Almost 15 years ago at the National Cancer Institute, Dr. Rosenberg and his colleagues found that administration of high dose Interleukin-2 ("IL-2") activates the innate immune system. Through binding to the IL-2 receptor, IL-2 activates Natural Killer (NK) cells to attack cancer cells. Activated NK cells have since been studied further by Professor Mark Lowdell at the Royal Free Hospital in London, and others, since the use of IL-2 therapy is limited because of its side effects, which include severe life-threatening infusion reactions and induction of autoimmune disease.
The importance of NK cells in the host system’s defense against cancer was recognized by Professor Mark Lowdell when he noted that patients who could mount an immune response to their Acute Myeloid Leukemia (AML) became long-term survivors after chemotherapy (see Figure 1). Lowdell et al determined that activated NK cells were the key to eliminating AML cells and that NK cells require two signals to kill a tumor cell – a priming signal followed by a triggering signal. NK-sensitive tumor cells provide both signals and the cancer is eliminated. NK-resistant tumors are not destroyed since they only provide one signal, the "trigger", but not the “priming” one. The “priming signal" can be provided by either cytokines, such as high dose IL-2 or IL-15, or by CNDO-109. In contrast to IL-2 or IL-15, NK cells activated by CNDO-109 (also referred to as Tumor Activated NK cells or TaNK cells) retain their activated state after cryopreservation and thawing, and do not trigger the side effects associated with IL-2 or IL-15. This allows commercialization of the process, since the NK cells can be activated with CNDO-109 and prepared at a central manufacturing facility under GMP conditions and shipped to the clinical center as a cryopreserved, patient-specific dose, ready for infusion. Thus, some of the logistics and timing pressures associated with other cell therapy products do not exist with CNDO-109-activated NK cells.
Although AML is the prototype tumor investigated using CNDO-109 activated NK cells, these activated NK cells are expected to be active against other cancer types. This is based on in vitro studies of CNDO-109-activated NK cells conducted by Professor Lowdell at the Royal Free Hospital in London using human specimens of prostrate, breast and ovarian cancer. Coronado also expects CNDO-109 to be active against tumors that have been successfully treated by high dose IL-2 therapy such as renal cell carcinoma and melanoma.
Figure 1: Long-term survivors of AML () developed leukemic cytotoxic activity ("LCA") > 12.5% to their presentation disease. Patients with LCA < 12.5% () had a worse outcome. The cells responsible for LCA are NK cells. "CR" means complete response.