Inside Perspectives on Cancer Immunotherapy: An Interview with MPM’s Christiana Bardon

Boston-based MPM Capital’s Christiana Bardon, M.D., describes immunotherapy as an exciting, transformative field in cancer treatment. She foresees dramatic improvements for patients over the next 10 years.

“We’ve just turned the corner in terms of understanding the best modalities for fighting cancer,” Bardon explains. “Now we can improve on the first generation of immunotherapy drugs, which have shown dramatic proof of concept. I think the field is really going to explode in terms of the number of therapies, the science and the combination opportunities.”

Bardon joined MPM in 2015 as a managing director of the fund. She is the founder and managing member of Burrage Capital, a long-short investment fund in biotechnology and healthcare. Previously, she was a health care analyst at Fidelity Investments covering biotechnology, life science tools and diagnostics. She started her career as an analyst at MPM.

Bardon earned her MS/BS from the Massachusetts Institute of Technology, her MD magna cum laude from Harvard Medical School, and her MBA from Harvard Business School. She was the recipient of a Howard Hughes fellowship, and completed a residency in internal medicine at the Brigham and Women’s Hospital at Harvard Medical School. Bardon currently serves on the Board of Fellows at Harvard Medical School.

WuXi AppTec Communications recently talked with Bardon about the various cancer immunotherapy approaches and about the strategy behind MPM’s $474 million Oncology Impact Fund, which was formed in collaboration with UBS AG. The interview with Bardon is part of a new series showcasing the industry’s most advanced innovations in drug development and the creative people behind them.

WuXi: What is your strategy for investing in the cancer immunotherapy field?

Christiana Bardon: As you know, I’m a partner in the MPM Capital Oncology Impact Fund, which is a fund that we raised last year dedicated to oncology. There is so much new and exciting progress going on in the field of cancer, especially immunotherapy, that we at MPM decided to dedicate an entire fund toward this. Our approach to investing in a fund is a portfolio approach, but here we are focusing on the multiple modalities within cancer and that includes cancer immunotherapy.

Our overall strategy revolves around investing in different modalities which provide meaningful benefit for patients. So these are not the incremental benefits we have seen on the drugs that have been approved over the last 20 years, such as chemotherapy drugs, but really drugs that are going to cure patients or dramatically change the course of their cancer.

We have modalities that are dedicated to checkpoint activation as well as immune activation, cell therapy and T-cell engagers. I think it’s also very exciting to see, especially because future cancer treatment will be a combination approach.

Another key strategy for us is improving on the first generation of drugs which have shown proof of concept. These first generation drugs, for example, cell therapy, have shown incredible efficacy, but in limited indications and in limited subsets of patients. Now we have a chance to improve upon these modalities so that we can reach a broader array of patients as well as a broader array of tumors. These improvements on the first generation of drugs involve less risk, which is why we’re very excited about this strategy.

WuXi: Is immunotherapy the best new weapon against cancer today?

Christiana Bardon: I would say immunotherapy has transformed cancer and will continue to be the best new weapon against cancer. If you think in years past, when we used chemotherapy, we were trying to kill tumor cells, but it was impossible to kill every last tumor cell. If a handful of tumor cells remained these tumor cells could then grow back to a full-fledged tumor. What is great about immunotherapy is that the body’s own immune system is the most effective tool for getting every last cancer cell. That is why, for the first time in the treatment of cancer, we are seeing cures in patients, and that is truly remarkable.

 WuXi: What are the most effective cancer immunotherapies?

Christiana Bardon: Checkpoint inhibitors are the most effective cancer immunotherapy approaches to date. They have been approved by the FDA in numerous indications such as melanoma, lung cancer and NHL. PD-1 inhibitors have also been incredibly efficacious. We’ve seen 20% of patients with long-term complete response.

Just to put that it into perspective, when I was training at the Harvard Medical School we treated melanoma with a chemotherapy drug called DTIC (Dacarbazine), which is incredibly toxic and not very effective. Only about 5% to 10% of patients have a response and for those who have a response it only lasts a few months. Then the second generation treatments were the targeted kinase therapies. There we saw incredible responses because we understood that melanoma was directed by a protein called, B-Raf, but the problem was the tumors were pretty good at mutating away from the targeted therapies and therefore their responses were not long-lived. They were better than the first generation chemotherapy responses, but they still didn’t cure patients.

