SOTIO has developed a method to generate autologous dendritic cells that express multiple tumor antigens on their surfaces to awaken oncology patients’ immune systems to attack the cancer.

Radek Spisek, Ph.D., the company’s Global CEO, observed that cancer cells express many different tumor antigens. In their ongoing effort to elude detection by a patient’s immune system, those tumor cells shed some of their antigens.

To counter this evasive strategy, SOTIO arms the patients’ dendritic cells, which Spisek describes as the immune system’s most important cells, with “multiple different tumor antigens,” he explained. “In case two of those antigens disappear from the tumor cell, or five of them, we still have many additional shots on goal. There are still additional targets for the immune response that can be explored and we believe that this is important,” he said.

SOTIO is developing its dendritic cell platform for treatment of lung, prostate and ovarian cancers. The Czech company’s most advanced program targets prostate cancer and it expects to complete its Phase III registration trial in Europe and in the U.S. in 2020. Next up is a Phase III trial in ovarian cancer, which will take four years to complete. The company is also in discussions to design a potential registration trial for lung cancer patients.

As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Spisek about his company’s technology and the challenges of developing new drugs for cancer.

Spisek participated in the founding of SOTIO in 2010 as Chief Scientific Officer and was appointed Global CEO in March 2018. He received his Ph.D. in immunology from the 1st Faculty of Medicine of Charles University in Prague and is a professor at Charles University’s 2nd Faculty of Medicine. Spisek also worked at the Institute de Biologie of Université de Nantes in France and the Center for Immunology and Immune Diseases at Rockefeller University, New York.

WuXi AppTec: Is your immunotherapy targeting early stage treatment of solid tumor cancers, including lung cancer?

Radek Spisek: In our cancer immunotherapy program, we already have very intriguing data in ovarian cancer, and initial data in lung cancer, that show positive signs of efficacy in our ongoing clinical trials, especially in patients who are at the stage of either minimal residual disease or minimal tumor burden; or patients who are in remission after the standard of care chemotherapy and have low tumor burden.

So, our approach seems to be best suited for patients who are diagnosed early, who have low tumor burden, where the immune system is still fully functional and when there is a great chance that successful immunotherapy might lead to induction of anti-tumor response and subsequently result in improvement of the prognosis of the patient.

WuXi AppTec: How much progress has been made in lung cancer drug research over the past 10 to 20 years?

Radek Spisek: There has been a revolution in the treatment of many solid tumors after the successful introduction with checkpoint inhibitors. They represent a novel class of treatments that exploit the immune system. The outcome is that you delete the immunosuppressive environment in the patients and you give the immune system a chance to get active, attack the tumor cells and eliminate them.

Almost 10 years ago, the introduction of checkpoint inhibitors for the treatment of melanoma, then non-small cell lung cancer and then many other solid tumors really represented a change of paradigm, which for me now signals the addition of a new modality to the three classical modalities of radiotherapy, surgery and chemotherapy.

Over the course of the past 10 years, checkpoint inhibitors have found their place in the standard of care treatment protocols, including those for lung cancer. It’s fascinating to see that they basically moved to a front-line treatment for lung cancer, and we now see many clinical trials where checkpoint inhibitors are tested as front-line treatments in head-to-head comparison with standard of care chemotherapy or in combination with chemotherapy.

This decade-long process in the development of checkpoint inhibitors for lung cancer really resulted in the substantial improvement in the prognosis of the disease. To me this represents a revolution and rightly so was recognized with a Nobel Prize in 2018 for Jim Allison, of the MD Anderson Cancer at the University of Texas, and Tasuku Honjo, of Kyoto University.

WuXi AppTec: How does SOTIO’s active cellular immunotherapy platform work in treatment of lung cancer?

Radek Spisek: It falls into the category of active immunizations, so it means you are trying to actively induce anti-tumor action in the patient’s body. You are trying to get an anti-tumor immune response that recognizes the tumor cells and eliminates the tumor cells, prolonging survival of patients with lung cancer.

There are many approaches that fall into this category of active immunization. What we are trying to explore is an approach based on dendritic cells. Dendritic cells are the most important cells in the human immune system. They are necessary for the induction of the immune response.

What dendritic cells do very well is present tumor antigens on their surfaces, which become accessible to the effector cells of the immune system, especially T lymphocytes. When T lymphocytes see the tumor antigens on dendritic cells, the T lymphocytes get activated, they proliferate, they amplify and then they can recognize tumor cells that express these tumor antigens and kill them.

In our clinical programs, we enroll patients into the clinical trial and then we artificially, in our cell therapy laboratories, generate hundreds of millions of dendritic cells from a particular cell subset in their blood.

Patients go to a blood transfusion center and spend two to three hours there while we collect hundreds of millions of white blood cells from their peripheral blood. From these white blood cells, we generate hundreds of millions of dendritic cells within one week. There is one additional step we do in our laboratories and that is we introduce the tumor antigens into the dendritic cells. Our cell therapy laboratories are in Prague, Czech Republic and in Beijing, China.

