Study of Personalized Immunotherapy in Adults With Metastatic Colorectal Cancer
* Personalized Live, Attenuated, Double-Deleted Listeria Monocytogenes (pLADD) Immunotherapy in Adults With Metastatic Colorectal Cancer - Phase 1
* At Stanford, California
* Inclusion Criteria:
-metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS)
-radiographically stable, measurable disease at Screening
- completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening
- on maintenance standard-of-care chemotherapies or on treatment holiday
- Eastern Cooperative Oncology Group (ECOG) 0 or 1
- adequate organ function
- progression of disease at the time of Enrollment
* Exclusion Criteria:
- BRAF V600E mutation
- known allergy to both penicillin and sulfa drugs
- implanted devices that cannot be easily removed
- immunodeficiency, immune compromised state or receiving immunosuppressive therapy
- enrollment in another therapeutic protocol after completion of frontline therapy
'This single arm study is designed to evaluate the safety and tolerability of a personalized treatment in adults with metastatic colorectal cancer by first analyzing the expression of tumor-associated antigens and then treating the patients with a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD)-based immunotherapy. pLADD is based on the attenuated form of Listeria monocytogenes that has been genetically modified to reduce its ability to cause disease, while maintaining its ability to stimulate a potent immune response. pLADD is manufactured using patient-specific antigens and is therefore individualized to each patient'
More information about the personalized LADD plataform:
' 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. .
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.