Pear Biotech Bench to Business: insights on ‘Designer Immune Systems,’ allogeneic stem cell therapies, and making an impact on the lives of patients with Ivan Dimov

Here at Pear, we specialize in backing companies at the pre-seed and seed stages, and we work closely with our founders to bring their breakthrough ideas, technologies, and businesses from 0 to 1. Because we are passionate about the journey from bench to business, we created this series to share stories from leaders in biotech and academia and to highlight the real-world impact of emerging life sciences research and technologies. This post was written by Pear PhD Fellow Sarah Jones.

Today, we’re excited to share insights from our discussion with Dr. Ivan Dimov, CEO and co-founder of Orca Bio. Ivan has co-founded three high-tech companies and two R&D centers, and he is now working to make next-generation cell therapies safer and more efficacious at Orca.

More about Ivan:

Ivan earned a Ph.D. in Applied Biophysics from Dublin City University and has since worked as a postdoc at UC Berkeley and as a visiting instructor and senior scientist at Stanford. His passion for translating his work and his tech-heavy background have made him an expert in electronics and bio-microelectromechanical systems (bio-MEMS) and have helped him to work on numerous projects and companies including Blobcode Technologies, Lucira Health, and Orca Bio. 

If you prefer listening, here’s a link to the recording! 

Insight #1: Instead of building a technology and then searching for the right application, it’s much more efficient to identify the right problem prior to creating a solution. 

• There are many approaches to starting a company and making new, impactful discoveries. As someone with a strong tech and engineering background, Ivan was trained to find and create interesting, powerful new technologies and go hunting for applications; he made hammers and went searching for nails. 
• However, when working with Dr. Irv Weissman at Stanford as a postdoc, Ivan learned to do things a little differently. 
• Though Ivan’s background was primarily in applied biophysics and bioengineering, the Weissman lab’s focus was medicine and biomedical research. Ivan acknowledged that when you work in medicine, you are exposed to an over-abundance of problems, and in this environment, Ivan learned that the most effective solutions are those that are tailor-made to fulfill a clearly defined need. 

Working with physicians was a huge change in mentality for me…you’re seeing suffering everywhere and you have all these problems, and you sort of have to figure out, okay, which problem do you want to focus on, and what’s the best solution or technology you can come up with for that problem? I think that’s probably the better way of doing innovation…rather than trying to squeeze in some technology that was thought of in a different context and trying to make it work.

• One such problem was related to the poor outcomes of stem cell transplants, a procedure in which a donor’s stem cells are harvested and administered to a recipient. Ivan explained that there wasn’t a way to sort out the good cells from the bad and ensure that the recipient was only receiving cells that would therapeutically benefit them and minimize unwanted side effects. 
• The idea of creating precise and well-defined stem cell therapies would become the central theme of Ivan’s work at Stanford and later of Orca Bio.

Insight #2: Academia is great for exploring, learning, and making mistakes. However, industry is where you can iron out the more mundane details of company creation and focus on impact and real-world use cases.  

• Having started three companies–Blobcode Technologies, Lucira Health, and Orca Bio–Ivan has extensive experience in taking ideas from academia to industry. 
• Lucira Health, a diagnostics company that has since been acquired by Pfizer, was spun out of Ivan’s work at Berkeley. The goal was to miniaturize a microfluidic chip that could be utilized as an at-home diagnostic. Notably, the company received approval from the FDA for their at-home COVID test that could read out results in about 30 minutes.
• While at Berkeley, Ivan spent time fine-tuning the idea and conducting proof-of-concept experiments for the chip. However, it became apparent that this academic setting wasn’t necessarily conducive to the less thrilling aspects of the project. Spinning out and starting Lucira allowed the team to more efficiently work on the ‘mundane’ details like reproducibility and clinical trial design.

[Academia is a safe place where] there’s a lot of openness to trying out new things… and the greatest thing about it is that you can try it and you can make a mistake and that’s okay. You can come up with a better alternative.

• While Ivan agrees that academic labs are a great place for ideation and company incubation, it’s important to be vigilant and humble enough to realize when it’s time to take the next step. Industry and academia each have their respective strengths, and Ivan learned that both were crucial to the growth and future success of his companies.

Insight #3: Stem cell therapies don’t have to be so risky: by cherry-picking the cells that a patient receives, long-term outcomes can be significantly improved.

• In leukemia, cells in the bone marrow and lymphatic system become cancerous and rapidly multiply. To treat this type of malignancy, patients often go through multiple rounds of chemotherapy, radiation, or targeted immunotherapy and may receive an allogeneic stem cell transplant. 
• Essentially, a conventional allogeneic transplant begins when the patient receives chemotherapy and/or radiation to wipe out all of the cancerous blood cells together with the patient’s healthy blood and immune cells. Once the cancer can no longer be detected, stem cells from the bone marrow of a healthy donor will be administered. These new cells can multiply and grow into mature, functioning blood and immune cells.
• For some patients, this treatment is curative and wipes out any trace of cancer from their systems. However, even after chemotherapy and radiation, some cancer cells may go undetected and cause a patient to relapse.

The problem with cancer is that if you leave even a little bit of it behind, even a single cell that hides and survives, it has the potential to reinitiate and restart your cancer from scratch… When you get into full remission–meaning we can’t measure any more cancer in you–it just means that our tests aren’t sensitive enough to see if it’s there or not there.

