Researchers at the University of Campinas tested the Brazilian immunotherapy drug OncoTherad on five patients who contracted the disease while being treated for bladder cancer. The drug attenuated the inflammation in their lungs and shortened their hospital stay.
Published on 03/23/2021
By Karina Toledo | Agência FAPESP – A drug under development by researchers at the University of Campinas in the state of São Paulo, Brazil, to stimulate the immune system to combat cancer could become an important weapon against the novel coronavirus SARS-CoV-2. The immunotherapy drug is being tested in clinical trials.
In tests with five patients who became critically ill with COVID-19 while undergoing treatment for bladder cancer, administration of the immunotherapy drug with antibiotics and corticosteroids attenuated the dysregulated inflammatory response in the lungs and shortened the average hospital stay from 18 to ten days while averting the need for intubation.
The most emblematic case was that of a 78-year-old man who was infected by the virus while on a cruise along the Brazilian coast and treated at the Municipal Hospital in Paulínia, not far from Campinas. The case is reported in an article published on the Social Science Research Network (SSRN) and not yet peer reviewed. The group’s research on treatments for bladder cancer is supported by FAPESP.
“This patient was admitted with 50% of his lungs damaged, a fever of 38.3 °C, headache, lack of appetite, shortness of breath, and below-normal oxygen saturation [87%, where normal saturation is above 94%],” said Wagner José Fávaro, a professor in UNICAMP’s Institute of Biology and principal investigator for the study.
Against medical advice the patient was reluctant to be intubated, Fávaro recalled. The subject had smoked for many years and had several chronic diseases, fearing he would not survive mechanical ventilation. “After speaking with his family, we opted for nasal oxygen therapy and administered the immunotherapy drug in conjunction with the antibiotics and corticosteroids recommended by the hospital’s standard protocol,” he said. “After 72 hours the patient’s blood inflammatory markers and coryza had improved significantly, oxygen saturation was 95%, and the fever had gone. On the seventh day saturation reached 98% without oxygen therapy. On the tenth day he was discharged.”
A CT scan of his chest performed on discharge showed that the lung damage had healed, and a serological test detected the presence of immunoglobulin G (IgG) antibodies specific to SARS-CoV-2, currently believed to confer lasting immunity.
Similar improvements were observed in four other patients submitted to immunotherapy, all of whom had bladder cancer as well as other chronic diseases and were over 65 years old. “The striking fact is that patients with these conditions typically deteriorate in the first few days after admission to hospital for treatment of COVID-19, but all subjects treated according to this protocol – administration of antibiotics and corticosteroids for six days and the immunotherapy drug for two weeks – exhibited signs of improvement from the word go,” Fávaro said.
Action mechanism
The immunotherapy drug has been patented by UNICAMP under the name OncoTherad. Its development began some 13 years ago, with the aim of stimulating the immune system to combat infectious diseases and tumors. “It’s a totally synthetic nanoparticle capable of inducing an immune response by T cells. This entails activating certain kinds of lymphocyte that produce interferon [IFN], an important protein to combat both cancer and some viruses and bacteria,” Fávaro said.
The drug has so far met safety requirements in a Phase I clinical trial. The researchers now aim to prove its effectiveness against advanced bladder cancer. “The study began with 30 patients (19 men and 11 women) who had already unsuccessfully undergone the treatments available on the market,” Fávaro said. “We’ve received many requests for inclusion of new participants. There are few therapeutic options for this type of tumor.”
Surgical tumor removal had been indicated for all participants, almost 80% of whom became free of the tumor after treatment with the immunotherapeutic drug, which began two years ago. “In the rest the disease returned less aggressively, permitting localized removal of the lesion,” Fávaro said.
With the advent of the pandemic, the UNICAMP group observed that while some of the volunteers in the clinical trial had been in close contact with people infected by the novel coronavirus, none manifested symptoms even though they were all high-risk for COVID-19. “Even participants with positive results in the PCR test [which detects viral RNA in blood] remained entirely asymptomatic,” Fávaro said.
The suspicion that the immunotherapeutic drug could reduce the aggressiveness of infection by SARS-CoV-2 grew among the UNICAMP scientists when research groups in other countries reported evidence that the virus was capable of inhibiting the human immune response by T cells. “It appears that a cytokine storm is triggered when lung cells are infected and that this inhibits the action of interferon-producing T cells. OncoTherad is precisely an activator of interferon production,” he said. Cytokines are pro-inflammatory proteins secreted by defense cells.
Lack of an adequate animal model for research on COVID-19, he added, has hindered proof of concept. Rats, mice and other animals used in this kind of experiment are not naturally infected by SARS-CoV-2. Only one imported rodent model genetically modified to express human ACE-2, the molecule to which the virus binds to invade cells, is currently available.
Metabolic alterations
To understand why patients treated with OncoTherad recovered faster than the average for severe cases of COVID-19, researchers at the Innovare Biomarker Laboratory, hosted by UNICAMP’s School of Pharmaceutical Sciences, compared the metabolites (especially lipids and organic acids) present in blood samples before and after immunotherapy.
The samples were analyzed with the aid of a mass spectrometer, which identifies substances in biological fluids in accordance with their molecular weight. Artificial intelligence techniques were used to interpret the results. This part of the study was conducted by PhD researcher Jeany Delafiori with funding from FAPESP and supervision by Professor Rodrigo Ramos Catharino.
“What we know so far is that this viral infection causes very strong oxidative stress in the organism,” Catharino said. “Blood samples collected before the treatment were found to contain many oxidized molecules and many molecules associated with inflammation, confirming the existence of an inflammatory storm.”
The metabolites in samples collected after the treatment closely resembled those found in the blood of a healthy individual. “In future it may be possible to use this ‘healthy’ metabolite profile to determine that a patient has recovered,” he said.
Catharino and his group will include more patients in the study in order to glean a better understanding of the immunotherapy drug’s action mechanism against the virus, and will compare samples from patients who have recovered from COVID-19 without receiving OncoTherad to see if there are differences.
Made in Brazil
If future studies confirm the immunotherapy drug’s potential to help severe COVID-19 patients recover sooner, Fávaro noted, the benefits for Brazil’s national health system (known as SUS, its Portuguese-language acronym) will be huge. “The cost of intensive care [in ICUs] would diminish significantly,” he said. “Moreover, reducing the need for mechanical ventilation would increase the number of severe patients who can be successfully treated.”
Ideally, he added, the treatment should begin as soon as oxygen saturation falls below 94% and the patient becomes short of breath or fatigued. “We’re including use against COVID-19 in the patent, which is 100% Brazilian science and publicly funded. If the drug passes clinical trials in all phases, the patent will be licensed to a pharmaceutical company, which will be required to provide it free of charge to patients treated by the SUS,” Fávaro said.
First, however, it will be necessary to extend the clinical trials to other patients with moderate or severe COVID-19, regardless of whether they also have cancer. The National Research Ethics Committee (CONEP) has been asked to approve a 140-participant one-year trial of OncoTherad as part of the Paulínia hospital’s standard clinical treatment.
The article “A 78-year-old urothelial cancer patient with faster recovery from COVID-19: potential benefit from adjuvant active immunotherapy” can be read at: papers.ssrn.com/sol3/papers.cfm?abstract_id=3609259.
Source: https://agencia.fapesp.br/33454