Now with these PD-1 inhibitors, for example, we’re seeing complete responses and long-term durable complete responses in 20% of patients. That is the type of meaningful clinical benefit we’re shooting for in the next generation of approaches.

One limitation of the first generation PD-1 inhibitors is there are still only 20% responses, not 100%. There are still many patients within melanoma who don’t respond to these PD-1 inhibitors and we need to understand why. The second thing is that not all cancers respond to checkpoint inhibition, especially ones with lower mutational load. We will need to understand how best to address those cancers. So there is still plenty of work to do.

WuXi: You mentioned combination therapies will play a role. How would you describe these combination therapies?

Christiana Bardon: I completely believe that combination therapies are going to be an area of focus over the next five years. When I was on Bloomberg TV during the (June 2016) American Society of Clinical Oncology Conference, the largest oncology conference in the US, that is exactly what I told our audience. The future is in combination therapies.

For one, I mentioned the first generation of checkpoint inhibition does not work for all patients, and it does not work for all tumors, so what we need to understand is what other drugs can combine with these checkpoint inhibitors to address the remaining patients.

In the future, I see a multi-modal approach and that might even include chemotherapy. I can envision a setting where patients are treated with antibodies, radiation, and even chemotherapy. Then we would come in with cell therapies or maybe even T-cell engagers to clear away the residual disease, the last remaining few cells that the immune system is very good at hunting down.

It actually turns out that cell therapies and T-cell engagers work better in a low tumor loading setting because you can avoid the toxicity when you have a lot of tumor burden. Then you would need a checkpoint inhibitor combination to maximize the efficacy of these cell therapies and T-cell engagers. Finally, you might actually finish up with a vaccine to prevent primary and even recurrent tumors.

We have always emphasized combination therapies because cancer is very complex. It has a very high mutational rate and therefore it’s very smart in avoiding our therapies. So you will need a multi-modal approach to cure patients.

WuXi: What do you see as the next major milestones in cancer immunotherapy over the next five years?

Christiana Bardon: As I’ve mentioned, we’ve seen the first generation of these drugs, but they all have a lot of limitations. For example, in the field of CAR-T (chimeric antigen receptor T-cell) therapies, we’ve seen incredible efficacy in pediatric acute lymphocytic leukemia (ALL), but that is a very limited population, and we honestly haven’t seen that kind of efficacy in adult ALL.

We’re now beginning to see emerging efficacy with CAR-T in B-cell lymphoma, but we haven’t seen any efficacy with CAR-T in solid tumors. The field is really ripe to start to improve on these first generation of technologies so we can expand the impact into all tumor types. For example, we recently invested in a company called TCR2 Therapeutics which developed a novel CAR-T technology for solid tumors.

The next major milestone will be to improve upon the modalities that we have already identified and bring them to a broader audience. T-cell engagers are a great example of this. The Bispecific T-cell engager, which was developed by one of my partners, Patrick Baeuerle, Ph.D. when he was with Micromet and which was acquired by Amgen, was incredibly efficacious with  a high response rate in patients with ALL. It had important limitations, including a very short half-life.  More than this, it needed to be chronically infused with an infusion pump. So we recently invested in another company called Harpoon Therapeutics, which seeks to improve upon the drug properties of the first generation T cell engagers and solve some of these problems.

Another major milestone will be to see these combinations of drugs start to work. For example, with checkpoints within the next two years, we will see data in other areas that are just entering the clinic such as the IDO inhibitor and multiple other modalities. These have the opportunity to really transform the efficacy of the PD-1 inhibitors to reach a broader range of patients in more tumor indications.

What’s also going to be exciting is to see these novel therapies address potentially new classes of cells. So for example, while we’ve worked primarily with T-cells, which are indeed the workhorse for fighting cancer, we may better understand and manipulate the role of natural killer cells as well as myeloid derived suppressor cells.

WuXi: Is there still room for small companies in the cancer immunotherapy space?

Christiana Bardon: Absolutely. There is always room for innovation. The truth is that smaller companies are more nimble and more aggressive in bringing innovation to the clinic. That’s just what we see historically in the biotech field and that is what keeps the industry alive.

