Obsidian Therapeutics is pioneering controllable cell and gene therapies to deliver transformative outcomes for patients with intractable diseases. In this interview, CEO Paul Wotton discusses the applications of Obsidian’s cytoDRiVE® technology in cell and gene therapy products to control expression of proteins for enhanced therapeutic efficacy.
Please describe the story behind the company: What sparked the idea, and how has it evolved so far?
Obsidian Therapeutics is a biopharmaceutical company based in Cambridge, Mass., and is about five years old. Our technology platform is based on research from Tom Wandless, Ph.D., of Stanford University.
Dr. Wandless developed a technology that can control protein and cell activity in response to the presence of a drug in a dose-dependent manner. This is done by engineering the gene by adding a “drug-responsive domain” or DRD, an artificial receptor added to the proteins. This means that a physician can control the activity of a cell, or the protein expression from a cell, by adjusting the dose of the drug administered to the patient.
The result is our platform, called cytoDRiVE®, with which we can now control cell and gene therapies in a dose-dependent manner, something that has never really been achievable before! With cytoDRiVE, we offer an element of control to the physicians, which resonates well with them as an ability to treat patients more precisely.
Our first program is focused on creating a safer, more accessible version of tumor-infiltrating lymphocytes (or TIL) therapy. There is a significant opportunity to displace conventional TIL therapy and to expand patient eligibility. Currently, there are limited effective late-line options for many solid tumors, TILs have demonstrated responses in patients with melanoma and NSCLC. Although there is clear potential for TIL therapies to prolong the survival of cancer patients, conventional TILs require IL-2 administration. IL-2 is highly toxic, expensive, and burdensome to administer.
We developed a program, called cytoTIL15™, that replaces the need for IL-2 with IL-15, manufactured by the cells themselves. We believe we can reduce the toxicity, cost, and administration burden of conventional TIL therapies, with the potential for improved duration of efficacy.
Additionally, approximately 20-30% of relapsed or metastatic melanoma patients are ineligible for conventional TIL therapies due to the toxicity concerns of traditional TIL therapies. By avoiding the administration of IL-2, we can improve the lives of melanoma patients, as well as make the treatment more accessible to a wider group of patients.
Since the foundation of the company in 2016, Obsidian has evolved from being a research-based company to a development company. Over the last 18 months, amid the pandemic, we have been able to grow: we’re now 75 people, with 40 new employees joining us in the past year. We are less than one year away from the clinic and 12 months away from potentially going public thanks also to the $115 million raised in a Series B financing announced last September.
Can you explain what cell therapies are all about, for those who aren’t familiar with them?
Cell therapies are at the forefront of biotech research and development. We improve a cell’s capabilities by integrating a gene into the cell’s mechanisms to be able to produce a desired protein. It could be IL-2 as well as TNF-alpha. We can have cells to make any protein we like.
When you apply cell therapy to a patient, it means that you engineer his/her cell to be able to respond to a specific signal. In our case, we’re engineering them with an IL-15 gene to make TIL cells more resilient and potent against melanoma, the most common type of skin cancer.
So far, we have been engineering the cells outside the patient’s body. Through our collaboration with Vertex, we are developing a technology to edit the gene directly in the body of the patient.
How is Obsidian revolutionary for oncology patients?
I joined Obsidian to address the high unmet medical need for new oncology therapies. The treatment for most patients involves surgery, radiotherapy, or chemotherapy, often with drugs that were developed decades ago. These therapies are broad and hit the whole patient’s body – they’re not precisely targeted to the tumor site. I saw this with my own eyes through a family member who unfortunately developed cancer.
Drug discovery and development have evolved to the point where it’s possible to fine-tune the treatment of patients with precision medicine; this is going to change the way cancer is treated.
With immune therapies, we can harness the patient’s own immune system and enhance it to be able to fight tumors, as it does naturally. When a patient has cancer, the body’s natural defenses are overwhelmed, and can’t cope with the growth of a tumor. By helping the body harness its natural protection, we can more safely and effectively treat tumors.
I strongly believe there will be a time when cancer will be treated with cell therapies or immune technologies as a first option, and chemotherapeutics may not be necessary over the longer term. I see that day coming.
What can you tell us about your technology, cytoDRiVE?
CytoDRiVE is a platform we developed that enables the amount of protein expressed in the body to be controlled using an FDA-approved small molecule.
By engineering a cell with a small DRD, we can switch on, switch off, and tune the amount of protein expressed using a small molecule. In our lead program, cytoTIL15, we use a small molecule called acetazolamide, which is an FDA-approved drug with a well-established safety profile. Acetazolamide interacts and binds to the DRD and regulates the expression of proteins, such as IL-15, IL-12, or CD40L.
We’ve been able to apply the cytoDRiVE technology to TILs. This is the procedure: tumor tissue is taken out of a patient, the lymphocytes that have found their way into that tumor are extracted, and engineered to contain membrane-bound IL-15 on the surface. The engineered cells are given back to the patient with the instruction to take an acetazolamide tablet once a day to keep the cells activated. If the physician wants to turn up or down the therapeutic activity, the physician prescribes more or less acetazolamide. Physicians can precisely control the time aspect of the treatment.
Have you encountered any misconceptions or ethical dilemmas related to your work?
With any form of medicine, it is necessary to weigh the benefits of the treatment against any risks. Plus, people often fear what is new.
CAR-T cell engineering has already been applied successfully in patients who have severe hematology-based cancers. We’re not doing anything funky to the cells in terms of ethics. We’re just taking the body’s own cells and improving them. I think everyone can see the benefits of that approach.
TIL therapy has actually been used in the past. When it works, it works really well. The challenge is that patients who are administered this therapy must undergo an IL-2 treatment, and that, in about half the cases, sends them to the ICU. Obsidian’s approach is making this therapy both safer and more effective, with a much better outcome for patients, potentially.
What do you think is required for cell therapies to become standard of care?
Broadening the use of cell therapies requires more awareness and experience in the clinic, but we’re getting there. Ten years ago, cell therapy was hardly an imaginable option for treating cancer patients. Nowadays, we have products like Kymriah, a CAR-T therapy, on the market. Gradually, people are getting more and more familiar with cell therapy. We’re increasingly seeing more phase 3 studies being conducted with cell therapies.
The success of this type of therapy will help to make it more and more visible and, consequently, more widely adopted by physicians and accepted and known by people. The one thing we have to pay attention to though is making sure we can manage the cost of those therapies so that our healthcare systems can afford them.
What are your future plans for Obsidian?
In the next twelve months, we plan to treat our first patient with our cytoTIL15 therapy. Partnerships with academic centers are extremely valuable for the clinical development of our technology. Moreover, such partnerships are really good opportunities to validate our concept and show its benefits.
All the preclinical work we’ve done, which we’re now showing at leading conferences worldwide, has shown us that our TILs are much better and last much longer than conventional TILs. This is an important validation of our work.
During the last two years, we’ve built a business plan to match the needs or desires of the market. Now, we continue in that direction thanks to our team as well as investors and advisors on our scientific advisory board. All these people are fully dedicated to what we’re doing and very supportive of our pioneering effort to change the way cancer is treated. Being surrounded by such a great group of people makes my life a lot easier.