Behind the Changing Landscape of Chordoma Research and Treatment with Joan Levy, PhD

Sarcomas are an aggressive type of cancer that can arise from soft tissues such as muscle and fat as well as tissues such as bone and cartilage. In 2018, there were an estimated 16,000 cases of sarcoma in the U.S. alone, comprising roughly one percent of all cases of cancer. One type of sarcoma that develops from bone is known as chordoma, and patients with this extremely rare cancer—there are only about 300 new diagnoses per year in the U.S.—have few treatment options.

To determine whether immunotherapy might be an effective option for this hard-to-treat disease, the Cancer Research Institute launched a partnership with the Chordoma Foundation to identify and fund promising chordoma research involving cancer immunology and immunotherapy with the aim of aiding the development of better treatments for these patients.

As part of Sarcoma Awareness Month in July, CRI spoke with Joan Levy, PhD, director of research at the Chordoma Foundation, in order to better understand the current state of the chordoma field and how this partnership might impact its future.

Arthur N. Brodsky, PhD:

Dr. Levy, thank you for speaking with us today. Most people reading this have never heard of chordoma. Could you please tell us more about this type of cancer?

Joan Levy, PhD:

Thank you for having me, Arthur. Chordoma is an ultra-rare type of cancer—diagnosed in just one in one million people per year—and occurs in the bones of the skull base and spine. Since it’s a bone cancer, it’s also considered a sarcoma. At any given time, fewer than one in 100,000 people are living with chordoma. Chordomas strike people of all ages, can be complicated to remove, and commonly regrow in the area where they originally developed. A combination of surgery and radiation have the potential to cure some chordoma patients, but complete cures are rare and it’s even more difficult to treat disease that has spread, or metastasized, to other parts of the body.

Arthur N. Brodsky, PhD:

What is the Chordoma Foundation and how is it helping fight this deadly disease?

Joan Levy, PhD:

The Chordoma Foundation was started twelve years ago by a small group of patients and family members including our executive director and co-founder, Josh Sommer, who was diagnosed with chordoma as a college student at Duke University. When Josh started to research chordoma, there were very few reasons for hope. There were not very many active researchers. There was very little known about the biology of chordoma, nothing understood about therapeutic targets, only one completed clinical trial, and no companies investing in research or treatments for chordoma.

It became clear that someone, or a group of people, had to take very active roles to learn more about chordoma in order to bring better treatment options to chordoma patients. The Chordoma Foundation was established in 2007 with a vision for a better future for chordoma patients. Our mission is to improve the lives of those affected by chordoma and lead the search for a cure. Since the Chordoma Foundation was started, we’ve been actively involved in building the research community by providing infrastructure, resources, and the ability for these different groups to communicate with one another.

Arthur N. Brodsky, PhD:

That’s great to know that you have worked to fill in this important gap and lay the groundwork to help this underserved patient population. You mentioned one of the reasons Josh started the foundation was because there wasn’t much research into the disease and there weren’t that many treatment options for patients. So, how is chordoma currently treated?

Joan Levy, PhD:

Currently, chordoma is treated primarily by surgery with or without radiation. There have been improvements in surgical techniques, and there have been improvements in the types of radiation that is used. However, there are still no systemic treatments that have been approved for chordoma patients. And the challenge is that 30-40 percent of patients will progress after treatment and have their disease spread, or metastasize, to distant sites. Unfortunately, when the disease becomes that advanced, sometimes it cannot be surgically removed and therefore there is a tremendous need to find systemic treatments for patients with advanced chordoma.

Arthur N. Brodsky, PhD:

When you say that there are no systemic treatments, does that mean that chemotherapy doesn’t work for chordoma?

Joan Levy, PhD:

Chemotherapy has been tried in chordoma and in the majority of patients who are classified as having conventional chordoma, the chemotherapy agents typically do not demonstrate any clinically significant activity. There’s a very small subset of chordoma that’s called de-differentiated chordoma, where chemotherapy has been shown to generate some responses but, again, the majority of chordoma patients will not respond to standard chemotherapy.

Arthur N. Brodsky, PhD:

This is where immunotherapy comes into the conversation, I imagine. While it has been effective in treating some cancer types, these treatments aren’t yet approved by the FDA for chordoma. I understand that these and other immunotherapies are currently being explored as potential options for these patients, right?