The tumor antigens are known to be present in lung cancer, and the outcome of their introduction is that the dendritic cells take up the tumor antigens and then they express them on the surface and this results in dendritic cells that are fully capable of inducing anti-tumor responses in the patient’s body.

Next we freeze the dendritic cells in liquid nitrogen so they remain viable and when the patient comes to the hospital outpatient clinic, the physician takes up the frozen vial of the dendritic cells, thaws the cells and by a subcutaneous injection, injects the cells and they migrate in the body to the lymph nodes of the organ where they interact with the T lymphocytes. They activate the T lymphocytes, which do their job and kill the tumor cells. This a complicated process that we need to do for every patient involved in the trials.

WuXi AppTec: How do you introduce the tumor antigens into the dendritic cells?

Radek Spisek: This is a specific element of our program that is patent protected, but most of it has been presented and published in scientific journals. What we decided to do a long time ago and what will differentiate our approach from other ones is that the source of the tumor antigens is the tumor cells.

We identified a mixture of two specific lung cancer cell lines that express many of the relevant antigens in lung cancer. We take the cell lines and kill them by a specific method called high hydrostatic pressure. This kills them but it also makes them express high levels of the tumor antigens. When they are killed, they are put together with the dendritic cells, which eat up or engulf the dead tumor cells – it’s called phagocytosis. Then they cleave the tumor cells to the individual tumor antigens and the tumor antigens are presented on the surface of the dendritic cells. This is what normally happens in vivo and we can make this process in vitro as well.

WuXi AppTec: How is this different from the CAR-T cell immunotherapy?

Radek Spisek: CAR-T cells are a totally different approach. They deal with the last component of this chain. I told you that we inject dendritic cells and we hope that in the patient’s body they activate T lymphocytes and the T lymphocytes then kill the tumor.

The CAR-T cell industry does something that is very smart. They take the T lymphocytes, which are the last piece of the chain of immune reaction, and they genetically modify the T lymphocytes so they can specifically recognize a tumor antigen in the body.

So, the outcome of the CAR-T cell production is hundreds of millions of T lymphocytes that when injected into the body go directly to the tumor and kill it. It’s cancer immunotherapy at a different level.

The main difference is that we are using a response against multiple tumor antigens. Through our approach, we inject the dendritic cells into the patient. They express many tumor antigens – let’s say 25 different tumor antigens – and this results in the activation of the immune response against multiple targets on the tumor cell. I personally believe this is extremely important because then you have an immune response that fights many targets on the tumor cell.

What very often happens in the development of the tumor is that the tumor tries to escape the immune response and one way the tumor tries to escape is it loses expression of some of its tumor antigens. If you only have a CAR-T cell active against one tumor antigen and that tumor antigen is gone – it’s not present on the tumor cell – the CAR-T cell cannot do anything. It can’t see the tumor any more.

What we have is a complex, robust immune response against multiple targets and in case two of those antigens disappear from the tumor cell or five of them we still have 20 shots on goal. There are still 20 targets for the immune response that can be explored and we believe that this is important. We see this benefit for patients in our lung cancer program and our ovarian cancer program. It’s a very significant benefit in terms of prolonging survival.

WuXi AppTec: How are you applying your platform to the development of immunotherapies for prostate and ovarian cancer?

Radek Spisek: We have a unique opportunity here. SOTIO started in 2010 and from the beginning we were funded by a very large Czech financial institution, called PPF Group.

SOTIO is being built as a company that doesn’t want to be focused on a single program. We have been building for the past 10 years an oncology-focused company with a diversified portfolio of programs that all explore different arms of the immune system.

At this stage we have six or seven programs at various stages of development. One program is focused on the dendritic cells and the dendritic cell platform has been optimized for lung cancer, ovarian cancer and prostate cancer. We have very interesting data from a Phase II program in ovarian cancer and in lung cancer where we see statistical significance of survival benefit in patients, which is the most important endpoint in oncology studies.

This year we also brought to the clinic, after extensive preclinical work, a program where we have a molecule that very efficiently stimulates T lymphocytes and NK cells. It’s a molecule based on interleukin 15 (IL-15). We call it a superagonist of IL-15. This is now a very popular field in oncology research – proteins that can very efficiently activate those T cells, expand them and make them proliferate. This program is at the Phase I clinical trial stage.

We are very close to bringing to the clinic one more program that is in the domain of antibody drug conjugates. We have a monoclonal antibody that recognizes tumor cells in gastric cancer and to this monoclonal antibody we attach a few molecules of a very toxic compound that kill the tumor cells.

The idea of this approach is that the antibody brings those toxic molecules very specifically to the tumor cells that express the specific target for the antibody. The tumor cell then takes up the antibody, which releases the toxin and the toxin kills the tumor cell. We believe we may have a very interesting program for clinic trials in the next year and a half.

SOTIO is looking for other portfolio programs and also doing minority investments into interesting biotech companies we want to cooperate with.

WuXi AppTec: What are some of the other ways your cancer immunotherapy differs from other immunotherapies?

Radek Spisek:  There is one more difference that is built into our clinical trials. We always incorporate long-term administration of the compound. In other words, our approach is not that the patient comes to the hospital and receives three shots of the vaccine and then that’s it.

