Episode 16 | Global Health Dialogues with Princess Dina and Dr Garo Armen

Princess Dina, it's a pleasure to be here.

Thank you very much for that. I'll be happy to do that. Princess Dina, you've had your own journey into understanding this horrible disease through your own very close affiliations. Cancer is a very complex disease, different in every single individual, and that difference makes it very challenging to battle. But luckily, we have a very sophisticated capability in our human bodies to tackle cancer and other diseases. This is the immune system, which has been with us since the beginning of time. It can recognize the enemy, whether it's cancer, an infection, or a pathogen, and mobilize the body to combat it successfully. This happens in most healthy people. But in some cases, where the cancer becomes overwhelming or the immune system is weakened, the enemy takes over. Science has now advanced to a point where we can exogenously influence the immune system to strengthen it and weaken the disease, and we've already had a number of successes. Immunotherapies, starting about 20 years ago, made a big difference for patients that were otherwise incurable, and now that progress is taking off.

I grew up in Istanbul until I was 17. Life brings about unanticipated things. My grandmother was one of the greatest blessings in my life. She was a remarkably wise lady who had gone through her own hardships. She became an expert in immunology without even knowing the term, because I was the first grandson, first grandchild. In those days, being a son as a grandchild had a special standing. She cherished me, and every time I got sick with a cold, flu, or sore throat, she would come to our house, bring sheets of cotton, heat them on the ceramic stove, and put them around my armpits. I used to wonder what she was doing. She was heating up my lymph nodes, which are full of immune cells. Immune cells need energy to be activated, and heat is a wonderful form of energy. Almost 3,000 years ago, Hippocrates said, 'That which a medicine cannot cure, surgery will cure. And that which surgery cannot cure, heat will cure.' What he meant by heat was immune activation. Immune activation has been with us for a long time, but medicine has taken its sweet time to understand its power.

The immune system requires energy, like any other bodily function. When challenged with an enemy like cancer, a virus, or bacteria, it needs activation, which requires energy provided by the body. Our normal body temperature is 98.6 Fahrenheit or about 36.5 Celsius. When the body needs the immune system activated, it naturally drives the temperature up to provide energy through heat. That heat is allocated from other sources. When our temperature goes up, it's a natural phenomenon to activate the immune system. It makes us feel uncomfortable and weak, which is the body telling us to lower physical activity so it can capture energy for immune activation. Unfortunately, modern medicine's immediate reaction to fever is to give drugs to bring it down, partly influenced by the profiteering of the drug industry. That's the wrong thing to do. Let the body temperature go up a bit to activate the immune system. Of course, if it goes to a dangerously high level, like 40 or 41 degrees Celsius, it's okay to bring it down to prevent convulsions. But up until that point, we need to bite the bullet and be uncomfortable for a brief period so the body can do its job.

It's a heartbreaking reality to see cancer patients suffer. I had my first experience with my young mother. She was 47 years old when she died after a short battle with breast cancer. Seeing that breaks your heart, and you feel helpless because you want to do something. Over the years, as I studied science and immunology, it became clear that the only effective way to battle cancer is by activating the immune system to recognize and defeat it. This is easier said than done. It's a very complex mission, but we came across wonderful science and technologies that convinced me it could be done. In the beginning, there were limited tools, but over time those tools have advanced. Today, we can literally cure patients who were incurable only a few years ago, and that proportion is growing. When I started the company in 1994 and used the term 'cure,' physicians and scientists said, 'Don't use that term. Cancer is incurable, and you'll lose credibility.' But we persevered and never gave up. Today, we are able to cure some patients. There's no question about that.

Before I do that, Princess Dina, let me say a couple of words about cancer and the immune system. Even without medication, the body naturally has the ability to fight diseases. Most healthy individuals with a competent immune system can recognize cancer before we even know it's there and mobilize the immune armies to kill it. You mentioned chemotherapy. Not all chemotherapy is necessarily bad. It can weaken the cancer, and if the immune system can then take over and defeat the weakened cancer, chemotherapy may work, despite its toxic side effects. But in most cases, when cancer advances to stage three or four and metastasizes, you need to help the immune system with drugs like checkpoint inhibitors. These are antibodies that do several things. They activate T cells, the armies of the immune system that do hand-to-hand combat. They also, in the case of PD-1 inhibitors, take the shield off the cancer so it becomes more exposed. In our case, our lead agents are a combination of a PD-1 antibody and a supercharged CTLA-4 antibody. PD-1 undresses the cancer. CTLA-4 not only activates T cells but also weakens regulatory T cells, which are a balancing act. It also upregulates memory T cells, so if the cancer disappears but a few cells remain, those memory T cells are ready to combat it. That's what we do. You also asked about what else we do. There's a complex system of cells and enablers that can combat cancer, and those are our pipeline products. It's like a toolbox. You need all the essential elements so you can call upon them as needed. That level of sophistication requires more science, like relevant biomarkers. That's happening as we speak. The rate of progress is really taking off. We made this much progress ten years ago, and today we're making much more progress very quickly because of the availability of these tools.

