Harnessing the Power of Proteins To Unlock Cell and Gene Therapies
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Immunotherapy is a novel type of treatment that utilizes the body's own immune system to fight against disease. Chimeric antigen receptor-modified T cells (CAR-T) therapies are a sub-type of immunotherapy, in which a patient's own T cells are removed from the body, genetically modified and reprogrammed to target and attack specific cancer cells, and then reinserted into the body.
The genetically engineered cell-therapy space is advancing rapidly, and scientists are continuously looking for approaches to adapt and improve current delivery methods.
We recently spoke with Paul Wotton, Ph.D., CEO at Obsidian Therapeutics, to gain his insights on the genetically engineered cell-therapy research area, and to learn how Obsidian Therapeutics' cytoDRiVETM platform can increases the specificity and safety of such therapies.
Molly Campbell (MC): In recent years, what have been some of the most exciting clinical breakthroughs regarding CAR-T therapies?
Paul Wotton (PW): The use of CAR-T therapies was initially limited to small clinical trials in patients with advanced blood cancers. However, the success of these trials, as seen by the remarkable responses from patients of all ages for whom all other treatments had stopped working, quickly captured the attention of researchers.
The world’s first-ever approved CAR-T therapy, Kymriah, made history in August 2017. Following that, progress with CAR-T cells and other adoptive cell transfer (ACT) approaches has greatly accelerated, with the scientific community developing a deeper understanding of how these therapies work and translating that knowledge into improving therapies. Some of these advances include the faster production of a batch of CAR-T cells as well as the improvement of the engineered T cells' ability to produce more T cells after injection into the patient (expansion) and survive longer in the body (persistence).
Researchers are leveraging their greater understanding of these therapies to pursue different targets, besides the commonly used CD19, to other molecules such as BCMA or CD22 – or a combination of targets. Now, researchers are also looking to apply this technology in solid tumors. The challenge here is to identify the appropriate target antigen that would be abundantly expressed by solid tumor cells but minimally present on normal tissues.
Other known obstacles to CAR-T cell-therapy for solid tumors include effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. One of the most recent and exciting clinical developments currently in progress is the generation of off-the-shelf CAR-T therapies that do not require the use of the patient’s own cells but are instead obtained from healthy donors. The idea is that not only the patient will avoid the painful procedure of cell extraction altogether but the treatment could be readily available with no manufacturing waiting time needed.
The clinical success of these types of therapies is reflected in the growing number of strategic partnerships in this area that have attracted a high level of investment and involve large pharmaceutical organizations. However, there is still much more to do with CAR-T therapies and we are looking to improve the effectiveness and safety of these therapies with our proprietary platform.
MC: Why are there safety concerns associated with genetically engineered cell therapies?
PW: Cell-therapy has shown significant therapeutic benefits in various disease indications. However, the promise of genetically engineered cell therapies as “living drugs” is restrained by serious safety concerns. These cells, once unleashed in the body, can be nearly impossible to control, and even toxic. While persistence and survival of the genetically modified cells are considered important factors for the successful elimination of the disease, the control of the cell’s biologic activity is critical to reducing toxicity while improving efficacy.
One of the main and most dangerous side effects of CAR-T cell-therapy is that as the genetically engineered cells expand and divide in the body, they produce chemical messengers called cytokines that help launch the immune system’s attack against the cancer cells by activating numerous immune cells such as B cells, T cells and Natural Killer cells. This flood of cytokines into the blood can often cause a condition called cytokine release syndrome (CRS) – or cytokine storm – defined as a large and rapid release of cytokines in the blood. CRS, if left uncontrolled, can induce symptoms such as high fever, body aches, headache, fatigue, low blood pressure, trouble breathing, nausea and diarrhea.
Another common safety concern is “on-target off-tumor” toxicity, resulting from a direct effect on healthy tissues that express the targeted antigen. While the selection of a target antigen is likely the most critical determinant to broaden the application of these therapies, the potential for off-tumor toxicity further reinforces the critical importance of controlling genetically engineered cells and their activity.
An example of this is seen in therapies that target human epidermal growth factor receptor 2 (HER2) in breast as well as other types of cancer. A study published in 2010 reported the death of a patient just five days after being infused with CAR-T cells targeting HER2 for metastatic colon cancer treatment. The cause of this was the low expression of the selected antigen, HER2, on the epithelial cells of the lung, which were directly attacked by the transferred cells. The lack of control over the genetically engineered cells once transferred into the body represents a highly unmet need that we are working to resolve with our proprietary technology.
