Are cancer cells resistant to promising immunotherapy?

The therapeutic strategy is consolidated as an option to treat tumours, but it only reaches 25% of these.

As a strategy to fight cancer, immunotherapy is the perfect plan for oncologists: to stimulate the body’s defences to identify tumour cells and attack them. Less aggressive than chemotherapy, more directed at the tumour focus and with a potential memory effect, these treatments have improved survival in tumours with an inferior prognosis and have become one of the great revolutions of the decade in the fight against cancer. So much so that its evolution has overwhelmed the scientific community, which can barely keep up with the dizzying pace of this phenomenon in clinical practice. Doctors already have patients living and taking the medication longer than the trials studied, some patients develop unexpected side effects, and oncologists still can’t answer why immunotherapy works for some people and not others. Experts agree that these treatments “have come to stay”, but there is still a long way to go: only 25% of tumours arrive.

Immunotherapy increases the survival of many skin, head or lung cancer patients.

The perfect plan against cancer had been cooking for years, but something was wrong. As if it were a car, no matter how much horsepower the researchers added to the immune system to make it stronger, the response was always insufficient. In the 1990s, James P. Allison and Tasuku Honjo — Nobel Prize winners and fathers of immunotherapy — twisted that perfect plan and began to prove that, to reactivate the immune system rather than strengthen it, it was necessary to lift the Brake. Honjo discovered some molecules (PD-1) attached to tumour cells, which acted as a retaining wall on the immune system. Allison, for her part, also found other obstacles, the CTLA-4 proteins, and developed an antibody that could bind to them and block their immune system break function. It took almost two decades to perfect this concept, and in 2011 it gave birth to the first immunotherapy, ipilimumab, against metastatic melanoma. Survival went from six months to years. Since then, the evolution of these treatments has been dizzying (there are currently some 2,000 trials underway with this therapeutic strategy).

“Immunotherapy has been the quick panacea for 25% of tumours. But there, a remaining 75% of their immune system has not yet recognised the tumour. The immunotherapy drugs we have so far are capable of awakening the immune system if it has previously recognised the tumour”, points out Josep Tabernero, director of the Vall d’Hebron Institute of Oncology of Barcelona (VHIO). Where immunotherapy works best is in hot tumours. That is when there is an activity of the immune system (lymphocytes) in the tumour environment. There are currently two families of drugs on the market that work to combat these brakes on the immune system. They are administered for melanomas and tumours of the lung, kidney, bladder, Hodgkin’s lymphoma, a subset of the breast and neck, and a subtype of the colon.

“The immunotherapy that we have so far releases this brake, but if the immune system has not recognised the tumour as something abnormal, no matter how much you release the immune system, it will not begin to affect the disease,” warns Tabernero. The search for mechanisms for the immune system to recognise and activate its defensive army is one of the pending issues. Researchers are testing oncolytic viruses (modified in the laboratory to enter the tumour and destroy it from within), monoclonal antibodies, vaccines and other therapeutic strategies to heat that tumour so that the immune system recognises the malignant cells. For now, immunotherapy does not work in 95% of colon tumours, in half of the cases of gastric cancer, pancreatic cancer, sarcomas or in 40% of lung tumours, for example.

“There is a lot of uncertainty with the optimal duration of treatment,” says oncologist Edurne Arriola. The selection of tributary patients of these drugs also drives oncologists crazy. “We have to improve the quality of care, that there are reference centres for biomarkers to be able to predict which patients are going to benefit,” says Vicente Guillem, president of the Foundation for Excellence and Quality in Oncology (ECO). In addition, the entity has presented a roadmap in which it calls for a registry of tumours from patients treated with immunotherapy to study the efficacy and safety of the patient, see toxicities and analyse overall survival. “Microsatellite instability, for example, is a marker and guarantees that 50% or 60% of these patients will respond to you regardless of where the neoplasm is because these tumours have many mutations, very rare, and they greatly stimulate the immune response.”, explains Edurne Arriola, an oncologist at the Hospital del Mar in Barcelona. Experts advocate deepening the study of the niche of patients who could benefit from optimised resources and guarantee equal access in all territories. Immunotherapies can cost between 3,000 and 4,000 euros per month per patient. 

Another limitation of immunotherapy is precisely his youth. The first drug was approved in 2011 for melanoma, but the therapy did not reach other more common tumours until five years ago. In addition, the laboratory times are slower than the reality imposed in the consultation. “Clinical studies define that the maximum treatment is two years. But now we see ourselves in the situation where the two years have passed, and we don’t know what to do because the patient is phenomenal, with the disease under control, and you don’t feel like removing the treatment. So there is a lot of uncertainty with the optimal duration of treatment”, says Arriola. But, according to experts, there are already cases of long-term survivors who stopped treatment after two years and have had a controlled disease for several years.

Although immunotherapy is well tolerated in most cases (95%), it also has more or less complex side effects. Overstimulation of the immune system can precipitate autoimmune conditions, such as thyroiditis, or other life-threatening illnesses, such as myocarditis. “We are beginning to see a decrease in thyroid or pituitary function, pancreatic alterations… It is not very frequent, but it can happen. The risk when you reactivate the immune system is that it goes too far”, exemplifies Tabernero. And the collateral damage still surprises in consultations. “, Clinical oncologists little know side effects, and a multidisciplinary approach is necessary to detect them early”, adds Javier Cortés,

Immunotherapies can cost between 3,000 and 4,000 euros per month per patient.

In addition, oncologists have begun to detect the first tumour resistance to these drugs. “Immunotherapy is fantastic because you modulate our body so that it fights whoever it has to fight, but tumours also learn to mould those defences. The problem is that we do not know the mechanisms by which tumours are resistant to the immune system”, adds Cortés.

Despite the limitations, experts say, immunotherapy has opened “a new era” in the fight against cancer. Although Guillem points out: “It will displace other types of treatment, but it will not end cancer in capital letters”.