There is absolutely tons of room for small companies in this space. But I think that because these are such large markets and such large applications – the PD-1 class, for example, is potentially slated to be a $20 billion market opportunity – what we’ll see is that the small companies will be acquired by the large company players as they seek to solidify their role as being the lead combination therapy provider.

I think this will also help pharma companies as they address potential pricing concerns when we stack multiple combination therapies. If they can provide these combination therapies that are more efficacious than the other guy who is only providing one, and they do it at the same cost, I think that is going to be transformative for patients.

WuXi: Do you expect investor enthusiasm to continue growing or plateauing over the next five years?

Christiana Bardon: That reminds me of a question when we were on a road show.  While we were discussing the efficacy of the first generation PD-1 inhibitors, people said, “Wow that sounds like cancer will be cured soon! Will there be anything left for you to do?”

My response was – absolutely there is still work to be done! I don’t think in my lifetime, we will cure everybody’s cancer, and every type of cancer.

Only in the last five years have we figured out that the immune system plays a role. Now there are hundreds and thousands of ways to apply that science and that thinking toward developing new therapies.

So, there is a ton of work to do. We had such an easy time raising our fund because people appreciate how transformative this can be. I would say we are at the cutting edge. We are not at the bleeding edge yet. Cell therapies have been around for over 20 years. The problem was we couldn’t really make them and we couldn’t make the cells grow in patients. They died very quickly and therefore had no efficacy. One of our partners, Mitchell Finer, Ph.D., is a leader in the cell therapy space. He was a previous chief scientific officer of bluebird bio. He’s been working on this for 20 years. And the truth is that it’s only recently that we have figured out how to make these cell therapies work. So good, we know how to make them work, but they don’t work that well and they don’t work in every patient. There are limitations, so now that we know it works, we can actually improve and transform these therapies to broaden the applicability. In the future cell therapies may be used for multiple tumors types with dramatic efficacy.

WuXi: Do you want to talk more about the Oncology Impact Fund? We noticed it has a social responsibility aspect.

Christiana Bardon: We actually think that’s a really big part of investing. One of my main personal philosophies is that life is a virtuous cycle. There are two points in a virtuous circle of investing in new technology. One is where does this new technology come from? And two, making sure that all patients can access the technology.

So what we’ve actually designed into our Oncology Impact Fund is that a portion of our fund, a major portion, will be returned to these two areas.

New innovation and early stage research comes primarily from the U.S. National Institutes of Health and the U.S. National Cancer Institute. This research will lead to the formation of new companies. So we have partnered with the American Association of Cancer Research to make sure that our money gets back to the most promising basic cancer research in the field, so that this virtuous cycle of new science leading to new therapies can continue.

The other aspect is making sure that all patients can access this therapy. So we’ve partnered with UBS to administer an access program, especially in the Third World, to make sure that all patients with cancer have access to these very exciting therapies.

WuXi: Aside from the scientific challenges, what are the top barriers in bringing cancer immunotherapies to patients?

Christiana Bardon: What is more complex about these new generations of modalities is that they are not like small molecule chemotherapy. Small molecules are easier to make and deliver to patients.

The new modalities, such as antibodies, and especially cell therapies, are much more complex to manufacture. A lot of companies have great ideas, but if you can’t make it, it’s not going to work. You have to make it consistently to FDA grade and specification with the appropriate quality assurance. Manufacturing is incredibly important in making sure these novel therapies can actually be reproducibly studied in clinical trials and approved.

I would say the second barrier is making sure these therapies have business models that make sense. CAR-T therapies, for example, are autologous. They require taking the cells from patients, modifying them, and giving them back to the patients. That’s a very complicated process. So we need to make sure that these next generation of cell therapies have a business model that makes sense so that companies can sustainably make therapies for patients.

I think the third issue is going to be pricing and access, especially if we see combinations of therapies with multiple modalities. That’s why when we invest in a company we want to see meaningful clinical benefit. People are willing to pay for a treatment if you can cure their cancer or convert their cancer to a chronic disease. That’s the hurdle you have to meet. So from that perspective, you have to swing for the fences to make sure you’re going to have a meaningful impact for patients and make sure that the system can find value in your therapy.