Guided missiles targeting tumor cells open a new route to combat cancer | Health
If more than half a century ago, science eagerly considered the potential of chemotherapy to fight cancer; or 15 years ago, oncologists did the same with immunotherapy, which boosted the immune system’s defenses to attack tumor cells; Today, the spotlight is turning to an innovative treatment that is showing promising results: antibody-drug conjugates (ADCs), treatments that work like a Trojan horse, delivering chemotherapy inside tumor cells to destroy them. The congress of the European Society for Medical Oncology (ESMO), the main European meeting for clinical research on cancer, was held last week in Berlin and gave a boost to a new generation of these precision missiles. During the event, study presentations demonstrated the potential of ADCs in several types of breast cancer and at different stages, not just metastatic.
These Trojan horses consist of an antibody that targets a type of antenna on the surface of tumor cells. These molecules carry a hidden chemotherapy payload, and when they reach their target, they bind to these receptors and release the entire drug into the tumor cells to selectively kill them. “ADCs are here to stay. It is a validated line of research and it is like a highway on which we can continue to move forward,” noted Aleix Prat, director of the Clinic Barcelona Comprehensive Cancer Center. Other studies presented at the event showed that this therapeutic approach also has potential for other tumors, such as ovarian, endometrial and pancreatic cancers.
In breast cancer, these precision missiles have changed the prognosis of the most aggressive tumors. They entered the therapeutic arsenal more than ten years ago, but new generations of these drugs are gaining more and more ground. Three years ago, for example, research showed that one of the new ADCs, trastuzumab-deruxtecan, increased the survival rate of women with HER2+ tumors (this subgroup represents 20% of all breast cancers) in the metastatic stages. And a new study presented this year at ESMO and published simultaneously in the prestigious New England Journal of Medicine (NEJM) also showed that another of these new precision missiles, sacituzumab govitecan, is more effective than conventional chemotherapy in the treatment of triple negative breast cancer (the most aggressive type, affecting 15% of patients) at advanced stages: the 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 Center in Barcelona and author of this research, affirms that, with this study, science confirms that when breast cancer metastases appear; that is, when malignant cells have spread to other parts of the body, these medications are the first treatment option. “This study adds another turning point and improves the prognosis of these patients. Little by little, we are progressing slowly but surely. During this congress, immunoconjugates were positioned as the most innovative, hottest and most spectacular”, notes the doctor, who is also scientific director of the IOB Oncology Institute in Madrid.
But this therapeutic strategy is not only 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 return – administering the ADC trastuzumab-deruxtecan followed by standard therapy before surgery improves pathological complete response. This means that there are no tumor cells in the breast or lymph nodes at the time of surgery after this treatment, a key parameter in reducing the risk of relapse.
Santiago Escriva de Romaní, oncologist from the Breast Cancer Group of the Vall d’Hebron Oncology Institute, participated in this research: “We observed an 11% higher pathological complete response rate. [when incorporating ADCs into treatment].” The doctor affirms that the development of Trojan horses constitutes “a turning point” in oncology: “ADCs are gaining ground significantly. They do not exclude chemotherapy, but they greatly help us to target it more precisely on tumor cells,” he adds.
Of this research, Prat says that in these early settings, the therapeutic potential they expect from these Trojans means that “they can cure more patients.”
A “new chapter” in oncology
In a statement, the European Scientific Society said that with the potential demonstrated by ADCs, oncology is “at the dawn of a new chapter,” focused on “smarter targeting, earlier intervention and deeper biological understanding of tumors.” The research presented at the congress, it is claimed, “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 just beginning to uncover, and which promises to reduce recurrence rates and improve survival in several types of cancer in the years to come,” Paolo Tarantino of the Dana-Farber Cancer Institute and Harvard Medical School said in the same statement.
The doctor, however, warned that the use of these drugs also presents new challenges, such as toxicity and defining the patient profile who will benefit the most. In Cortés’ study, for example, 66% of people receiving the ADC experienced side effects (62% of the control group also experienced side effects), mainly diarrhea and reduced immune defenses. “In general, Trojans produce toxicity that, compared to traditional chemotherapy, tends to be slightly better,” notes Cortés.
Another open area is refining the profile of patients who will benefit. In the study conducted by this Spanish doctor, around 50% of the patients in the trial saw their tumors shrink; 45% kept their tumor unchanged (neither growing nor shrinking) and 5%, during the first follow-up, experienced growth, explains Cortés. “Research is now focused on studying the resistance mechanisms of the Trojan horse. This could be due to alterations in the receptors that the antibodies must attach to, or there could be resistance in the mechanisms of cleavage and release of the chemotherapy payload that they carry. Ultimately, these treatments are an elegant way to deliver chemotherapy, and it could also be that the tumor is resistant to chemotherapy”, asks the oncologist.
Pending Challenges
Cortés also says that there are still many other questions to study: for example, how to combine different Trojans with each other; or how to combine one of these precision missiles with other treatments, such as immunotherapy. “We need to see how to optimize these Trojan horses: there are studies on antibodies that can attach to different receptors. [on tumor cells]or how to carry a load of two different chemotherapies,” he says.
Pilar Barretina, head of the medical oncology department at the Catalan Institute of Oncology (ICO) in Girona, emphasizes that there is “a boom in [this type of] drugs under investigation that opens many avenues. “This is one of the major promises we have today. There is a tsunami of ADCs coming, but we will have to see the results of their effectiveness, their tolerability and determine which patients can benefit the most,” she adds.
This oncologist, who presented at the congress a study on immunotherapy for advanced endometrial cancer, affirms that ADCs have been used “in almost all tumors”, but admits that the most advanced research concerns breast and lung cancer. “But very promising phase I trials have also been presented in ovarian and endometrial cancer,” she adds.
The “highway” that the ADCs have opened, according to Prat, to fight against cancer promises to be long, especially with the new generations of Trojan horses tested, which are increasingly precise. Along the same lines, the Clínic oncologist assures: “Technologically, [this precision missile] will be able to release anything. So far it has been chemotherapy, but we are already starting to see models of combination with immunotherapy or others. For example, Cortés adds, research on radioligands is starting to gain traction. This is a sort of Trojan horse that, instead of chemotherapy, carries radioactive isotopes in its payload to create selective radiation. “It’s extremely powerful. There is already good data on certain tumors, such as prostate cancer,” he adds.
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