Obsidian advances destabilizing domains
CAMBRIDGE, Mass.—Targeted toward unlocking the full potential of cell therapy in oncology, biotech Obsidian Therapeutics Inc. has presented preclinical data on its next-generation CAR-T platform at two separate conferences in February and April. The presentation included initial in-vivo proof-of-concept data demonstrating Obsidian’s strategy for pharmacologic control of cell therapy by employing destabilizing domains (DDs)—small, fully human protein domains that confer conditional stability to a fused payload protein.
Steven Shamah, Obsidian senior vice president and head of research, who presented the poster at the Keystone (Colorado) Symposium on Emerging Cellular Therapies in February, states he was “excited to present data on our platform in our first series of applications to the scientific community, as we have seen precise and robust control of gene expression using our technology in vitro and in vivo.”
“We are also sharing our first data on fully human approaches to engineering immune cells with pharmacologic operating systems,” Shamah says. “These data are foundational to our goal of putting control of CAR-T and other cell therapies in the hands of clinicians and patients, thereby enabling safer, more effective cancer treatments.”
Dr. Tariq Kassum, chief operating officer and head of corporate development at Obsidian, says the company is working on many projects, including a CAR-T cell that secretes powerful immunostimulatory cytokines only upon activation by a specific small molecule (i.e., the patient taking a specific pill at a specific time); a CAR-T cell whose proliferation can be controlled independently of antigen stimulation to ensure persistence of therapeutic cells and potentially to reduce the need for toxic preconditioning regimens; and a CAR-T cell which is active only in the presence of a specific small molecule and therefore can be turned on and off depending on the patient’s needs.
According to Kassum, “All engineered cellular therapies contain transgenes, which are genes inserted into the DNA of cells via a series of genetic engineering techniques.”
“In the case of CAR-T, a transgene may be the chimeric antigen receptor (the CAR), itself, or a cytokine packaged alongside the CAR,” he reports. “In current CAR-T therapies, the expression of these transgenes is uncontrolled, and therefore, their impact on the activity of the CAR-T cell is uncontrolled. Our technology allows for the expression of these transgenes to be tightly controlled via the use of small molecules.”
“An example of enhanced efficacy might be the aforementioned use of an immunostimulatory cytokine to enhance the antitumor activity of a CAR-T cell directed towards a solid tumor,” Kassum says. “An example of a more favorable safety profile may be a CAR-T cell that can be turned off after a tumor has been fully cleared.” He adds that the company believes that “small-molecule control represents a game-changing development in cellular therapies.”
“Our long-term goal is to use our technology platform to unlock the full potential of cell therapy in oncology,” he explains. “This includes CAR-T but also other cells of the adaptive and innate immune system that have potential antitumor activity. “
Kassum tells DDNews that moving forward, the company plans to share more of its results at various conferences this year and to continue advancing programs toward the clinic, in addition to looking into possible collaborations.
The technological foundation of Obsidian’s approach is the use of DDs, pioneered by Obsidian’s scientific founder, Thomas Wandless.
“While existing cell therapies in oncology have shown substantial efficacy, the range of applications is still narrow, and significant toxicities limit broader adoption,” said Michael Gilman, CEO of Obsidian. “By equipping cells with new tumor-fighting powers, and by putting dynamic dosing control in the hands of the treating physician, we believe we can improve safety, efficacy and durability of CAR-T therapies. Moreover, we think Obsidian’s pharmacologic operating systems will enable us to build entirely new classes of living medicines.”
Obsidian has licensed technology relating to DDs from Stanford University and has recently launched a research collaboration with Dr. Crystal Mackall of the Stanford School of Medicine, focusing on the use of DDs to regulate CAR activity in CAR-T products.
Building on the Keystone conference, lead author Celeste Richardson, vice president of Cell Therapy at Obsidian, will present a poster entitled “Enhancing Adoptive Cell Therapies Through Exogenous Regulation: Destabilizing Domains For Next-Generation CAR-T” at the 2018 American Association for Cancer Research Annual Meeting in Chicago.
“In the absence of a specific small-molecule ligand, the fusion protein is rapidly degraded, whereas in the presence of the ligand, the fusion protein becomes stable and functional,” Richardson stated. “Obsidian uses this approach to equip engineered cells with controllable functions that can be precisely tuned by the administration of non-immunosuppressive, small-molecule medicines that are readily available and dispensed by the treating physician.”