The U.S. Food and Drug Administration has cleared CoRegen’s Investigational New Drug (IND) application for CRG-150, allowing the company to initiate a first-in-human Phase I/IIa clinical trial of its autologous CRISPR-engineered regulatory T (Treg) cell therapy in patients with advanced solid tumors. The study will evaluate safety and preliminary efficacy in metastatic triple-negative breast cancer (TNBC), metastatic HR-positive/HER2-negative breast cancer, and metastatic prostate cancer at leading academic cancer centers.
The clearance advances into the clinic an immunotherapy strategy that differs fundamentally from existing cell therapies. Rather than engineering cytotoxic lymphocytes to recognize tumor antigens, CRG-150 uses CRISPR gene editing to reprogram regulatory T cells (Tregs), with the goal of reversing the immunosuppressive tumor microenvironment and restoring endogenous antitumor immunity.
The approach emerged from more than three decades of research at Baylor College of Medicine on steroid receptor coactivator-3 (SRC-3), a transcriptional regulator that sits upstream of numerous immune signaling pathways. According to CoRegen, CRISPR-mediated disruption of SRC-3 fundamentally alters Treg biology, removing one of the mechanisms tumors use to evade immune surveillance.
“What was fantastic about this discovery was that it allowed us to engineer a regulatory T cell to knock out SRC-3,” said Suneet Varma, chairman of the board of CoRegen. “By knocking out SRC-3, we have essentially removed the cloak of invisibility that cancer was hiding behind. Once you remove that cloak of invisibility, the tumor is recognized by the immune system, and CD4-positive T cells, CD8-positive T cells, and natural killer cells flood the tumor.”
The company reports that preclinical studies in multiple murine solid tumor models demonstrated durable tumor eradication following treatment with SRC-3-disrupted regulatory T cells. Investigators subsequently rechallenged animals with the original tumor and observed rapid elimination consistent with immunologic memory. In additional experiments, mice challenged with different tumor types, including pancreatic cancer after initial treatment of triple-negative breast cancer, also mounted antitumor responses, suggesting that the mechanism may not depend on a single tumor antigen or histology. Those findings now await validation in humans.
“This is a new, never-been-done-before approach to immuno-oncology,” Varma said. “We’ve cured many, many mice. But we need to now treat and cure humans. There’s a lot of work between here and there.”
Reversing the biology of immune suppression
Since the identification of FOXP3 as the master transcription factor governing regulatory T-cell development more than two decades ago, Tregs have become recognized as essential regulators of immune homeostasis. By suppressing excessive immune activation, they prevent autoimmunity and maintain peripheral tolerance. The same biology, however, is frequently co-opted by cancer. Many solid tumors recruit or expand Tregs within the tumor microenvironment, where they suppress cytotoxic T lymphocytes and natural killer (NK) cells, limiting endogenous antitumor immunity and contributing to resistance against immunotherapy.
That dual biology has made Tregs both attractive and challenging therapeutic targets. Most clinical development in the field has focused on harnessing their suppressive properties. Multiple companies are developing autologous, allogeneic, and CAR-engineered Treg therapies for autoimmune diseases, inflammatory disorders, and transplantation, where augmenting immune tolerance is desirable. By contrast, relatively few cell therapy programs have sought to manipulate Tregs in oncology because selectively disrupting their immunosuppressive function without broadly compromising immune regulation has proven difficult.
For example, last week, the FDA approved Orca Bio’s Tregzi, an unmodified donor-derived cell therapy designed as an alternative to traditional matched-donor stem cell transplantation for blood cancer patients. The therapy uses three purified donor cell populations—including regulatory T cells, conventional T cells, and hematopoietic stem and progenitor cells—selected to preserve immune control while supporting blood system recovery. By leveraging naturally occurring immune-regulating cells, Tregzi aims to reduce complications such as chronic graft-versus-host disease, marking a key milestone for the broader effort to harness Tregs as a next-generation approach in cancer treatment.
CoRegen’s strategy is to alter Treg biology directly through CRISPR-mediated disruption of SRC-3, a steroid receptor coactivator that functions as a transcriptional regulator upstream of numerous immune signaling pathways. Sonal Gupta, MD, PhD, chief medical officer of CoRegen, explained that SRC-3 occupies a regulatory position upstream of numerous genes involved in immune signaling, including pathways associated with immune checkpoint regulation. “What we do is use CRISPR editing to knock out the SRC-3 gene,” Gupta told Inside Precision Medicine. “That changes the biology of regulatory T cells.”
