-based researchers to develop a humanized DDR1-targeting monoclonal antibody, PRTH-1016.
“We demonstrated that PRTH-101 reverses immune exclusion by disrupting collagen-fibre alignment in tumours in mice,” says Li.
Parthenon Therapeutics (now known as Incendia Therapeutics) subsequently licensed this therapeutic antibody and, in 2023, initiated a phase I clinical trial (NCT05753722) involving patients with advanced solid tumours. The study aims to assess the safety and tolerability of PRTH-101, both alone and in combination with an immune checkpoint inhibitor, while seeking preliminary evidence of anti-tumour activity.
Precision immunotherapy
The revelation of DDR1’s pivotal role in immune exclusion, coupled with the development of PRTH-101, offers renewed hope for a targeted and effective approach to combat triple-negative breast cancer.
Li emphasizes the collaborative environment required for successful translational research. “It takes a village for tumours to build a defence line to keep immune cells at bay — and it also takes a village to rally expertise from different fields to develop effective ways to overcome that barrier,” he says. “GW Cancer Center provides a fantastic venue to gather all the necessary resources and expertise, and assemble a wonderful team.”
Illustrating the power of this approach, Chalasani envisions future studies involving biopsy samples from early-stage triple-negative breast cancer patients before and after anti-DDR1 treatment in future studies. Her goal is to identify biomarkers that can enable doctors to predict which patients are most likely to benefit, sparing others from unnecessary treatment and its associated side effects.
“No two tumours are the same,” she says. “We need to move away from the blanket treatment approach where everyone gets everything, and figure out exactly who needs what in a more targeted, precise way.”
With ongoing research and collaboration, the vision of precision immunotherapy for triple-negative breast cancer patients may soon be realized. Importantly, GW Hospital remains committed to ensuring equitable access to high-quality cancer care through its education and outreach programmes.
“Our emphasis is firmly on clinical need and how we can make an impact for all our patients, particularly those in underserved communities,” Chalasani says. “There is disparity in access to care and novel treatments for these patients, and we need to improve that.”