Cell BT is committed to the development of CAR T-cells for the treatment of hematologic malignancies, solid tumors, and is exploring non-oncologic applications. Unlike current CAR T-cell technologies, Cell BT pioneered a novel co-stimulatory/signaling pathway called DAP 10/DAP 12 to give our CAR T-cells several unique advantages. As a critical component of the CAR T-cell construct, the intracellular signaling domain is responsible for the proliferation, cytotoxicity, persistence, and cytokine release characteristics of CAR.
DAP 10/DAP 12 alters the above characteristics in the following manner:
Cell BT has identified a new target for hematologic malignancies called HuLym-1 as our current lead program. Unlike CD19, CD20, CD22 currently approved or in clinical development, HuLym-1 targets the HLA-DR molecule expressed on the surface of B cell malignancies. The Lym-1 antigen when targeted does not down-regulate unlike conventional targets, thereby preventing the re-emergence of antigen negative tumors and clinical failure. Other advantages include:
Using a stringent metastatic lymphoma model (Raji) and lower doses than conventional use (2M cells per mouse), in vivo studies show complete tumor clearance out to day 57 of the huLym-1 DAP. Even at 5M cells per dose, the CD19 constructs did not show equivalent results.
Ovarian Cancer is a major unmet medical need, accounting for the highest mortality rate among women with gynecologic tumors. Currently, there is only one front-line treatment which is responsible for a 17% survival rate at 5 years which has not improved in several decades.
Cell BT will initially focus on ovarian cancer for which the company has identified 5 novel targets, a subset of which will be used to construct CAR T-cells to eradicate tumor. This approach addresses the antigen heterogeneity concerns seen in solid tumors. Ovarian cancer was chosen as the focus due to its intra-abdominal location facilitating direct intraperitoneal administration of CAR T-cell to the tumor unlike other solid cancers located in deep organs and tissues. This is important because CAR T-cells require rapid binding to antigen to prevent inactivation, a problem not confronted in bloodborne hematopoietic malignancies. As shown below, recent data from our laboratories has shown that after intravenous inoculation of T-cells, the therapeutic CAR cells become trapped in the lung for several hours before being sequestered in the liver and spleen for 2-3 days. Upon release from these organs, the CAR T-cells re-enter the patient’s circulation and only then become available to the tumor microenvironment. This long delay contributes to the inactivation of the CAR T-cells and is one of the major obstacles of cell therapy against solid tumors.
Real time PET/MRI images of CAR T-cells after intravenous administration in tumor- bearing mice demonstrating early trapping of cells in the lungs followed by dramatic uptake in the liver and spleen for up to 3 days, causing poor uptake in tumor.