BIRMINGHAM, Ala. – A clinical-stage biopharmaceutical company developing intellectual property licensed from the University of Alabama at Birmingham and two other institutions is testing its technology to treat glioblastoma multiforme, the most aggressive type of cancer that originates in the brain.
In a preclinical study published in the Nature portfolio journal Scientific Reports, researchers led by Larry Lamb, Ph.D., former associate professor of medicine at UAB, scientific co-founder and current chief scientific officer at IN8bio Inc., report that IN8bio’s proprietary Drug Resistant Immunotherapy (DRI) technology resulted in significant improvement of survival outcomes in a mouse model of human primary high-grade gliomas. A Phase I interventional clinical trial is being conducted at UAB of IN8bio’s INB-200, the DRI technology, in adults with newly diagnosed glioblastoma multiforme who are also receiving temozolomide (TMZ) chemotherapy. The clinical trial is led by Burt Nabors, M.D., professor in the UAB Department of Neurology.
DRI was developed based on two observations. First, when tumors are damaged by TMZ treatment, they develop stress-induced ligands on the cell surface. Normally, these signals would incite the immune watchdog gamma-delta T cells to recognize and kill the damaged tumor cells, through their ability to differentiate between healthy and diseased tissue. However, the second observation reveals a problem — TMZ therapy kills lymphatic immune cells, including the gamma-delta T cells. This hinders the immune system’s ability to leverage the TMZ-induced state of increased tumor vulnerability.
In DRI, peripheral blood mononuclear cells are collected from the mouse or patient. The gamma-delta T cells in that collection are purified, and then they are given a gene that makes them resistant to TMZ. Next, the drug-resistant gamma-delta T cells are expanded and reintroduced into the mouse or patient, concomitantly with TMZ chemotherapy. The resistant gamma-delta T cells should then be able to recognize the stress-induced ligands on the surface of TMZ-treated tumor cells and start to eliminate them.
In the Scientific Reports study, intracranial tumors were established in the mice using classical or mesenchymal patient-derived xenolines of glioblastoma.
In the UAB clinical trial, IN8bio earlier this year successfully completed treatment of the first cohort of three newly diagnosed glioblastoma patients, using its genetically modified gamma-delta T cell candidate for treating the solid tumors, says William Ho, CEO and co-founder of IN8bio. The gamma-delta T cell treatment, called INB-200, was generally well tolerated by the three patients, with no observed infusion reactions, cytokine release syndrome, neurotoxicity or dose limiting toxicities, the company reported at the 2021 American Society of Clinical Oncology Annual Meeting. All three patients exceeded their expected median progression-free survival based on their respective age and O-6-methylguanine-DNA methyltransferase status. Additional data from this Phase I trial is expected later this year. The second cohort of patients will receive multiple repeat doses of the DRI gamma-delta T cells.
IN8bio is the first company to advance genetically modified gamma-delta T cells into the clinic. The company is located in New York City, while its primary scientific operations remain in Birmingham, Alabama.
This summer, IN8bio completed an initial public offering of 4 million shares of common stock at an offering price of $10 per share. Net proceeds for IN8bio after expenses were $32.6 million.
This coming year, the IN8bio research lab expects to graduate from Birmingham’s Innovation Depot — a business incubator — into a new, 10,440-square-foot IN8bio lab and office space in the Martin Biscuit building at Birmingham’s Pepper Place, Second Avenue South and 29th Street, which is currently under development.
Ho says the IN8bio DRI approach targets an evolutionarily conserved pathway, the DNA Damage Response, that has potential applicability across a broad range of solid and liquid tumors for which chemotherapy remains the mainstay of treatment.
“This includes potentially combining INB-200 with other approaches such as checkpoint inhibitors and other targeted therapies in orthogonal combinations to maximize the tumor impact,” Ho said. “Combined with our expertise in genetically engineering these cells ex-vivo, we look forward to continuing to develop our deep pipeline of gamma-delta T cell-based therapies for cancer.”
Co-authors with Lamb for the Scientific Reports study, “A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas,” are Larisa Pereboeva and Samantha Youngblood, UAB Department of Medicine, Division of Hematology and Oncology; G. Yancey Gillespie, James M. Markert and Catherine Langford, UAB Department of Neurosurgery; L. Burton Nabors, UAB Department of Neurology; and Anindya Dasgupta and H. Trent Spencer, Emory University Department of Pediatrics, Atlanta, Georgia.
The UAB departments of Medicine, Neurology and Neurosurgery are part of the UAB Marnix E. Heersink School of Medicine. At UAB, Nabors holds the William Austin Brown Endowed Professorship in the O’Neal Comprehensive Cancer Center.
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A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas
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