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Trispecific antibody activates CD 4 cells to curb breast cancer growth in mice

Reuters Health - 10/03/2022 - A novel "trispecific" antibody to HER2, CD3 and CD28 inhibited breast cancer growth in mice via a mechanism involving CD4 cells, researchers say.

"Immunotherapies show remarkable efficacy in treating cancers, but they work in only a fraction of cases," Dr. Gary Nabel of ModeX Therapeutics in Natick, Massachusetts told Reuters Health by email. "A next generation of immune therapies uses new technology, trispecific antibodies, and is showing promise preclinically in directing immune cells to tumors, where they can block cancer cell proliferation at the same time they stimulate the immune system to kill malignancies."

Dr. Nabel, the senior author of a report in Nature, added that clinical trials of the trispecific antibody SAR443216 are underway now, sponsored by Sanofi.

Dr. Valeria Fantin, Head of Oncology Research at Sanofi, also commented in an email to Reuters Health. "Until now, it was widely believed that CD8 T cells were the key mediators of tumor cytotoxicity, while CD4 T cells primarily played an indirect role supporting tumor regression."

"Our recent work characterizing the mechanism of action of HER2/CD3xCD28 trispecific antibody provides new evidence on the ability of CD4 T cells to directly inhibit tumor cell growth via a previously unrecognized mechanism, i.e., by blocking tumor cell cycle progression at the G1/S phase and production of proinflammatory cytokines."

"The ability of this trispecific antibody to elicit a CD4 T cell-mediated anti-proliferative effect on tumor cells provides a novel mechanistic insight that may be further exploited for future cancer immunotherapy," Dr. Fantin said.

Dr. Nabel and colleagues note in their paper, "Effective antitumor immunity depends on the orchestration of potent T cell responses against malignancies. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined."

The current study does just that: it demonstrates that the trispecific antibody to HER2, CD3 and CD28 stimulated breast cancer regression of breast in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumor cell cycle progression.

In preclinical experiments in vitro and in a humanized mouse model, the team showed that, as expected, CD8 cells exhibited cytolysis in vitro but did not confer protection in the absence of CD4 cells in vivo, probably due to the lack of CD4 help required for their survival.

Unexpectedly, however, CD4 T cells alone inhibited tumor cell proliferation in vitro through G1/S cell cycle arrest. TNF also played a role in mediating antitumor activity that led to tumor regression in vivo, revealing previously unrecognized mechanisms of protection by this T cell subset.

Furthermore, when T cell subsets were transferred into the mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth.

RNA microarray analysis showed that CD4 T cells decreased tumor cell cycle progression and proliferation, and also increased pro-inflammatory signaling pathways.

"Collectively," the authors write, "the trispecific antibody to HER2 induced T cell-dependent tumor regression through direct antitumor and indirect pro-inflammatory/immune effects driven by CD4 T cells."

All authors are or were employees of Sanofi while engaged in this research project and many hold shares and/or stock options in the company. ModeX employees performed additional informatic evaluation of data, graphic illustration and writing at ModeX. Dr. Nabel was formerly chief scientific officer at Sanofi.

SOURCE: https://go.nature.com/3pNusQL  Nature, online February 23, 2022.

By Marilynn Larkin

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