Dagger cells against resistant leukemia

Scientists have created a cell therapy based on the use of cells known as “stab cells” (STAb in English) to combat a type of leukemia that has been having few treatment options.

The researchers are from the Josep Carreras Leukemia Research Institute in Badalona, ​​Barcelona, ​​and the 12 de Octubre University Hospital in Madrid, Spain.

The new therapy, known as STAb-T, could be used to treat T-cell acute lymphoblastic leukemia (T-ALL) in patients who have failed chemotherapy or bone marrow transplantation.

STAb-T therapy, developed thanks to the support of the Spanish Association Against Cancer, is an evolution of the so-called CAR-T therapies that are currently revolutionizing cancer treatment. CAR-T therapies are based on modifying the patient’s own immune cells (T lymphocytes) so that they are capable of expressing artificial (chimeric) receptors that recognize and kill tumor cells.

The advance of one with respect to the other consists in the fact that in CAR-T therapy, the T cell expresses a receptor with a monospecific antibody capable of recognizing a target in the tumor, while STAb therapy is based on the secretion of a special type called bispecific antibody that can recognize two targets, one in the tumor cell and the other in the T cell. In this way, the bispecific antibodies create a kind of artificial bridge that puts the therapeutic T cells in contact with the tumor cells, facilitating the elimination of the latter and keeping healthy T lymphocytes safe.

This distinction is essential to be able to treat T-cell acute lymphoblastic leukemia. In the case of B-cell acute lymphoblastic leukemia (B-ALL), CAR-T cells, by recognizing a single target, destroy both the diseased B cells and the healthy, although these patients can lead a normal life thanks to the periodic supply of immunoglobulins (antibodies) obtained from healthy donors.

In T-ALL it is more difficult to apply CAR-T therapy, since the cells used to fight the tumor (T lymphocytes) are the same ones that are diseased and their use can cause an immunodeficiency state incompatible with life. In addition, there is no replacement therapy available as there is in B-cell leukemias.

T-cell acute lymphoblastic leukemia is a rapidly progressing type of leukemia resulting from the abnormal proliferation of T-cell lymphoblasts (immature white blood cells) in the bone marrow and blood. It is a so-called rare disease that accounts for about 10 to 15 percent of all acute leukemias diagnosed in children and 20 to 25 percent of those that affect adults. In total, approximately 100 cases a year are detected in Spain.

STAb-T therapy for the treatment of T-ALL, created by the Mixed Cancer Immunotherapy Clinical Research Unit of the 12 de Octubre University Hospital and the Spanish National Cancer Research Center (CNIO), and led by Dr. Luis Álvarez-Vallina and the team from the Josep Carreras Leukemia Research Institute – doctors Pablo Menéndez and Diego Sánchez-Martínez – could be an improvement compared to CAR-T, especially in relapsed patients with a reduced number of T lymphocytes normal.

In the research, Anaïs Jiménez-Reinoso, Néstor Tirado and other members of both teams have shown that STAb-T cells work very efficiently in in vitro and in vivo animal models. Different options are currently being considered to bring this therapy to clinical trials.

Diego Sánchez and Néstor Tirado, from the research team. (Photo: Josep Carreras Leukemia Research Institute)

Immunotherapy strategies and adoptive cell therapies still benefit few patients. “It is necessary to develop strategies aimed at very specific targets for each disease and adapted to each patient” explains Dr. Álvarez-Vallina. In his opinion, “the future in cancer and leukemia research lies in the creation of personalized therapies that provide options for all those who today cannot find an alternative to conventional therapies. STAb-T therapy is on this path.”

“Furthermore – he concludes – while in the case of CAR-T therapies many hospitals are centers that produce this therapy, in the case of STAb-T cells it is a completely new therapy that appears at the Hospital Universitario 12 de Octubre and which represents an innovation in the field of cell therapies”. It is important to highlight that STAb-T therapy may be applicable to multiple types of cancer and some of these modalities are in clinical development.

The research team exposes the technical details of the new therapy in the academic journal Journal for Immunotherapy of Cancer, under the title “Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers”. (Source: Josep Carreras Leukemia Research Institute)