Cell therapy - the process of introducing new cells into a patient in order to treat a disease – comes in many forms. Bone marrow transplants have been curing patients with refractory hematologic malignancies for decades, and the first cellular immunotherapy for cancer was approved by the FDA in April 2010. In the future, pluripotent and multipotent stem cell therapies promise potential cures for conditions ranging from heart disease and diabetes to neurological disorders and spinal cord injuries.
The problem for the field is that once the new cells have been administered to the patient, they are on their own – no longer under the control of the physician, but functioning instead within a highly complex biological system. This system presents multiple obstacles that confound the therapeutic effect of the new cells, and conversely, the new cells can be detrimental to the system – and harmful to the patient. Greater control over the function and fate of the cells is needed. Bellicum's core technology extends the physician's reach beyond the point at which the cells are administered, by incorporating application-specific controls inside the cells. These controls are operated remotely by a small molecule drug, which the physician can administer at any time, depending on the application:
Our DeCIDe™ therapeutic vaccines for cancer and infectious diseases give the physician control of CD40 and Toll-Like Receptor (TLR) signaling pathways in dendritic cells, thereby overriding feedback mechanisms in the immune system which would otherwise limit the effectiveness of the vaccine. The drug is administered 24 hours after the vaccine, when the vaccine cells have migrated to the patient's lymph nodes. First generation autologous DeCIDe™ vaccines are paving the way for a second generation that can be supplied off the shelf, without the need for autologous cell processing.
Our CaspaCIDe™ self destruct switch gives the physician control of caspase 9 signaling, which directly activates apoptosis (programmed cell death) in a context-specific manner, allowing preferential elimination of CaspaCIDe™ cell subpopulations. The drug is administered when necessary to eliminate transplanted cells should they become harmful, or after they have served their purpose.
How It Works
Protein-protein interactions are a key component of biological regulatory networks. Dimerization – naturally occurring physical interaction between two identical proteins - is an important subset of protein-protein interactions and is frequently involved in signal transduction.
Chemical Induction of Dimerization (CID) is an artificial system in which the signaling protein is re-engineered so that dimerization is induced not by upstream signaling proteins, but by a specially designed drug. The system comprises:
The CID Protein, a single, chimeric protein containing (1) a CID Binding Domain, which interacts with the drug; (2) a CID Signaling Domain, which is a form of the natural protein whose signaling function is being co-opted; and (3) other elements as needed for the specific application. At least two Binding Domain repeats are needed for signaling molecules (such as CD40) that are activated by trimerization. The CID protein is typically inserted into the target cell at the genetic level using standard molecular biology techniques such as viral transduction, and the genetic sequence can be designed so that the CID Protein is only expressed under certain specific conditions, if necessary, thereby providing a second level of control. Genetic modification is most readily accomplished in cells outside the body, so the first clinical applications (and proof of principle) are either in settings in which cells can be practicably collected from the patient and then readministered, or in cell transplantation settings.
The drug, AP1903, cross-links the CID Binding Domains, bringing the two CID Signaling Domains together in their natural protein-protein configuration, thereby triggering downstream signaling. When the drug is present, signaling is turned on, and in the absence of drug the signal is turned off; thus, the drug is referred to as the CID Master Key.
CID technology has been used to control a wide range of important biologic functions in cells and whole organisms, through the selection of appropriate CID Signaling Domains. At Bellicum we are using the technology to treat human disease.