We have data that show it’s important to continuously boost the immune response. If you boost it once in four weeks, the tumor response goes down because it’s not very strong and it’s important to boost it again. We basically have in our clinical program one year of treatment for the patients where we continuously boost the immune response. It’s our belief, and it’s now supported by the data, that this long-term administration is important for the clinical efficacy of these approaches.

WuXi AppTec:  What major challenges have you faced in developing your immunotherapies? What lessons have you learned that you can share with other CEOs?

Radek Spisek: There’s an obvious answer to this one. What we are trying to do is very challenging with respect to the logistics of the process. Manufacturing and administering the cells is very complex – we have built a whole logistical system around it.

The fact is we need to produce cells for each individual patient. In clinical medicine, people call this an autologous approach. For every single patient involved in your clinical program you need to generate a compound specific for that particular patient.

This has significant logistical challenges. We need to have a network of blood transfusion centers where we collect the cells from patients. Then the cells need to make it from the blood transfusion unit to the SOTIO manufacturing site – one of the largest cell therapy facilities in Europe.

And because we are working with living cells, we need to ship the cells within 30 hours to keep them alive, so we can work with them and modify them. Then at the end of the manufacturing process we need to get the cells to the hospital and back into patients’ bodies via subcutaneous injections.

The major complication – and the major drawback – of these autologous therapies is the need to produce a specific cellular product for each individual patient. That’s the biggest challenge that we overcame.

We have a very sophisticated network of fully functional blood transfusion units. We have very sophisticated software solutions for the logistics of cell shipment. We manufacture the cells in the Czech Republic then ship them and store them in facilities that are close to the clinical side. But this, of course, represents an additional cost of goods that complicates the process and makes it more expensive.

WuXi AppTec: How will you maximize the value and benefit of your therapies for patients globally?

Radek Spisek: If our clinical trial programs are successful and these cell therapies are approved, the vision of the company leadership and investors is to commercialize them – and we believe that can be done globally. We can already serve the U.S., the Europe and China with the existing process.

We are doing a large, global prostate cancer clinical trial that includes sites in the U.S. and Europe. There are almost 1,200 patients enrolled in the trial and there has never been a single mistake in the logistics and the processing of the cells. We have also done all sorts of financial analyses that show us this program might be commercially viable if it gets on the market at a similar price point to other oncology products.

WuXi AppTec: How soon will your immunotherapy reach the market?

Radek Spisek: We will have the results of the prostate cancer trial in 2020. The next program, is in ovarian cancer. The timeline from the beginning of the registrational trial to the analysis of the results is four years from now. We now have two shots on goal: next year with prostate cancer and four years from now with ovarian cancer. We are still discussing the design of the potential registrational trial for the lung cancer program.

WuXi AppTec: What are the top impediments for delivery of better medicines faster and cheaper for patients?

Radek Spisek: The biggest issue is one that cannot be solved easily. In SOTIO we’ve been screening more than 300 new oncology programs a year. We are trying to identify oncology programs at the stage of preclinical studies and there are very few approaches, I think, that have a reasonable chance to make it to the market and be successful.

This is not an impediment that is caused by the regulatory environment. It is also not caused by the lack of financial resources. It’s really the nature of oncology – of tumor cell biology. We are at the stage where many mechanisms of the tumor cell have been explored. There are many drugs out there and the prognoses of many cancers have improved significantly.

And I think what we’ve seen over the past 10 years is there are a very limited number of programs that can be game changers. This is an inherent problem of oncology research at this stage. I see very few effective programs at the preclinical level that make me believe they can become new drugs in oncology.

Then, of course, what I see from our experience is the financial need required for text book development in oncology. The cost per patient in clinical trials is increasing tremendously. I have seen a 30 percent to 40 percent increase in the clinical trial costs in the past five years. This is really getting to the point where many companies are struggling to find the financial resources to follow the clinical development program. For me, this is currently the biggest hurdle.

You often hear people comment on the complicated regulatory environment in oncology. I don’t share this opinion. I think that regulators, especially the US Food and Drug Administration, are actually trying to create an environment that facilitates the approval of compounds that look promising at the stage of early clinical data. When the compounds look interesting, there are mechanisms to speed up development and accelerate approvals.

But really, the financial burden of increasing clinical trial costs is currently the biggest hurdle in the development of new compounds.

WuXi AppTec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure in cancer?

Radek Spisek: I am on the more skeptical side of this. From the 15 years of experience I have in oncology research, it’s very rare to see complete game changers that lead to a cure.

I am more a believer in incremental improvements and in the combination of the different treatment modalities. This is what you see in most of the solid tumors. Incremental improvements in the prognosis of the disease come from introduction of new drugs that provide some benefit and then combining these novel treatments with pre-existing ones. This leads to a gradual improvement in the prognosis of the patients.

I don’t expect to see a dramatic shift in the case of lung cancer that would result in 100 percent survival from the 20 percent survival you currently see in advanced patients. I doubt there will be a treatment like this.