She compares unmodified Tregs to “bouncers at a nightclub,” preventing immune cells from entering tumors. Following gene editing, the cells no longer maintain that suppressive phenotype, allowing endogenous immune cells to infiltrate the tumor microenvironment. Unlike checkpoint inhibitors, which interrupt individual inhibitory pathways such as PD-1/PD-L1 or CTLA-4, the company hypothesizes that reprogramming Tregs through SRC-3 disruption may produce broader remodeling of tumor immune suppression.
The therapy is also differentiated from CAR T cells. “CAR T cells directly kill the cancer cells by targeting something on the cancer cell, and, in our case, we genetically modify regulatory T cells,” said Gupta. “Regulatory T cells play a very important role in the tumor microenvironment. They basically do not allow the endogenous immune system to kill the cancer. When we gene-modify them the way we do, they allow the endogenous immune system to enter and kill the cancer cells.”
From laboratory discovery to first-in-human testing
The origins of CRG-150 trace back more than three decades to the laboratory of the late Bert W. O’Malley, MD, at Baylor College of Medicine. O’Malley, widely regarded as one of the founders of molecular endocrinology, spent much of his career studying steroid receptor coactivators (SRCs), proteins that regulate large transcriptional networks controlling cellular behavior.
According to Varma, bringing that body of work together with advances in regulatory T-cell biology transformed a long-running academic research program into a therapeutic platform. “Our goal was to take this tremendous body of evidence and receptor biology and move what was in an academic laboratory into a biotech environment where we could demonstrate the potential impact in patients,” he said.
CRG-150 begins with collection of autologous peripheral blood cells rather than bone marrow. Regulatory T cells are isolated, edited using CRISPR to disrupt SRC-3, expanded ex vivo, and then reinfused into the patient.
Gupta believes beginning with an autologous product provides the strongest opportunity to demonstrate proof of concept. “Autologous really is the gold standard,” she said. “Because the cells come from the patient, they’ve already been exposed to the tumor antigens.”
Another potentially important distinction is the absence of lymphodepleting chemotherapy prior to treatment. Current CAR T therapies typically require depletion of endogenous lymphocytes before infusion, adding toxicity and limiting outpatient administration. “Unlike CAR T cells, these patients do not have to undergo depletion and have their immune system knocked out before receiving therapy,” Gupta said. “There is potential for this therapy to actually be outpatient.”
Varma noted that because the therapy relies on a standard blood collection rather than more invasive procedures, the collection process should also be broadly accessible. “Not all autologous therapies are created equal,” he said. “We wanted the process to be as simple as possible and the vein-to-vein time as manageable as possible.”
The company has partnered with Lonza under a multi-year manufacturing agreement to support clinical production. Varma said manufacturing consistency formed an important component of the IND package reviewed by the FDA. “The FDA concurred that we had achieved what we needed to achieve to proceed,” he said.
Gupta added that recent advances in Treg manufacturing have substantially improved the feasibility of clinical development. “Being able to expand regulatory T cells to generate sufficient doses for patients has been a very important advance,” she said.
Testing a new therapeutic paradigm
Historically, novel oncology therapies enter clinical testing in heavily pretreated patients before moving into earlier treatment settings if efficacy is demonstrated. Varma believes CRG-150 may ultimately challenge that paradigm because its mechanism depends on mobilizing endogenous immunity. “We would really benefit from a healthier immune system, since that’s what we’re activating,” he said. “Scientifically, it suggests the therapy should ultimately be used earlier.”
The initial study, however, appropriately begins in advanced disease. The Phase I/IIa trial will use a dose-escalation and cohort-expansion design. Phase I will establish safety and identify the recommended Phase II dose, followed by expansion cohorts evaluating preliminary efficacy in metastatic TNBC, HR-positive/HER2-negative breast cancer, and metastatic prostate cancer. According to Gupta, the long-term objective is to generate sufficient data to support discussions with the FDA regarding a subsequent registration study.
The company reports strong interest from academic investigators participating in the study. “We’ve had more interest from clinical sites than we can currently support,” Varma said.
The FDA clearance positions CoRegen within a rapidly evolving landscape of engineered immune cell therapies. Most current Treg programs are directed toward restoring immune tolerance in autoimmune disease or transplantation, whereas oncology developers have largely focused on engineered effector cells such as CAR T cells, T-cell receptor-engineered T cells, and tumor-infiltrating lymphocytes. CRG-150 occupies a distinct niche by seeking to reprogram, rather than expand or eliminate, regulatory T cells within the tumor microenvironment.
The company is already exploring future iterations of the platform, including allogeneic products and in vivo approaches, as well as expansion into additional tumor types including pancreatic cancer, glioblastoma, melanoma, colorectal cancer, and non-small cell lung cancer. For now, however, the focus is on determining whether a strategy that has generated durable immune responses across multiple preclinical solid tumor models can safely translate into patients. The Phase I/IIa trial will provide the first opportunity to answer that question.
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