Putting the CAR T before the horse
WEST LAFAYETTE, Ind.—Aimed at developing targeted small-molecule drug conjugates (SMDCs) for personalized therapy, biopharmaceutical Endocyte Inc. has joined hands with Purdue University in an exclusive agreement to research, develop and commercialize SMDC therapeutics for the treatment of disease. Word of the new research came to light in a late-breaking poster session of the American Association for Cancer Research (AACR) in New Orleans, April 19 on the application of Endocyte’s SMDC technology in a chimeric antigen receptor (CAR) therapy setting.
The collaborative effort was launched through a longstanding partnership with Dr. Philip S. Low, Endocyte founder and chief science officer and director of the Purdue Center for Drug Discovery. Endocyte holds the global rights to the CAR (receptor) and SMDC (adaptors) for all indications.
“This technology and these data reflect a potentially significant advance in overcoming several challenges specific to CAR therapies, as well as the powerful versatility of Endocyte’s SMDC platform,” stated Ronald Ellis, president and CEO at Endocyte.
“This is still in the early stages of research, and we look forward to our continued collaboration with Phil Low and his lab to further explore the potential of this CAR therapeutic approach as we look to build our SMDC platform in immuno-oncology,” he said.
Ellis notes that the collaboration takes a novel approach to a universal T cell overcoming key challenges of current CAR technologies/therapies.
“The few challenges common to most CAR T cell technologies include safety management (potential for uncontrolled cytokine response and tumorlysis), limitations on efficacy due to tumor heterogeneity and high cost of therapy,” Ellis says.
Endocyte's novel approach consists of universal CAR T cells engineered to bind with extremely high affinity to FITC (fluorescein), and small-molecule bispecific adaptor molecules that bind to various targets unique to cancer cells (e.g., folate receptors (FR), prostate specific membrane antigen (PSMA), NK-1R, etc.).
“These CAR T cells are not active until FITC is introduced via the adaptor molecules,” Ellis noted. “Once administered, the adaptor molecules bind to their targets on diseased cells and then the CAR T cells are drawn to them via their affinity to FITC.”
The result is the potential to manage safety by adapting the dose of the adaptor molecules (which clear relatively quickly, allowing for potential control of the rate of cytokine release and tumor lysis), to target heterogenetic disease through the use of multiple adaptor molecules to target different receptors, and to utilize a single CAR T cell to hit all of these targets (lowering costs), he says.
“The research captured in the AACR poster highlights three different targets (FR, PSMA, NK-1R),” Ellis says. “These targets are present in varying degrees in multiple tumor types, including non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer and others. For most patients, more than one of these targets will be present in their disease, suggesting that optimal therapy requires multiple targets.”
Ellis adds that Endocyte will continue to collaborate with Low to “expand the preclinical work performed to date to advance the therapy and potentially expand the number of adaptor molecule targets.” Endocyte is also planning “dialogue with companies participating in this space to explore the possibility of additional collaborations,” he says. “We are not yet in a position to announce plans for additional (posters).”
Low explains that T cells are the immune system's natural defense against cancer and other harmful entities in the human body, according to a Purdue newsletter. But first, the cells must be activated and taught by the immune system to recognize cancer cells in order to seek out and destroy them.
“Unfortunately, many types of cancer manage to thwart this process,” Low says.
In the 1990s, scientists found a way to genetically engineer T cells to recognize a specific cancer.
“These engineered T cells, or CAR T cells, have been recently used as treatment for cancer, but the traditional engineered T cell treatment can be too effective, sometimes killing tumor cells too fast and triggering a toxic reaction in a patient, and sometimes not stopping once the tumor has been destroyed and continuing to seek out and destroy healthy cells important to bodily functions,” Low explains. “We have found a potential way to control the engineered immune cells to overcome the limitations posed by CAR T-cell therapy.”
The technology has been tested in animal models, but no human trials have been performed.
A study in mice showed the anti-tumor activity was induced only when both the engineered CAR T cell and the correct adaptor molecules were present, Low says. The system also offers the potential to treat multiple cancer subtypes at once.
Low's research has focused on the design and synthesis of technologies for targeted delivery of therapeutic and imaging agents to treat cancer, inflammatory and autoimmune diseases and infectious diseases.
Low has developed molecules that target folate-receptors and prostate-specific membrane antigen on the surfaces of cancer cells. Approximately 85 percent of ovarian cancers, 80 percent of endometrial and lung cancers and 50 percent of breast, kidney and colon cancers express folate receptors on their cellular surfaces. Prostate-specific membrane antigen receptors are found on nearly 90 percent of all prostate cancers. Other tumor-specific ligands developed by Low's lab can target each of the other major human cancers, he says.
Each CAR T cell has thousands of receptors on its surface to which an adaptor molecule can bind, Low says. One CAR T cell could have a variety of adaptor molecules bound to its surface, and the cancer cell it targets will depend on which of those adaptors first encounters a targeted cancer cell. Once the CAR T cell binds to a cancer cell, it begins the process of destroying it. When that process is complete, the CAR T cell is released and can bind to a new cancer cell.
According to Low, “In the past a new CAR T cell had to be designed for each desired cancer target. This system uses the same blind CAR T cell for all treatments. The adaptor molecule is what needs to be changed, and it is far easier to manipulate and swap pieces in and out of it than the T cells.”