Mustang Bio said today it plans to develop CRISPR/Cas9-enhanced chimeric antigen receptor engineered T-cell (CAR-T) therapies for cancer through a license from Harvard University and a research collaboration agreement with Beth Israel Deaconess Medical Center (BIDMC).

The value of both agreements was not disclosed. CRISPR stands for clustered regularly interspaced short palindromic repeats.

Mustang Bio, a subsidiary of Fortress Biotech, said that technologies related to the development of off-the-shelf CAR-T, as well as CRISPR/Cas9 gene-editing platforms, will be used in combination with Mustang’s CAR-T cell therapies toward treatments for hematologic malignancies and solid tumors under the company’s licensing agreement with Harvard’s Office of Technology Development.

Mustang’s pipeline includes six CAR-T therapy candidates toward the development of CRISPR-enhanced CAR-T therapies targeting hematologic malignancies and solid tumor cancers. Furthest along are two Phase I candidates—Mustang’s lead CAR-T therapy, the glioblastoma multiforme treatment MB-101, and MB-102, which is being developed for both acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm.

MB-101 targets interleukin-13 receptor subunit alpha-2 (IL-13Rα2), which according to Mustang has limited expression in normal tissue but is overexpressed on the surface of greater than 50% of glioblastomas. The company’s CAR T cells are designed to express membrane-tethered IL-13 receptor ligand with high affinity for IL-13Rα2 and reduced binding to IL-13Rα1 in order to reduce healthy tissue targeting.

MB-102 targets CD123, a subunit of the heterodimeric interleukin-3 receptor (IL-3R) that is widely expressed on human hematologic malignancies, including AML. Mustang says it is investigating CD123 as a target for adoptive cellular immunotherapy in AML, since high CD123 expression is associated with enhanced AML blast proliferation, increased resistance of blasts to apoptosis, and poor clinical prognosis.

First Foray Intro CRISPR

According to Mustang Bio, the collaborations mark Mustang’s first foray into CRISPR—though the company has also teamed up on CAR-T R&D with the City of Hope as well as the Fred Hutchinson Cancer Research Center.

On December 11, the City of Hope will present positive initial Phase I data on Mustang’s MB-102 in AML and blastic plasmacytoid dendritic cell neoplasm during an oral session at the American Society of Hematology (ASH) Annual Meeting in Atlanta. Last year, Mustang’s lead CAR-T therapy MB-101 generated a complete response in a glioblastoma patient, according to a study published in The New England Journal of Medicine).

The technologies licensed from Harvard were developed in the lab of Chad Cowan, Ph.D., a principal investigator at the Harvard Stem Cell Institute and an associate professor in Harvard’s Department of Stem Cell and Regenerative Biology.

In 2014, Dr. Cowan and Harvard colleague Derrick Rossi, Ph.D., published a study in the journal Cell Stem Cell detailing the use of CRISPR/Cas9 to block the human immunodeficiency virus (HIV) from invading and destroying the immune systems of patients. Using CRISPR/Cas, teams led by Drs. Cowan and Rossi knocked the CCR5 receptor out of blood stem cells, showing that they could give rise to differentiated blood cells without CCR5. Such gene-edited stem cells, they said, could be introduced into HIV patients via bone marrow transplantation to give rise to HIV-resistant immune systems.

Under a separate collaboration agreement, Dr. Cowan will lead preclinical research programs at BIDMC, where he is an associate professor of medicine in the Division of Cardiovascular Medicine. His lab’s research has been focused on molecular underpinnings of metabolic diseases that include coronary artery disease and type 2 diabetes.

“Mustang is committed to advancing the development of innovative immunotherapies for the treatment of cancer. CRISPR/Cas9’s demonstrated precision may enable us to more effectively and accurately deliver our CAR-T therapies and to enhance the tumor killing ability and persistence of the CAR T cells in the patient’s body, which could lead to safer and more potent treatments,” Mustang Bio president and CEO Manuel Litchman, M.D., said in a statement.

Both of the CAR-T therapies approved by the FDA earlier this year are designed to treat forms of cancer: Novartis on August 30 won the FDA’s first CAR-T therapy approval for Kymriah™ (tisagenlecleucel), followed in October by an FDA nod for Yescarta™ (axicabtagene ciloleucel) by Gilead Sciences’ Kite subsidiary.

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