Unfortunately, humans like to oversimplify things because simplification is easier to understand. We tend to think, for example, that more chemotherapy is better. In fact, they overload the patient with chemotherapy until the patient becomes too weak to tolerate it. We are learning that this is the wrong thing to do, particularly when using combinations of drugs. We have to use things in moderation because the body is an expert balancer. Even too much immunotherapy can be harmful if the immune system turns its own cells into targets. This balance is something modern medicine hasn't yet mastered. We tend to think more is better, rather than a balanced approach with cytotoxic drugs in moderation combined with immunotherapeutic drugs, with individualization dictated by the physician, not standard of care. Standard of care is an escape mechanism for physicians to eliminate liability. That's not a good thing. We have come to a point where individualized therapies need to be considered, requiring adjustments from standard of care. The regulatory system in the US has been behind the ball on these concepts because they like to check boxes and standardize everything, as if we are robots. Developing the same treatment protocol for every person with variable cancers, immune systems, and reactions is wrong. But humans always advance with learning. I'm hopeful that with a little courage and originality, we will master these subjects and cure diseases, rather than just treat them for a short period before people succumb.

Retrocytes, you say?

Yes, correct. A number of years ago, we used a retrocyte display platform to make antibodies. When antibodies were first being experimented with, they were chimeric antibodies, partly mouse and partly human. Over time, science allowed us to develop all human antibodies. The purpose is that if you use antibodies that are part mouse and part human, your body can develop a reaction over time to reject that antibody. With all human antibodies, like those in our portfolio, the body's reaction to reject them becomes non-existent. That is the next generation, now in practice for some time, and it is the preferred way to go.

Vaccines are fascinating. There's been a lot of controversy recently about the use of vaccines. Vaccines are driven by two things. One is the recognition of what you're going after. For example, if you have a virus or bacteria, you can identify fingerprints that guide the immune system to the right place to destroy it. In addition to the fingerprint, you need a little bolstering of the immune system to go after those targets powerfully. That's the adjuvant technology we developed. It is now one of the most successful in the world. It is the basis of the shingles vaccine by GlaxoSmithKline called Shingrix, the most successful shingles vaccine. That's an important breakthrough. One thing I'd like to caution against is that if you overwhelm the immune system by vaccinating too much, like during COVID with booster vaccines every several months, it throws the immune system into a tizzy. It overworks the immune system, taking energy away from other things. If you overwork the immune system and then get challenged by another virus, bacteria, or cancer, it will have less energy to combat those diseases. You need to keep a proper balance. Vaccinate appropriately to avoid immune exhaustion, which weakens the immune system's ability to fight other diseases.

It is preventative.

It's preventative, but again, the Shingrix vaccine is just two vaccines.

And you're done. It's not continuous.

Now we're embarking on a very complex subject. One reason I got fascinated with doing something meaningful in cancer is that cancer is a different disease in every single individual. We may wrongfully think that breast cancer or lung cancer is the same in every individual, but it isn't. It is a mutation of the normal tissue of that person, whether lung, prostate, or breast. Because every individual has unique DNA, when cells transform, they are unique to that patient. No two cancer types are exactly the same. Therefore, individualization of vaccines to treat cancers is absolutely imperative. That requires taking DNA from the cancer cell and making a specialized vaccine for that individual. But the challenge doesn't stop there. Vaccines have limited charging power. By themselves, they are unlikely to be effective in late-stage patients, stage three or four. Hence, a vaccine in combination with a checkpoint molecule like our botensilimab or basiliximab, or both, becomes much more effective in battling the disease in a curative fashion.

Princess Dina, I think you are qualifying to come in and work with us as a scientist. You've deeply

Well, before I answer that, let me delve into the subject of cold and hot tumors. Cancers are tricky systems. The reason a cancer advances is because it learns in some individuals and with certain cancers how to survive. It learns to survive by hiding itself from the body's immune system. And so, in those cases, cancers, for

For example, many cancers, such as the majority of colon cancers (95%), are cold tumors that hide from the immune system. Only 5% are MSI-high and respond to immunotherapy. We designed our molecules to undress cold tumors, converting them to hot tumors with our vudalimab antibody, which exposes myeloid cells to chew up cancer cells. This technique was not available until our discovery and has made an incredible difference for patients.

