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Spanish Researchers Developing Autologous 'STAb' Therapy to Overcome CAR T-Cell Limitations

 T cells and cancer

NEW YORK – A Spanish research team is gearing up to study what it believes could be a more effective autologous T-cell therapy than CAR T-cell therapy.

The researchers from the Spanish National Cancer Research Center (CNIO) and the 12 de Octubre University Hospital in Madrid call the approach STAb T-cell therapy. It involves engineering patient-specific T cells to secrete T-cell engaging antibodies against a given target.

"STAb" stands for secretion of T-cell engager antibodies, and Luis Alvarez-Vallina, the head of CNIO's H12O-CNIO Cancer Immunotherapy Clinical Research Unit, is among the researchers pushing to move STAb T-cell therapy into clinical trials for patients with hematologic malignancies and solid tumors.

According to Alvarez-Vallina, his team is in the final stages of securing regulatory clearance to begin a first-in-human trial of STAb T-cell therapy in Europe this summer. The researchers plan to enroll around 15 patients with CD19-positive lymphomas and other advanced hematologic malignancies. If this preliminary trial goes well, Alvarez-Vallina and his colleagues hope to test STAb T-cell therapy in BCMA-directed multiple myeloma next, and in anticipation of that, they published preclinical data this week in the journal Science Translational Medicine.

The process behind STAb T-cell therapy is similar to CAR T-cell therapy, said Alvarez-Vallina. Patients' T cells are harvested, modified ex vivo to target certain cancer antigens, and then reinfused as a one-time treatment.

Rather than engineering the T cells to express a chimeric antigen receptor, however, the STAb T-cell approach involves engineering them to secrete bispecific antibodies once they're reinfused into the patient. This allows the engineered cells, once infused, to recruit the other, non-engineered T cells in the vicinity. "We can redirect all the T cells, improving the cytotoxic potential of the system," he said.

This recruiting phenomenon could also mean that fewer STAb T cells need to be infused to accomplish the same effect as CAR T cells, Alvarez-Vallina proposed. "Recruiting other T cells to attack the tumors could be a good option to reduce the final number of cells that we need to infuse in the patient, and eventually, this is going to be really important for reducing the production time and also the cost of the final product," he said, adding that this is something he and his colleagues hope to assess and confirm when the approach enters human trials.

Additionally, he said that the recent preclinical study shows the STAb T-cell approach could have a unique advantage when it comes to treating B-cell maturation antigen (BCMA)-expressing multiple myeloma. "In many patients, we see soluble BCMA, and that impacts the functionality of CAR T cells," he said. "In contrast, the STAb T cells produce quite a lot of bispecific antibodies, and the impact of the soluble BCMA on the cytotoxicity profile of the cells becomes quite low." In other words, in contrast to the potential for soluble BCMA to affect the ability of CAR T cells to kill cancer cells, this doesn't seem to be a problem for STAb T cells, at least in preclinical studies.

Once his team secures European regulatory clearance, the forthcoming first-in-human clinical trial is expected to launch in multiple centers across Spain. The study has a basket design, and researchers will enroll patients with various lymphoma indications into multiple cohorts. "We are even considering the option of including some patients who have relapsed after CAR T-cell therapy," he said.

In the first-in-human trial, researchers will assess the treatment's toxicity profile and determine its ideal dose. The 15 patients enrolled in the CD19-targeted STAb T-cell therapy trial will be tested first to ensure their cancers express the target.

And after this week's publication of the preclinical data, Alvarez-Vallina said his team will prioritize a BCMA-targeting STAb T-cell therapy trial next. The process of designing a clinical trial protocol and securing clearance from European regulators could take around two years, he said, though he's hoping to move the treatment into the clinic faster.

Looking ahead, Alvarez-Vallina said that he and his team are also exploring the idea of developing STAb T-cell treatments for solid tumors. Historically, CAR T-cell therapies have shown limited efficacy in solid tumor indications, in part because it's been difficult to identify a target that's only expressed on the cancer cells and not healthy tissues. Alvarez-Vallina said he and his team have some ideas for solid tumor targets and potential multi-targeting approaches for their STAb T-cell therapy, though these are confidential as of now.

Alvarez-Vallina and colleagues also have ambitions to expand their STAb T-cell therapy clinical trials into additional centers and enroll more patients across a greater diversity of indications in other regions. Of course, accomplishing this would take funds that can be more challenging for academic researchers to come by than for commercial biopharmaceutical companies to raise.

To this end, he and his team are simultaneously exploring partnership ideas with biotechs and even considering spinning out a small company of their own.

"We have ideas for how we can accelerate the implementation of the STAb-T idea and be in the clinic as soon as possible," he said. "We want to help patients as soon as possible. … That's the main goal for us."