Lymphoma and leukemia are currently the main focus of the CAR-T cell therapy program, an innovative cancer treatment launched in June by Instituto Butantan, the University of São Paulo (USP) and the Regional Blood Center of Ribeirão Preto. Nevertheless, with the recently inaugurated production units in the capital and in the interior of São Paulo, it will also be possible to develop CAR-T cells for other types of blood cancer, such as multiple myeloma and acute myeloid leukemia, and even for solid tumors, such as gliobastoma and melanoma. The partnership between the institutions aims at making the treatment available in the Brazilian Unified Health System (SUS), since the high cost of US$ 500,000 makes the therapy practically inaccessible.
The treatment collects and genetically modifies the patient's defense cells (T lymphocytes) so that they are able to fight cancer. This alteration uses vectors produced in the lab, which contain the genetic information of the receptor of an antigen of the tumor cell – that is, it presents a “piece” that fits and recognizes the cancer cell. One such antigen is CD-19, specific for lymphoma and leukemia cells.
“There is already research in advanced stages abroad, mainly in the United States and Europe, with CAR-T cells for other neoplasms. We can reproduce them initially on a small scale, as we did with CD-19, and then scale up for testing on patients. The forecast is that we start working with new targets by the end of 2023”, says the medical director of the Laboratory of Cell Therapy at the Blood Center of Ribeirão Preto, Gil Cunha de Santis.
Multiple myeloma is an aggressive cancer that affects plasma cells, bone marrow cells responsible for producing antibodies. They multiply rapidly and compromise the production of other blood cells, causing anemia and increased susceptibility to infections. The disease also affects the bones, causing pain and spontaneous fractures. Acute myeloid leukemia occurs in myeloid cells, which are responsible for the production of blood cells (leukocytes, platelets and red blood cells), and is more common in adults.
In the case of CAR-T aimed at solid tumors, which has also been studied around the world and can help especially people with inoperable tumors, the challenge is that the cellular composition within a tumor ends up being variable – that is, the cells that are in the center, for example, are different from those located at the ends. Thus, receptors for different antigens would be needed to neutralize all cancer cells.
The path of CAR-T to SUS
In Brazil, since 2019, the Regional Blood Center has been treating acute lymphocytic leukemia, another type of leukemia that mainly affects children, and lymphoma, which affects lymphocytes. So far, nine patients aged 13 to 64 years have undergone treatment and most have achieved partial or full remission. These volunteers entered the experimental study for compassionate use, on medical advice, when conventional treatments have not worked and options are exhausted.
In view of the promising results, Butantan, USP and the Regional Blood Center developed an advanced program to produce CAR-T cells in São Paulo and Ribeirão Preto. The next step towards approval of the treatment by the National Health Regulatory Agency (Anvisa) is the development of a clinical trial. It has already been designed and its protocol is now approved by the National Research Ethics Committee (Conep), and will soon be submitted to the regulatory agency for analysis.
The phase 1/2 study will include 20 subjects with B-cell non-Hodgkin's lymphoma and 20 subjects with B-cell acute lymphocytic leukemia. Adverse effects, clinical response after 30 and 90 days of therapy, duration of response and overall survival of volunteers will be evaluated. The individuals will be followed up for 12 years after the procedure – the standard amount of time for medicine to consider a patient cured.
A technology for the books!
The history of CAR-T involves more than 60 years of studies. The first T cells containing a chimeric antigen receptor (CAR) were produced in 1987 in Israel and, in 2009, American scientists were able to prove the effectiveness of the therapy against leukemia. The technology has been approved by the Food and Drug Administration (FDA) in 2017 and is now available in Europe, the United States, Canada, China, Japan, Israel, Australia, New Zealand and Singapore.
A great advantage of the therapy is that it is personalized and made with the patient's own cells, causing much less adverse effects than chemotherapy, for example. That is because CAR-T cells are specific for cancer, so they don’t target healthy cells.
In addition, studies indicate that CAR-T cells continue to circulate in the body even after treatment, reducing the chance of relapses. That's what happened to the first two patients to be treated in the US in 2010, who had end-stage leukemia. They achieved remission and remain disease-free to this day, according to an article published in Nature.