Lab studies explain how new cancer drug works as it enters patient testing

LA JOLLA, CA-For some people, cancer immunotherapies are life-changing. These treatments can turn the body's own immune system against a tumor, either eliminating it or shrinking it enough to make surgery possible. But these therapies don't work for everyone, can gradually stop working or can come with a host of side effects, including severe inflammation.

A new experimental therapy aims to change that. Scripps Research scientists are testing SAR'877, a bispecific molecule designed to restore immune cells' ability to fight cancer. The results of preclinical work are encouraging, and an ongoing phase 1/2 clinical trial is showing early signs of effectiveness even in those who have stopped responding to other immunotherapies. Now, new research published on April 30, 2026, in JCI Insight helps explain why: The drug revives exhausted T cells more precisely than existing approaches without triggering the dangerous inflammation that has limited similar drugs in the past.

What we showed is that you can deliver the immune-stimulating signal to the cells that need it most, says John Teijaro, a professor at Scripps Research and co-senior author of the study. This rescues their function more effectively than anything else we've seen in this setting.

The new molecule was designed to fight T cell exhaustion : a drop in activity that happens when immune cells face a chronic threat, such as a tumor or long-term infection. While that exhaustion evolved partly to protect the body's tissues from an overactive immune response, in cases of cancer, it allows tumors to grow unchecked.

Therapies that have been developed over the past few decades aim to stop this exhaustion. Checkpoint inhibitors like pembrolizumab work by removing a molecular brake called PD-1 that turns off the immune system's T cells. On the other hand, cytokines like interleukin-15 (IL-15) can rev up immune cell activity-but this can lead to severe inflammation.

As a bispecific molecule, SAR'877 takes a combined approach. It uses an antibody that targets PD-1 so that it binds directly to T cells and releases their brake. But attached to the antibody is also a purposefully weakened version of the cytokine IL-15. The weakened IL-15 has an effect only on nearby cells. And because it's tethered to the PD-1 antibody, this cytokine primarily acts on exhausted T cells.

To test whether the approach worked, Teijaro's team turned to a model of chronic viral infection originally developed decades earlier in the lab of Scripps Research professor Michael Oldstone. This model has become one of immunology's most trusted tools for testing whether a drug can revive immune function.

Using a version of SAR'877 adapted for mice, Teijaro's lab showed that the drug cleared the virus from the blood and kidneys more effectively than a PD-1-blocking antibody alone, untargeted IL-15 alone or both drugs given at once. Detailed analysis of immune cells revealed that SAR'877 selectively activated only certain groups of T cells already primed to respond to the virus rather than broadly stimulating all immune cells.

One of the most unexpected findings from these experiments involved CD4 helper T cells, which support other immune cells rather than directly attacking cancer cells. While cancer immunotherapy has largely focused on revving up CD8 killer T cells, CD4 cells appeared to play an unanticipated central role in the effectiveness of SAR'877.

We were surprised by the magnitude of the CD4 response since we didn't expect IL-15 to do much for those cells, says Teijaro. But we saw a dramatic increase in CD4 activity, and when we removed those cells from mice, the drug's benefit largely disappeared.

That observation suggests that more research is needed on how these overlooked cells could help turn up immune activity against viruses and cancers.

The researchers then tested the drug's effect on 12 different mouse tumor models. The drug shrank tumors in all 12 models and completely eliminated tumors in some mice, including more than two-thirds of those with liver cancer and breast cancer.

Teijaro's lab is now investigating whether combining SAR'877 with anti-inflammatory drugs could further reduce side effects and allow for higher, more effective doses, potentially allowing more patients to benefit.

About SAR445877 (abbreviated as SAR'877/formerly KD050): SAR'877 is an investigational anti-PD-1/IL-15 fusion protein developed by the biopharmaceutical company Sanofi. Preclinical trials have been conducted by Sanofi and Scripps Research. Sanofi is currently evaluating SAR'877 in an ongoing phase 1/2 clinical trial in adults with advanced inoperable solid or metastatic tumors. Donald Shaffer, head of the Immunomodulation and Cell Reprogramming Cluster at Sanofi, is co-senior author of the study.

In addition to Teijaro and Shaffer, authors of the study, PD-1-targeted IL-15 mutein activates CD8 and CD4 T cells in infection and cancer, include Isaraphorn Pratumchai, Jaroslav Zak, Maheeka Bimal and Kristi L. Marquardt of Scripps Research; and Marie Bernardo, Julien Tessier, Joon Sang Lee, AHyun Choi, Anthony M. Byers, Mikielia Devonish, Roberto Carrio, Dan Lu, Stella Martomo, Jeegar Patel, Yu-an Zhang, Ingeborg M. Langohr, Virna Cortez-Retamozo, Dinesh S. Bangari, Angela Hadjipanayis, Xiangming Li and Valeria R. Fantin of Sanofi.

This work was supported by funding from Sanofi, Kadmon Corporation, the National Institutes of Health (5R01AI164744, K22CA292568), start-up funds from The University of Utah, and the Huntsman Cancer Foundation.

LINK:	https://www.scripps.edu/news-events/news/20260618-teijaro-jci-insight/...
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