For over a century, attenuated bacteria have been studied as a potential immunotherapy to treat cancer. In particular, Listeria monocytogenes have proven to be particularly adept at inducing powerful antigen-specific immunity, specifically the priming of antigen-specific CD4+ T helper and cytolytic CD8+ T cells.
Aduro’s Live, Attenuated Double-Deleted Listeria (LADD®) platform is based on proprietary attenuated strains of Listeria monocytogenes engineered to express tumor antigens (e.g. foreign substances) to induce specific and targeted immune responses. Deletion of two virulence genes, which control the infection of hepatocytes and bacterial spread, enables the safe administration of the Listeria without compromising its therapeutic benefit.
The attenuated strain of Listeria is then modified with new genetic material to encode and express specific tumor antigens. The engineered Listeria is designed to activate the patient’s antigen presenting cells (APCs), including dendritic cells, the primary initiators of both the innate and adaptive immune responses.
LADD has important benefits as an immunotherapy approach to stimulate an immune response:
- ACTIVATES: Immediately activates a potent innate response following intravenous administration by triggering multiple sensing receptors in immune cells
- WELL-TOLERATED: Shown to be well-tolerated while retaining the ability to activate both innate and adaptive immunity
- COMBINABLE: The mechanism of action, together with its very good safety profile, allows for combination with checkpoint inhibitors, chemotherapy and/or other treatment regimens
- ENGINEERABLE: Can be engineered to produce one or multiple tumor antigens, including patient-specific neo-antigens
- SUSTAINABLE: Are not neutralized by the patient’s immune system, therefore allowing for repeat administration and sustained enhancement of tumor antigen-specific T cell immunity
- MANUFACTURABLE: Can be manufactured through a relatively simple and cost-effective process
CRS-207 is Aduro’s most advanced immunotherapy product candidate utilizing the LADD platform. It is engineered to stimulate an immune response to mesothelin, a tumor-associated antigen expressed by multiple tumor types that contributes to the malignant phenotype of cancer cells and has limited expression in normal tissue. Mesothelin is expressed at high levels in a number of tumors, including mesothelioma, pancreatic, ovarian, gastric, and lung cancers. Aduro is currently conducting trials evaluating CRS-207 in patients with mesothelioma and ovarian cancer.
Beyond CRS-207, several product candidates derived from the LADD platform are under clinical evaluation. Janssen Biotech, Inc. licensed two separate LADD product candidates for prostate and lung cancers from Aduro in May and October 2014, respectively. Janssen is conducting two Phase 1 trials of LADD agents – one evaluating ADU-741/JNJ-64041809, engineered to stimulate an immune response to multiple cancer antigens in patients with prostate cancer and a second evaluating ADU-214/JNJ-64041757, engineered to stimulate an immune response to the antigens mesothelin and EGFRvlll in patients with lung cancer.
Additionally, Aduro is advancing a program exploring the use of neoantigens, or the tumor markers specific to an individual’s cancer and derived from the patient’s own tumor cells, in a second generation personalized LADD (pLADD) technology. To create a patient-specific pLADD therapy, a physician begins by removing tumor cells from the patient. These cells are analyzed in order to molecularly characterize (sequence) the tumor, including any mutations that are unique to the patient’s own tumor cells. Predictive algorithms for antigen processing are run to identify pertinent tumor antigens. Aduro then creates a LADD strain that includes the patient-specific neoantigens for administration. In pre-clinical models, pLADD has been shown to induce anti-tumor immune responses specific to tumor neoantigens which correlated with longer survival. A Phase 1 trial in patients with gastro-intestinal cancers is planned.