Researchers use custom molecule to halt growth of multiple myeloma and diffuse large B cell lymphoma in mice

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Compared to control (left), treatment with a soluble BCMA receptor inhibitor (right) increases the number of cancer cells dying (brown) in multiple myeloma tumor cells growing in mice. Credit: © 2022 Miao et al. Originally published in Journal of Experimental Medicine. 10.1084/jem.20220214

Researchers at Stanford University have created “pain receptor” cells that inhibit the growth of multiple myeloma (MM) cells and diffuse large B cell lymphoma (DLBCL) in mice. Cells, which are described in a study to be published July 26 in Journal of Experimental Medicine (JEM), were also found to be non-toxic in monkeys, suggesting that they could be used to treat one of these deadly diseases in humans, which are the most common blood cancers. in the world.

Both MM and DLBCL are cancers that arise from the body’s immune-producing B cells. The five-year survival rate for patients diagnosed with one of these diseases is less than 60%. In recent years, the use of CAR T cells to specifically kill B cells has proven effective in some patients. However, this immune system often comes with significant side effects and is not appropriate elderly patientsof which MM and DLBCL are particularly common.

“Effective and safe therapies are therefore needed for patients who have run out of current treatment options,” said Dr. Yu Rebecca Miao, a professor in the Department of Radiation Oncology at Stanford University. Miao led the new research with Dr. Kaushik Thakkar of Stanford University and Professor Amato J. Giaccia, who now works at the Oxford Institute for Radiation Oncology at the University of Oxford.

Miao and colleagues suspect that two cell signaling proteins named APRIL and BAFF may be effective therapeutic targets for MM and DLBCL. By binding to several different cell surface receptor proteins, APRIL and BAFF control the growth of normal B cells. But the increased levels of APRIL and BAFF increase the growth and survival of harmful bacteria, facilitating the development of blood cancer and resistance to treatment. Specifically, APRIL is associated with MM progression, while BAFF is associated with DLBCL.

BCMA is a B cell receptor that binds to APRIL and BAFF. Miao and colleagues investigated whether the soluble form of BCMA, which is not attached to the B cell surface, would act as a “deceptive receptor” to eliminate excess APRIL and BAFF and inhibit these proteins cause the growth of cancerous B cells.

The researchers found that soluble BCMA was able to bind to APRIL and inhibit the growth of MM in mice. However, the scavenger receptor only binds weakly to BAFF and thus fails to reduce the size of DLBCL.

So Miao and colleagues engineered a soluble mutant form of BCMA that binds strongly to APRIL and BAFF. This gene, named sBCMA-Fc V3, was able to inhibit the development of both MM and DLBCL in rodents.

Notably, sBCMA-Fc V3 also reduced the activity of APRIL and BAFF in cynomolgus monkeys without causing any significant effect. This suggests that treatment with sBCMA-Fc V3 or similar denatured receptors may be safe and effective in humans.

“Together, our data support sBCMA-Fc V3 as a clinical candidate for the treatment of MM and DLBCL,” Miao said. “The biological functions of BAFF and APRIL are not limited to B cell disease but extend to autoimmune diseases and other pathological diseases B The cellssuggests an appropriate clinical indication for sBCMA-Fc V3.”

The group is developing and validating a three-in-one CAR T therapy

Additional information:
Yu Rebecca Miao et al. Journal of Experimental Medicine (2022). DOI: 10.1084/jem.20220214

hint: Researchers use conventional cells to stop growth of multiple myeloma and diffuse large B cell lymphoma in mice (2022, July 26) retrieved 26 July 2022 from /news/2022-07-custom-molecule-halt- growth-number.html

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