WUGEN’s UCART7 Built on Fratricide-Resistant & Allo-Tolerant CART-T Platform Targeting T-Cell Malignancies

WUGEN’sUCART7 Built on Fratricide-Resistant & Allo-Tolerant CART-T Platform targeting T-Cell Malignancies

WUGEN Inc. was launched in 2018 to develop and commercialize a novel CAR-T therapy platform including “off-the-shelf” fratricide-resistant CAR-T cell therapy for T-cell malignancies. By securing an exclusive license agreement from Washington University in St. Louis, the startup possess exclusive rights to “UCART7” from the laboratory of the noted bone marrow specialist and oncologist John F. DiPersio at Washington University in St. Louis. They will initially target UCART7 against blood cancer therapies.

Too Many Deaths

Despite a number of therapeutic advances targeting hematologic cancers over the last decade, patients still relapse hence the ongoing march for novel therapeutic approaches.  And the statistics sum up the clear and present danger.  A new blood cancer patient occurs every three minutes according to the Leukemia Research Foundation. At least 175,000 new cases are expected in the United States and in total, blood cancers represent 10 percent of all new cancer cases diagnosed. At least 68, 000 patients are expected to die from these cancers in the next 12 months.  WUGEN will target some of these cancers with a powerful, modified CART-T cell platform licensed from Washington University in St. Louis

What is CAR-T Therapy?

CAR-T therapy represents the most recent immunologic approach to fighting certain cancers—they can be quite effective at selectively killing cancer cells while also overcoming conventional drug-related resistance mechanisms.

How does it Work?

If the immune system is working properly, the immune system wants to kill cancer cells. It creates an army of T cells to patrol the body for signs of infection and other diseases. The T cell inspects suspicious cells, and immediately attack when they find abnormal cells—all while limiting the damage to healthy cells.  T cells have protein receptors on their surface, and these claw like constructs attach themselves to antigens (protein fragments found on the surface of all cells). When a receptor attaches to an abnormal antigen, like one found only on a diseased cell, the T cell turns on and releases toxic chemicals that damage the abnormal cell and recruit other immune helpers to the area.

However, cancer cells seek to survive and can develop ways to fool the immune system by:

  • Disguising themselves as healthy cells
  • Producing so many antigens on their surface that the T cells are confounded diminishing its ability to sustain an effective attack. 
  • Deception: finding ways to turn off the immune response against the diseased cells

Patients Human System Trained to Kill the Cancer

CART T-cell therapy represents a way to see through the deception. Thousands of a patients T cells are collected in a process similar to blood donation. Then, using a modified and inactive virus, an artificial gene for a specific receptor is inserted into these collected cells, effectively reprogramming the cells so they now produce special receptors called chimeric antigen receptors (CARS) on their surface—effectively transforming them to CART-T cells.

After the CAR-T cells multiply in the lab, they are injected into the patient. The receptors on the CAR-T cells help them find and destroy cancer cells throughout the patients body.

Unlike most cancer treatments, CAR-T cell therapy typically needs to be administered only once, because the CAR-T cells multiply in the patient’s body. With their anti-cancer effects persisting and potentially even increasing over time.

CAR-T Challenges with T-Cell Malignancies

T cell malignancies are represented by a group of hematologic cancers  (e.g. leukemia, lymphoma, multiple myeloma) involving a high rate of relapse and death. Patients have little recourse if there is relapse. WUGEN founder Matthew Cooper, a protégé of Dr. DiPersio at Washington University as well as DiPersio himself published a study articulating what would become the foundation of the WUGEN platform—UCART7. They embarked on this important research mission because there are no CAR-T cell therapies for application to T-cell malignancies in the clinic. CAR-T and T-cell malignancies share the target proteins—hence the resulting fratricide. 

Led by a quest to overcome “CART-T fratricide” and autologous T cell harvesting challenges, the University of Washington, St. Louis-led team utilized CRISPR/Cas9 gene editing to delete expression of CD7 and the T-cell receptor alpha chain on CAR T cells in a quest to prevent fratricide and graft-versus-host disease (GvHD).  With the UCART7-based strategy, researchers can now further develop the “fratricide resistant and allo-tolerant” early-stage asset to drive the ultimate goal of treating relapsed or refractory T-ALL and non-Hodgkin’s T cell lymphoma without the need for autologous T cells.

Demonstrated Efficacy

Demonstrating an efficacy against T-ALL cell lines and primary T-ALL  less the inducement of xenogeneic GvHD, UCART7 doesn’t require autologous T cells (e.g. cells obtained from the same individual).

Getting Started

WUGEN, based in St. Louis, MO has already opened up offices in San Francisco and San Diego. Leadership represents a key ingredient for any successful biotech venture and WUGEN has done well in this endeavor. In addition to founder Matthew Cooper, the company recruited biotech and venture capital (RiverVest Ventures) savvy Dr. John McKearn who brings three decades of drug discovery, development and investor experience to bear for the venture to position and prepare for growth. McKearn is respected in academic and business circles, having co-authored more than 70 published, peer-reviewed scientific papers not to mention holding over 50 patents and many patent applications focusing on cancer treatment and inflammatory disease.  McKearn brought over Karen Gheesling-Mullis as VP R&D Project Management from RiverVest Ventures as well. A really smart move as Ms. Gheesling-Mullis brings truly serious drug development and regulatory submission pedigree spending over 20 years at Pharmacia and then Pfizer. Also on board is their VP of R&D Dr. Ayman Kabakibi whose path has crossed with McKearn at past biotech ventures.

Inflexion Point

And in April of this year as the nascent venture approached a critical inflexion point, the leadership expanded to include Mark Lewis, PhD, Vice President of Finance and Business Operations, signaling to the market their intentions of formalizing business infrastructure and raising institutional capital.

Lead Research/Investigators

John F. DiPersio, MD, PhD

Matthew Cooper, PhD

Call to Action: Keep an eye on WUGEN as they appear to have a sophisticated platform to address current deficiencies of CAR-T cell therapies in T-cell based malignancies (e.g. those such as blood cancers). TrialSite News has included UCART7 in its tracker for future updates.