Reimagining Solid Tumor Immunotherapy With SRC-3-Edited Tregs

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

For years, the cell therapy field has focused on one central objective, which is to engineer immune cells that are better equipped to recognize and destroy cancer. That strategy has transformed the treatment of several hematologic malignancies, but solid tumors have remained remarkably resistant. Their complex tumor microenvironment and ability to evade immune surveillance continue to frustrate developers pursuing the next breakthrough.

CoRegen believes the solution may not lie in building a stronger immune attack. Instead, the company is attempting to remove the biological mechanisms that prevent the immune system from recognizing tumors in the first place.

During Episode 135 of Cell & Gene The Podcast, I had pleasure of talking to Sonal Gupta, MD, PhD, Chief Medical Officer of CoRegen, when she explained how the company’s investigational cell therapy CRG-150 takes a fundamentally different approach by engineering regulatory T cells, (Tregs), rather than conventional effector T cells. She shared that the goal is not to create more aggressive immune cells, but to eliminate one of cancer’s primary defense mechanisms and allow the body’s own immune system to do what it was designed to do.

Looking Beyond Conventional Cell Therapy

Dr. Gupta’s interest in joining the CoRegen team began with the science itself. The company’s platform emerged from decades of research at Baylor College of Medicine studying steroid receptor coactivators, work led by the late Bert O’Malley, MD, widely recognized as a pioneer in molecular endocrinology.

Those discoveries eventually centered on Tregs, immune cells responsible for preventing excessive immune responses and autoimmune disease. While Tregs normally protect healthy tissue, tumors have learned to exploit them.

“Tregs act like the immune system’s brakes. They prevent the body from attacking its own cells. What cancer is very smart at doing is hijacking these checks and balances and using Tregs to prevent the immune system from recognizing cancer cells,” said Dr. Gupta.

Rather than engineering immune cells to attack tumors more aggressively, CoRegen modifies those Tregs by knocking out SRC-3, a master regulatory gene that influences nearly one thousand downstream genes involved in immune suppression.

“The beauty of knocking out SRC-3 in Tregs is that you’re not just working on one pathway. You’re working on multiple pathways,” said Dr. Gupta.

That distinction could prove significant. Many immunotherapies target individual immune checkpoints such as PD-1 or PDL-1. Tumors often adapt by activating alternative suppressive pathways, limiting long term effectiveness. By targeting SRC-3 upstream, CoRegen hopes to influence numerous immune checkpoint pathways simultaneously.

“What we’re doing is lifting that cloak of invisibility around solid tumors and allowing the body’s own immune system to kill the cancer cells,” she said.

A Different Way to Think About Solid Tumors

The approach represents more than another engineered cell therapy. It reflects a broader shift in thinking about how solid tumors should be treated. Instead of focusing exclusively on creating increasingly potent immune cells, CoRegen is attempting to reshape the tumor microenvironment itself. If successful, the company’s strategy could simplify treatment while potentially overcoming one of the biggest limitations facing current immunotherapies.

“As you know, cancer cells are very smart,” said Dr. Gupta. “Immune checkpoint inhibitors work for a few years, and then they stop working because cancer starts upregulating other immunosuppressive pathways.”

Because CRG-150 targets multiple downstream pathways through a single upstream mechanism, Dr. Gupta believes patients could ultimately benefit from a simpler therapeutic strategy. “This one-time therapy can work on multiple pathways. Instead of combinations of immune checkpoint modulators or sequential therapies, you have one treatment that can do that. It simplifies the treatment paradigm.”

Another notable aspect of the platform is that it does not require lymphodepletion before treatment. Unlike many autologous cell therapies that require depletion of the patient’s immune cells to make room for engineered cells, CoRegen’s therapy depends on preserving the patient’s immune system.

Translating Biology Into Clinical Evidence

As CRG-150 enters clinical evaluation, CoRegen’s priorities extend well beyond demonstrating safety. Dr. Gupta explained that understanding how the therapy behaves inside patients will be equally important. The company plans to evaluate cellular kinetics, tissue trafficking, persistence, circulating tumor DNA, circulating tumor cells, and additional biomarkers that may help explain treatment responses while refining future patient selection.

“We are interested in understanding the cellular kinetics of CRG-150, the trafficking, the persistence, early anti-tumor activity biomarkers, when we begin seeing responses, and how to identify the right patients,” said Dr. Gupta.

These translational questions could prove just as valuable as the initial efficacy data. Understanding why patients respond (and equally importantly why they do not) may help determine how broadly the platform can ultimately be applied across solid tumors.

Tune in to hear all the additional details, nuance, and actionable information during my full-length conversation with Dr. Gupta on Episode 135 of Cell & Gene: The Podcast.