• Once the stem cell transplant is complete, it takes a couple of weeks for the new immune and blood systems to get up and running. The hope is that these new immune cells can wipe out any remaining cancer cells that may be hiding out. 
• In addition to the potential for relapse, patients frequently develop either acute or chronic Graft-vs-host-disease (GVHD), complications in which the new immune cells from the donor start to attack the patient’s (host’s) own cells and tissues. GVHD can affect many parts of the body and can even lead to death. 

In a standard transplant, your chances of surviving for twelve months free of relapse or free from GVHD is somewhere around 30-40%. With Orca Bio… we can get rates somewhere between 70-80% ideal survival rates.

• So how do they do it? Ivan’s goal at Orca Bio is to revolutionize the cell therapy space by creating a high-precision cell therapy that gives patients only the most efficacious donor cells. 
• Orca’s unique platform identifies and sorts for donor cells that have the highest therapeutic benefit. By removing cells that either harm or don’t help the patient, the patient’s chances for relapse or developing GVHD are dramatically reduced.
• With what they call their ‘designer immune system,’ Orca’s approach aims to help patients recover more quickly, prevent relapse, and be safe enough for older or sicker patients who can’t receive traditional stem cell transplants.

Insight #4: To solve the problems of current allogeneic stem cell transplants, you have to balance killing the remaining cancer cells with protecting the patient’s own tissues and cells.

• When designing an immune system to infuse into patients with blood cancer, it can be difficult to kill cancer cells without harming other cells in the patient’s body. 
• In a healthy immune system, cells called regulatory T cells (T-regs) monitor and regulate what effector T cells are doing. Such effector T cells can help promote inflammation and eliminate cancer cells. However, when a patient has cancer, there is an imbalance between these two cell types, and the immune cells don’t effectively kill the cancer cells. 
• These types of cells are often involved in autoimmune disorders and can also play a role in the development of acute GVHD shortly following the stem cell transplant or in chronic GVHD, long after the treatment has concluded. 
• Orca Bio’s first product, Orca-T, helps to restore balance in the immune system by first bringing stem cells and T-reg cells into the patient’s body to let them set up the immunoregulatory environment. Once the T-regs and stem cells have had a chance to settle in and begin restoring the patient’s immune and blood systems, conventional T cells with cancer-killing capabilities are administered.
• Orca-T has reached Phase III clinical trials for indications such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoid leukemia (ALL), and mixed-phenotype acute leukemia (MPAL) in patients with matched donors who are younger than 65. Matched donors are those that share the same human leukocyte antigen (HLA) profile, and this means that these cells are less likely to be identified as intruders in the patient’s body, thus reducing the risk for GVHD.
• Patients receiving Orca-T first receive chemotherapy and/or radiation to target cancer cells and suppress their immune systems. The first dose of Orca-T is an infusion of stem cells that regenerate the blood and T-regs that help set the immune landscape. Two days later, the patient receives an infusion of conventional T cells that can begin to attack any remaining cancer cells. 

What’s amazing about this approach is that by doing that, you’re not turning off the effector T cells from destroying the cancer. You’re just turning off alloreactivity in the key organ sites where you might create GVHD, but you’re still keeping it on for wherever the cancer might be.

• Moving forward, the company is continuing its work on Orca-T by expanding the age range of patients who can be treated with the drug.
• The pipeline also includes next-gen cell therapy treatment, Orca-Q.
• To solve the problem of limited matched donor availability, Orca-Q is a high-precision cell therapy that has been tailored for haploidentical, or half-matched donors. These donors are typically parents, children, or siblings and can be much easier to find. However, the risk for GVHD increases with a half-matched donor compared to a fully matched donor.
• Orca-Q has so far shown positive results in Phase I in oncological indications and is being investigated for autoimmune and hematological indications, as well. 

Insight #5: Sometimes science is personal: reflecting on Orca’s journey, Ivan and his team have a deep understanding of how their work can change lives.

• Having treated more than 400 patients so far, Orca has seen firsthand how patients can benefit from their novel stem cell transplants. 
• In particular, patients who are too old or too sick for traditional transplants now have a fighting chance.

One of the most incredible stories was about my co-founder’s [Nate Fernhoff’s] father-in-law. He was 71 years old when he was diagnosed with myelodysplastic syndrome. He had an aggressive variant of the disease…however, physicians feel very skittish about treating folks at that age with a myeloablative allogeneic bone marrow transplant, so they’re offering a reduced protocol [with a much worse chance of controlling the cancer]. We started looking for clinical trials, anything that would cover folks of that age.

• Dr. Fernhoff’s father–in-law, Mikhail Rubin, was diagnosed with a rare form of blood cancer and found that his options for treatment were extremely limited. The most successful and aggressive forms of treatment were offered only to younger patients. 
• Meanwhile, Orca’s clinical trials had so far proven to be safe and effective. The Orca team sprang into action and started working to convince physicians and the FDA to allow them to treat patients older than 65 and expand the enrollment criteria for the trial.
• Ivan noted that this exclusion of the most dire patients stems from the industry’s hesitancy to add further risk to clinical trials.

In April of 2021, we were given the permissions, and were able to treat him. It’s been a phenomenal recovery. He recovered much faster than any of his younger counterparts even though a lot of physicians thought it would take months in the hospital for him to get out. Yet, in the first year after, he started riding his mountain bike and did 3,000 miles on his bike.

• Not only is Mr. Rubin back to biking, he has also been cancer-free and GVHD-free for three years now. 
• While science tends to be objective in nature, personal connections and motivations help drive the mission and make work like this possible.