MC: Please can you tell us about the development of the cytoDRiVETM platform?
PW: CytoDRiVE™, Obsidian’s breakthrough technology, is based on the discoveries of our scientific founder, Professor Tom Wandless, Ph.D. Wandless is a leading researcher in chemical and systems biology at Stanford University. His peer-reviewed work published in Cell in 2006, led to the development of a synthetic biological cassette that can be inserted in a gene vector to produce a protein that can be controlled with the use of small-molecule drugs. In this manner, the protein of choice can be stabilized or rapidly degraded by the cellular machinery.
In 2008 his lab published yet another ground-breaking paper in Nature Medicine demonstrating the use of this platform in living mammals using mice. The publication described the successful regulation of an immunomodulatory cytokine, resulting in tumor burden reduction in mouse models. Additionally, the lab used this approach to control the function of a specific protein after systemic delivery of the gene that encodes it to a tumor, which laid the foundation for the development of Obsidian’s platform.
MC: How does the cytoDRiVETM technology enable control over the level and timing of protein activity in cell and gene therapies?
PW: CytoDRiVE™ is designed to regulate protein levels in both cell and gene therapies, creating an “operating system” for living drugs. This platform has the potential, for the first time, to allow physicians to precisely control genetically-engineered cells’ activity to increase treatment efficacy and reduce toxicity, using easily accessed FDA-approved drugs with proven safety.
The cytoDRiVE™ platform is conformed of three essential components: a small protein called a drug-responsive domain (DRD), a therapeutic protein of choice (attached to the DRD), and a small molecule that can bind to the DRD and induce the activation of the therapeutic protein. Safe, well-known FDA-approved small molecules can be used for this purpose, and the choice of therapeutic protein is almost limitless. With cytoDRiVE™, the protein levels can be precisely adjusted by adding more or fewer doses of the small molecule drug, acting as “light switch dimmer” to pharmacologically control the protein activity.
We can apply the cytoDRiVE™ technology to design controllable intracellular, membrane-bound and secreted proteins. This versatility has the potential to expand the use of this platform to a large range of disease indications and therapeutic applications.
MC: Obsidian Therapeutics is working in collaboration with Celgene to discover and develop novel regulated cell therapies that utilize cytoDRiVETM. Specifically, the collaboration is focused on two immunomodulatory factors, IL12 and CD40L. Why are you choosing to focus on these two factors? What progress has been made thus far?
PW: Our collaboration with Celgene has been a transformative event for the company. The choice of IL12 and CD40L as our initial focus is based on years of research that demonstrate the potential of these two molecules for cancer therapies.
Targeted delivery of CD40L activates antigen-presenting cells and induces cancer cell death. CD40L is a potent inducer of Th1 responses, stimulates both the innate and adaptive immune system, and induces apoptosis of tumor cells. CD40L is also capable of suppressing the effect of T regulatory cells, further supporting the anti-tumor activity by reducing the immunosuppressive microenvironment surrounding the cancer cells. As CD40L is one of the strongest inducers of immune cells’ activation, an important concern is the potential for systemic over activation and concomitant toxicity. Indeed, dose-limiting toxicity has been reported in humans, which is why the accurate control of protein activity will become critical in its use against tumors. Interleukin 12 (IL-12) represents an ideal candidate for tumor immunotherapy due to its ability to activate and bridge both innate and adaptive immune cells.
Systemic delivery of IL-12 has demonstrated substantial anticancer efficacy by reversing the immune suppression commonly associated with the tumor microenvironment and enabling anti-tumor activity from the adoptively transferred cells. However, IL-12 can also cause significant toxic effects in humans if left uncontrolled. For this reason, the capability to regulate this specific immune signaling molecule has the potential to achieve the desired anti-tumor activity without the commonly associated safety concerns.
MC: What are Obsidian Therapeutics' next steps in the cell and gene therapy space?
PW: We are currently in the process of designing IND-enabling studies to bring cytoDRiVE™-modified cell therapies into clinical trials as soon as possible. Although we are initially focusing on cancer we are planning to expand our platform to multiple other disease indications, as the potential of this technology is virtually limitless. If you can make a protein or cytokine, our cytoDRiVE™ platform can regulate it.
Paul Wotton was speaking with Molly Campbell, Science Writer, Technology Networks