A new generation of precision missiles – antibody-drug conjugates (ADCs), which are treatments that work like a Trojan horse, delivering chemotherapy to the interior of malignant cells to destroy them – has being added to the fight against cancer.
If, more than half a century ago, science looked expectantly at the potential of chemotherapy to combat cancer, or 15 years ago, oncologists did the same with immunotherapy, which energised the immune system’s own defences to attack tumour cells, now the spotlight has turned to this innovative treatment reaping promising results, reports El País.
At the recent European Society for Medical Oncology (ESMO) congress in Berlin, study presentations showed ADCs’ potential in several types of breast cancer and at various stages, not just metastatic.
These Trojan horses are formed by an antibody that targets a kind of antenna on the surface of tumour cells. These molecules carry a hidden chemotherapy payload, and when they reach their target, they bind to those receptors and release the entire drug into the tumour cells to selectively kill them.
“ADCs are here to stay. It’s a validated line of research and it is like a highway along which we can continue to advance,” noted Aleix Prat, director of the Clinic Barcelona Comprehensive Cancer Centre.
Other studies showed that this therapeutic approach also has potential for other tumours, such as ovarian, endometrial and pancreatic cancers.
In breast cancer, these precision missiles have shaken up the prognosis of the most aggressive tumours. They entered the therapeutic arsenal more than a decade ago, but new generations of these drugs are gaining more ground.
Three years ago, for example, research demonstrated that one of the new ADCs, trastuzumab-deruxtecan, increased the survival rate of women with HER2+ tumours (this subgroup accounts for 20% of all breast cancers) in metastatic stages.
And a new study presented this year at ESMO and published simultaneously in the New England Journal of Medicine (NEJM) has also shown that another of these new precision missiles, sacituzumab govitecan, is more effective than conventional chemotherapy in treating triple-negative breast cancer (the most aggressive type, affecting 15% of patients) in advanced stages: median progression-free survival was almost 10 months in those treated with this Trojan horse (in those treated with chemotherapy alone it was seven months).
Javier Cortés, director of the International Breast Cancer Centre in Barcelona and author of this research, asserts that, with this study, science confirms that when breast cancer metastasis appear – that is, when malignant cells have spread to other parts of the body – these drugs are positioned as the first treatment option.
“This study adds another twist and improves the prognosis for these patients. Little by little, we are making slow but steady progress.
“At this congress, immunoconjugates have positioned themselves as the most innovative, the hottest, and the most spectacular,” noted the doctor, who is also scientific director of the IOB Institute of Oncology Madrid.
But this therapeutic strategy isn’t just suitable for the most advanced stages of cancer.
Another study presented at the conference and published in the Annals of Oncology showed that in patients with high-risk, HER2-positive early breast cancer – who are more likely to have the disease recur – administering the ADC trastuzumab-deruxtecan followed by standard therapy before surgery improves the pathological complete response.
This means there are no tumour cells in the breast or lymph nodes at the time of surgery after this treatment, a key parameter for reducing the risk of relapse.
Santiago Escrivá de Romaní, an oncologist at the Breast Cancer Group at the Vall d’Hebron Institute of Oncology, who participated in this research, said: “We found an 11% higher rate of complete pathological response (when incorporating ADCs into treatment).”
The doctor asserts that the development of Trojan horses is “a turning point” in oncology: “ADCs are gaining significant traction. They don’t allow us to rule out chemotherapy, but they greatly help us target it more precisely to tumour cells,” he added.
Regarding this research, Prat said that in these early contexts, the therapeutic potential they anticipate from these Trojan horses means that “they can cure more patients”.
A ‘new chapter’ in oncology
In a statement, the European scientific society stated that, with the potential shown by ADCs, oncology is “on the threshold of a new chapter”, focused on “smarter targeting, earlier intervention, and a deeper biological understanding of tumours”.
The research presented at the congress, it said, “marks the official entry of a new generation of drugs into the curative field”.
“This is a therapeutic strategy with enormous potential, which we are only just beginning to discover, and which promises to reduce recurrence rates and improve survival in multiple cancer types in the coming years,” said Paolo Tarantino of the Dana-Farber Cancer Institute and Harvard Medical School in the same statement.
The doctor did warn, however, that the use of these drugs also presents new challenges, such as toxicity and defining the patient profile that will benefit most.
In Cortés’ study, for example, 66% of those receiving the ADC experienced side effects (62% of the control group also experienced side effects), primarily diarrhoea and decreased immune defences.
“In general, Trojan horses produce a toxicity that, compared with traditional chemotherapy, tends to be somewhat better,” Cortés notes.
Another open area is refining the profile of patients who will benefit. In the study led by this Spanish doctor, around 50% of the patients in the trial saw their tumours shrink; 45% maintained their tumours unchanged (neither growing nor shrinking), and 5%, during the first follow-up, had experienced growth, said Cortés.
“Research is now focusing on studying the mechanisms of Trojan horse resistance. It could be due to alterations in the receptors where the antibodies must attach, or there could also be resistance in the mechanisms of cleavage and release of the chemotherapy load they carry.
“Ultimately, these treatments are an elegant way of administering chemotherapy, and it could also be that the tumour is resistant to chemotherapy,” the oncologist pondered.
Pending challenges
Cortés also argues that there are many other issues still to be investigated: for example, how to combine different Trojan horses with each other; or how to fit one of these precision missiles with other treatments, such as immunotherapy.
“We need to see how to optimise these Trojan horses: there are studies on antibodies that can attach to various receptors (on tumour cells), or how to carry a load of two different chemotherapies,” he said.
Pilar Barretina, head of medical oncology at the Catalan Institute of Oncology (ICO) in Girona, said there is “a boom in (these types of) drugs under investigation that opens up many avenues”.
“It’s one of the major promises we have today. There’s a tsunami of ADCs coming our way, but we’ll have to see the results of their efficacy, tolerance, and which patients can benefit most,” she added.
This oncologist, who presented a study on immunotherapy for advanced endometrial cancer at the congress, said ADCs have been used “in almost all tumours”, but that the most advanced research is in breast and lung cancer.
“But very promising phase 1 trials have also been presented in ovarian and endometrial cancer,” she pointed out.
The “highway” that, according to Prat, ADCs have opened to combat cancer, is expected to be long, especially with the new generations of Trojan horses being tested, which are increasingly precise.
Along these lines, the oncologist from the clínic assures: “Technologically, (this precision missile) will be able to release anything. So far, it’s been chemotherapy, but we are already starting to see combination designs with immunotherapy or others.”
For example, research with radioligands is beginning to gain traction. These are a kind of Trojan horse that, instead of chemotherapy, carries radioactive isotopes in its payload to create selective radiation.
“It’s extremely powerful. There’re already good data on some tumours, such as prostate cancer,” he adds.
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