Researchers at the Spanish National Cancer Research Center (CNIO) and the University Hospital October 12 have engineered a new variant of cancer-fighting T cells that can suppress multiple myeloma (MM) tumors in mice, while showing superior persistence and endurance compared with standard engineered chimeric antigen receptor (CAR) T cells.

The new type of T cell therapy design is based on STAb-T cells, which, instead of relying on CARs, secrete bispecific antibodies that can also activate other T cells by targeting the proteins BCMA and CD3. In a study reported in Science Translational Medicine, the scientists showed that, when administered to multiple myeloma cells and to mouse models, the STAb-T cells killed the cancer cells and controlled disease progression more effectively than immunotherapy using traditional CAR T cells.

While the team acknowledges that it will be at least two years before such treatments reach patients, the promising effects and durability of the STAb-T cells indicates this approach could represent a much needed treatment option for patients with refractory or relapsed multiple myeloma, which remains incurable.

Research lead Luis Álvarez-Vallina, MD, PhD, at the Cancer Immunotherapy Unit (UNICA), department of immunology, University Hospital October 12 and colleagues reported on their development in a paper titled “Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.” Reporting on their in vitro tests and in vivo preclinical studies, including tests in xenograft models of multiple myeloma, the team concluded “These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.” The work was carried out in collaboration with researchers at the Josep Carreras Leukemia Research Institute; the Hospital Clínic de Barcelona; the University of Salamanca and the Complutense University of Madrid.

Luis Álvarez-Vallina, head of CNIO’s H12O-CNIO Cancer Immunotherapy Clinical Research Unit.
Luis Álvarez-Vallina, head of CNIO’s H12O-CNIO Cancer Immunotherapy Clinical Research Unit. [Laura M. Lombardia / Centro Nacional de Investigaciones Oncologicas (CNIO)]
Multiple myeloma is the second most common hematological cancer in adults, after lymphomas. CAR T cells have already been approved to treat refractory multiple myeloma, and so far have displayed strong anticancer activity in the clinic and a relatively good safety profile. CAR T cell therapy involves modifying the individual’s T cells in the laboratory so that they acquire the capacity to recognize and fight tumor cells.  “In recent years these cancers have begun to be treated with CAR-T cell immunotherapy,” explained Álvarez-Vallina, “which has meant a substantial improvement over previous therapeutic tools.”

However, most patients still end up relapsing or progressing after treatment, in part because the CAR T cells lose their effectiveness over time and can’t persist. MM patients who have relapsed face survival times as low as six months. “ … although patients now have longer survival times, a significant proportion of patients experience relapse, and relapse treatments are needed,” Álvarez-Vallina continued. And as the authors added, “… although recent therapeutic strategies have markedly improved survival, relapsed/refractory (R/R) MM remains an incurable cancer.”

To overcome the limitations of CAR T cell therapy, Álvarez-Vallina, Laura Díez-Alonso, PhD, also at the at the Cancer Immunotherapy Unit (UNICA), Department of Immunology Hospital Universitario 12 de Octubre, and colleagues constructed an alternative T cell therapy design based on STAb-T cells. In both cases, the cells, modified in the laboratory, recognize the same antigen, B cell maturation antigen (BCMA), which is only present in tumor cells.

“B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval,” the authors wrote.

Rather than express a CAR, the newly developed STAb-T cells secrete bispecific T cell–engaging antibodies targeting BCMA and CD3. In this way, the modified cells are designed to target and attack only cancer cells. The team’s’ reported study found that when administered to multiple myeloma cells and to mouse models of multiple myeloma, the engineered STAb-T cells killed the cancer cells and controlled disease progression more effectively than traditional CAR T cells. The results also showed that STAb-T cells outperformed CAR-T cells in that they recruited natural, non-modified T cells in the body to also fight cancer cells, thus amplifying therapeutic effect. “… expansion and persistence of adoptively transferred STAb-T cells, as well as polyclonal recruitment of both gene-modified STAb-T cells and unmodified bystander T cells to the tumor microenvironment (TME), can lead to substantially increased antitumor responses,” they noted.

The STAb-T cells in addition resisted inhibition by soluble BCMA, allowing them to expand robustly and persist to suppress the cancer over long periods of time in the mice. “STAb-T-based immunotherapies could potentially benefit from strategies to overcome resistance to T cell-redirecting approaches, such as dual-targeting therapies,” Díez-Alonso and colleagues noted.

“Finally, we also demonstrated that STAb-T cells generate immunological memory,” said Álvarez-Vallina. After recapitulating the disease in animal models and treating them with STAb-T cells, the team obtained cells from various organs—mainly spleen and bone marrow—and observed new memory STAb-T cells being produced.

“This is important,” explained Álvarez-Vallina, “because the persistence of CAR-T cells in the body, i.e., immunological memory, is related to the extent of the antitumor effect and, therefore, to a better control of the disease. The fact that we have shown that memory cells are also generated in STAb-T immunotherapy probably indicates that we could have long-term control of the disease in treated patients.”

Noting limitations of their work, the authors concluded, “In summary, anti–BCMA STAb-T cells may represent an alternative to current treatments for patients with R/R MM based on TCEs and CAR-T cells because they have certain advantages, such as the reduced impact of sBCMA on the BCMA-specific activation of STAb-T cells, as well as the continuous secretion of TCEs. This allows for a rapid and efficient recruitment of the endogenous T cell pool in the TME and the expansion and persistence in vivo of memory STAb-T cells to generate long-term BCMA-specific responses.”

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