An innovative treatment that has proved to be highly effective against certain types of blood cancer (lymphoma and acute lymphoblastic leukemia) is getting closer to the Brazilian population.
In June, the Government of the State of São Paulo, through a partnership between Butantan, the School of Medicine of the University of São Paulo (FMUSP), the School of Medicine of Ribeirão Preto (FMRP-USP) and the Ribeirão Preto Blood Center, will inaugurate two cellular therapy production units for the treatment of cancer: the Advanced Cell Therapy Center (Nucel), installed at the “Cidade Universitária” (USP’s campus) in São Paulo (SP), and the Advanced Therapy Center (Nutera), located in Ribeirão Preto (SP). The initiative is part of a cooperation agreement between the institutions. Together, the units will be capable of treating about 200 to 300 patients per year.
Therapy with CAR-T cells (acronym for chimeric antigen receptor) is developed at the Center for Cell-based Therapy of FMRP-USP. The first volunteer, who received the experimental treatment two years ago, achieved complete remission of an end-stage lymphoma. Other patients who opted for treatment also experienced remission. “It is a personalized treatment, as it uses the patient's own defense cells to fight the disease. It is an absolutely revolutionary therapy that, in my opinion, will change the treatment of cancer in the coming years”, says the president of Instituto Butantan, Dimas Covas, hematologist leading the study.
Although it is already applied in different countries, cell therapy still has a major obstacle: its high cost, which can reach US$ 500,000 per application in each patient. The partnership between Butantan, the Ribeirão Preto Blood Center and USP in the construction of the two units aims to expand access to treatment and ensure that it reaches the Unified Health System (SUS).
“It is a technology of extreme importance for public health. Butantan's role is to offer its production capacity, experience with processes conducted under good manufacturing practices, clinical development and delivery of biopharmaceuticals to try to reduce the cost of this therapy as much as possible", says Butantan's innovation manager, Cristiano Gonçalves, who is responsible for the institution's Innovation and Technology Licensing Office.
The units in São Paulo and Ribeirão Preto will have an advanced structure that will allow the development, production and storage of technology in a single place. Facilities include quality control laboratories, virus production rooms, CAR-T cell production clean rooms, media and solution preparation rooms, and areas for storing the final product and inputs in cryogenic tanks.
The initiative is supported by the Government of the State of São Paulo. “With this new program, São Paulo reinforces its pioneering spirit in research and in offering innovative, highly complex treatments to Brazilians”, says the Secretary of Science, Research and Development in Health of the State of São Paulo, David Uip.
Tests on patients
As cell therapy is still in an experimental phase in Brazil, patients have so far received compassionate treatment – by medical decision, when the cancer is in an advanced stage and there is no other authorized therapy alternative. This type of study is not yet regulatory, that is, it does not influence the final approval of the treatment by the Brazilian Health Regulatory Agency (Anvisa), but it strengthens the possibility of approving a clinical study with more volunteers.
"Right now, Butantan, the Blood Center and USP are preparing to submit the phase 1 clinical study to Anvisa", says Cristiano. According to him, with the works completed in June, the next step is to install, qualify and certify the equipment and train the teams to start operating. Phase 1 is expected to start in October this year, with 30 patients with blood cancer – specifically, non-Hodgkin's B-cell lymphoma.
Teaching the immune system to fight cancer
CAR-T Cell technology is a type of immunotherapy that uses T lymphocytes, cells of the immune system responsible for fighting pathogens and killing infected cells. The treatment consists of removing and isolating T lymphocytes, activating them, “reprogramming” them to be able to identify cancer cells and then infusing them back into the individual's body. Then, the modified defense cells come back stronger to eliminate the tumor cells. This entire process, from cell collection, modification and administration to the patient, can last around 60 days.
But how does it work? After the blood is collected, the doctor determines cell parameters to separate only the cell group of interest (the T cells). Then, the researchers apply a reagent that stimulates the activation of these cells. “Once the T lymphocytes are activated and multiplied, they are placed in contact with a lentiviral vector – a modified virus incapable of causing disease. This vector contains the genetic information of a receptor that recognizes the antigen called CD-19, which is expressed on the surface of tumor cells of hematological neoplasms [blood cancer]”, explains biomedical doctor and laboratory technologist Virginia Wagatsuma, from Nucel.
As it contains the genetic information of the CD-19 receptor, the vector makes the T cell express it on its surface, giving rise to CAR-T cells that will be used in therapy – and which will bind to the CD-19 present in tumor cells. The product is frozen and undergoes rigorous quality control tests, before being infused into the patient in a process similar to blood transfusion. Back in the bloodstream, this set of CAR-T cells recognizes and binds to cancer cells, inducing cell death.
A synonym of hope
For Dimas Covas, his first patient to receive cell therapy was an unforgettable experience. “He was an elderly man who had already had four different treatments for lymphoma and had exhausted his possibilities. Within the first 30 days of applying CAR-T cells, most of the cancer cells were gone and he went into remission. Unfortunately, five months later, he had a domestic accident, suffered a head trauma and didn’t make it. This story greatly marked the lives of all those who devoted their efforts to treating him,” he states.
The hematologist reinforces that Butantan, partnered with USP and the Ribeirão Preto Blood Center, will keep on working so that this therapy can be offered on a large scale to the Brazilian population.