In the context of clinical trials, things are advancing rapidly. One important element is invariant NKT cells through our subsidiary MNK Therapeutics. I call them intelligent NKT cells because they examine the environment, figure out what's going on, and summon other immune components to balance killing cancer and not harming the body. This beautiful science is advancing, and governments are interested for cancer and antibiotic-resistant pathogens. I'm very excited about how the science is developing.

AI is an important tool; I use it every day as an assistant. But in science and medicine, it's in embryonic stages because we need a lot of data from real-life experience, which is limited because regulatory systems inhibit quick research. In the US, progress is slow; in China, it is taking off at a rate that spins our heads. We need to catch up by encouraging clinical science. For example, our drug botensilimab is available only in France with full reimbursement, and US patients travel long distances to access it. That is a flaw of the regulatory system that needs to speed things up.

That's right.

I think I'm an optimistic fellow. I think the world will equilibrate. Access will be available regardless of a country's economic circumstances. We are trying to make that happen by allowing access to our drugs in Armenia and working with Zydus Pharmaceuticals to make medicines available in India more affordably. The healthcare administration is also pushing for affordability and equalization of access regardless of geography.

I think very much so. It is also a function of the greed factor that starts from Wall Street and emanates to companies, driving profitability quarter to quarter, leading to many compromises that shouldn't be allowed. I have nothing against profitability, but if those profits are wisely invested back in research that produces curative benefit, not just incremental, then we can overcome the biases that inhibit progress.

Yes.

Yeah. It is a major flaw of the system that needs to be corrected fundamentally. Over 20 years ago at ASCO in Chicago, a trial result for Tarceva in pancreatic cancer extended life by 13 days, and nobody asked about the patient's quality of life. The regulatory system measures success by checking a box in a case report form of when the patient died. That creates incremental benefit at what expense. It is a tragedy.

Cancer vaccines: there is no preventive cancer vaccine because you cannot know what cancer a person will develop. Therapeutic cancer vaccines can be customized using mRNA, but by itself it is not sufficient for late-stage disease; it must be used in combination with something else, and the right combination is key. Technology in healthcare is advancing at a snail's pace in the US due to regulatory inhibitions and medical system conformity. Blockages need to be removed by leadership that gets rid of nonsensical rules and focuses on science. China is doing this, and the US is behind.

I think that may be a bit of an exaggeration. There is really no evidence I have seen that supports the widespread utility of these agents in curing cancer. Perhaps prevention may be possible, but we need more science and diligence. It is too simplistic to expect those agents to cure everybody.

Looking at agents like ours that have treated over 1,200 patients in nine different cancers, I would say we are a good 50% of the way there. The next 5 years will be very exciting, but that excitement depends on the regulatory system working collaboratively with innovative companies without biases. Patients cannot wait. We have patients traveling to France, UK, Switzerland, and Brazil to pay out of pocket for our drug. Every day lost in treatment commencement is important because their disease progresses. Speed is critical to bring innovation to fruition.

There were times when I felt maybe I should quit, but they lasted only 10 seconds because my conviction was that we were on the right track to do something remarkably beneficial for patients. It would have been irresponsible to give up. No regrets. It has been difficult; we have raised $3 billion over the years.

A series of events, Princess Dina, that started about four years ago. For example, Chris Liu, a young oncologist, described a 70-year-old lady with hepatocellular carcinoma and an American football-sized tumor in her abdomen. We put her on botensilimab, and within a couple of months, her tumor disappeared. She is now two years out, free of disease. That is a miracle. It doesn't happen every day, but we have quite a few patients like that.

We have studied over 1,200 patients. The big concentration has been in MSS colorectal cancer, the 95% difficult-to-treat cancers. Beyond that, sarcomas, ovarian, lung, endometrial, breast cancer. Some results have been remarkable: a few breast cancer patients in Netherlands, recommended for mastectomy, had their tumor completely disappear in less than 7 weeks and decided against surgery.

It would be very easy. I would basically reform regulation, reform government policies. I would mandate that companies make compromises in reducing their level of greed, and allow for access anywhere in the world for drugs that deserve to get to patients. The obstacles are not just from originator countries but also recipient countries. For example, with a malaria vaccine with GlaxoSmithKline, local governments wanted to cut themselves into the profit, becoming an obstacle. The fundamental human flaw is extreme greed.

I am not a believer in that. There is so much abuse and wasted money on research. There is a clubishness of research institutions like NCI and NIH, where an exorbitant amount of money went into substantiating biases. It is not the amount of money we spend; it is what we spend it on that is most critical.

Thank you very much, Princess Dina. It is a pleasure to be with you, and your insights are just remarkably deep. Thank you very much.