A drug developed by researchers at the State University of Campinas (Unicamp) to stimulate the immune system to fight cancer – still undergoing clinical trials – could become an important weapon against the new coronavirus (SARS-CoV-2). In tests carried out with five patients who developed the severe form of covid-19 while battling bladder tumors, the combination of immunotherapy with antibiotics and corticosteroids alleviated the unregulated inflammatory response in the lung and reduced the average hospital stay from 18 to 10 days, without the need for intubation.
The most emblematic case was that of a 78-year-old patient, who contracted the infection during a cruise along the Brazilian coast and was treated at the Municipal Hospital of Paulínia, a city near Campinas. The details were described in an article published in the Social Science Research Network repository, still without peer review. The research is supported by FAPESP.
“This patient arrived at the hospital with 50% of the lung affected, fever of 38.3o C, headache, lack of appetite, difficulty breathing and oxygenation level in the blood below normal [87%, quando deveria estar acima de 94%]”, says Wagner José Fávaro, professor at the Unicamp Biology Institute and coordinator of the study.
Despite the medical recommendation, the patient resisted the idea of ??”going to the tube”, says the researcher. A longtime smoker and bearer of several chronic diseases, he feared not to leave mechanical ventilation alive. “After talking to the family, we decided to do only oxygen supplementation by intranasal catheter and administer the immunotherapy associated with antibiotics and corticosteroids of the standard protocol of the hospital. After 72 hours of hospitalization, the inflammatory markers in the blood had significantly decreased, the oxygen saturation it was 95%, the runny nose had subsided and the fever was gone. On the seventh day, without the intranasal catheter, the blood oxygen level reached 98%. On the tenth day he was discharged. “
The tomography examination performed before hospital discharge revealed that the lung lesions had healed and, in the serological test, the presence of antibodies of the type IgG (immunoglobulin G), which are specific against SARS-CoV-2 and confer long-lasting immunity, were detected , as far as we know.
Similar results were observed in four other patients undergoing immunotherapy, all with bladder cancer and other chronic diseases and over the age of 65 years. “What is striking is that individuals in these conditions tend to get worse in the first days of hospitalization for COVID-19. But everyone we treat with this protocol – which consists of administering antibiotics and corticosteroids for six days and the immunotherapy for two weeks – presented signs of improvement from the beginning “, says Fávaro.
Mechanism of action
Patented by Unicamp under the name “OncoTherad”, the immunotherapy started to be developed about 13 years ago with the aim of stimulating the immune system to fight infectious diseases and tumors. “It is a fully synthetic nanoparticle capable of inducing an immune response in T cells in the body, that is, activating certain types of lymphocytes that produce a protein called the interferon [IFN], important both to fight cancer as well as some viruses and bacteria “, explains Fávaro.
The safety of the drug has already been proven in the first stage of clinical trials. Researchers are currently seeking to confirm its effectiveness against advanced bladder cancer. “The study started with 30 patients (19 men and 11 women) who had already undergone unsuccessful treatments available on the market. But we have received many requests for inclusion of new participants. There are few therapeutic options for this type of tumor”, he says. the researcher.
All members of the study had an indication for surgical removal of the bladder and, after treatment with the immunotherapy, started two years ago, almost 80% were free of the tumor. “In the others, the disease returned with less aggression, which allowed the localized removal of the lesion”, says the researcher.
When the pandemic came, the Unicamp group noted that some of the volunteers in the clinical trial maintained close contact with people infected with the new coronavirus. And, although they all belong to the COVID-19 risk group, none showed symptoms of the infection. “There was a participant who even with the PCR [teste que detecta o RNA do vírus no sangue] positive remained totally asymptomatic “, says Fávaro.
The suspicion that the immunotherapy could reduce the aggressiveness of the SARS-CoV-2 infection began to take shape among Unicamp researchers when international groups released evidence that the virus was able to inhibit the T-cell response in the human body, tells Fávaro.
“Apparently, when lung cells are infected with the new coronavirus, a storm of cytokines begins [proteínas com ação pró-inflamatória secretadas por células de defesa] which inhibits the action of interferon-producing T cells. And OncoTherad is precisely an activator of the production of interferon “, he explains.
According to the researcher, the lack of an adequate animal model for the study of COVID-19 has hampered the proof of concept. Rats, mice and other animals used in this type of experiment are not naturally infected by SARS-CoV-2. There is only one imported model of a genetically modified rodent to express the human ACE2 enzyme – a molecule to which the virus binds to invade cells.
Metabolic changes
To understand why patients treated with OncoTherad recovered faster than the average of severe cases of COVID-19, researchers at the Innovare Laboratory of Biomarkers, based at the Faculty of Pharmaceutical Sciences at Unicamp, analyzed blood samples and compared the set of metabolites (various metabolic process products that are active, mainly lipids and organic acids) present in the fluid before and after immunotherapy.
The samples were analyzed by a mass spectrometer, a device capable of identifying substances in biological fluids according to the molecular weight of each one. The interpretation of the results was supported by artificial intelligence techniques. This part of the research was conducted by doctoral student Jeany Delafiori, with support from FAPESP and guidance from professor Rodrigo Ramos Catharino.
“What we already know is that the infection causes a very strong oxidative stress in the body. In the blood samples collected before the treatment, we observed many oxidized molecules and many molecules associated with inflammation, which corroborates the existence of an inflammatory storm”, says Catharino .
In the samples collected after treatment, the set of metabolites was more similar to that found in the blood of a healthy individual. “In the future, it may be possible to use this ‘healthy’ metabolite pattern to determine the patient’s recovery,” says the researcher.
In addition to including more patients in the study to better understand the mechanism of action of immunotherapy in COVID-19, Catharino’s group intends to compare samples from patients who recovered from the disease without receiving OncoTherad and see if there are differences.
Made in brazil
If new studies confirm the immunotherapeutic’s potential to accelerate the recovery of severe cases of COVID-19, the benefits for the Unified Health System (SUS) will be immense, evaluates Fávaro. “The costs of hospitalization in the Intensive Care Unit [UTI] would significantly decrease and, as the need for mechanical ventilation is reduced, the number of critically ill patients who can be successfully treated increases, “he says.
For that, according to researcher, the ideal would be to start the treatment when the level of oxygen in the blood is below 94% and the patient begins to experience difficulty in breathing or tiredness. “We are adding the use against COVID-19 in the patent, which is the result of 100% Brazilian science, financed with public resources. If the drug is approved in the last stages of the clinical trial, the patent will be licensed to a pharmaceutical company, which should supply it for free for SUS patients, “says Fávaro.
Before that, however, it will be necessary to expand clinical studies to other patients with moderate or severe COVID-19, regardless of whether they are cancer patients. A study with 140 participants is being processed by the Research Ethics Committee (Conep) for the use of OncoTherad immunotherapy associated with standard clinical treatment at Hospital Municipal de Paulínia. The study is expected to last for one year.