Joan Levy, PhD:

Immunotherapy is being explored in a few different ways. Physicians are using some of the different types of immunotherapies in chordoma patients with very advanced disease [who have no other options] and there have been anecdotal reports of some responses. The Chordoma Foundation is also supporting a few clinical trials that are testing immunotherapies. Some of these trials involve vaccines against the key driver of chordoma, a protein called brachyury. That’s being studied in combination with radiation in the advanced chordoma patient population. And checkpoint immunotherapy trials are also being used in combination with radiation and other types of treatments in clinical studies.

Arthur N. Brodsky, PhD:

So, I know that there are some trials that welcome “all comers” and patients with almost any cancer type can enroll, but other trials that are specifically for patients with a certain type of cancer. Are these immunotherapy trials specifically for chordoma patients?

Joan Levy, PhD:

The trials that I just mentioned are specifically for chordoma patients, however, you bring up a really good point. There are other immunotherapy trials that are open to patients with a variety of advanced solid cancers, including chordoma patients. So, between the chordoma-specific studies and the “all comer” studies there are a number of trials testing immunotherapies that are relevant for chordoma patients. The Chordoma Foundation has a lot of this information for patients on our website and our clinical trials catalogue, which includes all chordoma-specific trials including these immunotherapy trials that I’ve mentioned as well as relevant trials that chordoma patients can enroll in. These involve immunotherapies, targeted agents, and other combinations.

Arthur N. Brodsky, PhD:

Given how rare chordoma is, as you mentioned, there isn’t a great deal of investment being made in research to better understand the biology of chordoma, which is likely hindering the development of potential cures for these patients. So in that light, how do you hope that the collaboration between the Chordoma Foundation and the Cancer Research Institute (CRI) could help advance this research and ultimately help patients in the clinic?

Joan Levy, PhD:

I want to address that in a few different ways. The first thing that I want to state is one of the great successes of the Chordoma Foundation is that we’ve been able to build a network of researchers who work together across the chordoma community. We went from a handful of investigators a decade ago to over 350 researchers worldwide who are interested and are actively involved in studying chordoma today.

Collaboration has been a huge driver of this progress and I think this particular collaboration between the Chordoma Foundation and Cancer Research Institute will be extremely beneficial for a number of reasons. One is by addressing the need to understand findings from the lab and then translate them to the clinic, which is the main goal of this funding opportunity. This is extremely important when it comes to taking therapeutics that are being used in other cancer indications that might also be beneficial in chordoma, and advancing these immunotherapies into chordoma specific clinical trials.

I think it’s a prime opportunity where some immunotherapies are being tested in chordoma patients, but we really need to understand why they will or will not work in different patients.  The collaboration with CRI aims to really help us better understand the different interactions between immune cells and chordoma tumor cells, why patients might respond better to certain treatments, and be able to identify better combinations with immunotherapies that we may be able to bring to chordoma patients.

Arthur N. Brodsky, PhD:

It definitely seems like there would be a benefit to leveraging existing approaches and brining them to bear against chordoma. Beyond helping chordoma patients, could you talk a little bit about why it’s important to fund research and work on developing better treatments for these patients with rare cancer?

Joan Levy, PhD:

Well in terms of rare cancers, we have to remember that chordoma is an ultra rare cancer. But with respect to rare cancers as a whole, rare cancers, which includes pediatric cancers, represent about 25 percent of all cancers. So I think it’s really important not to ignore this large subset of the cancer population because they are critically in need of new therapies in general.

In chordoma, and in many of these rare cancers, once the tumor has been removed and then grows back you might not be able to surgically remove it again depending on where it is. I really think in the advanced setting of chordoma and other rare cancers, it’s critically important to try to find systemic therapies. Especially since the classic chemotherapy agents are not working in the majority of chordoma patients. We really need to come up with a new wave of targeted and immune therapeutics for study and to bring better treatments to patients.

Arthur N. Brodsky, PhD:

In general, checkpoint immunotherapy’s clinical success started with cancers like melanoma or lung cancer. For various reasons, these tumor types respond relatively well to immunotherapy. One being that they usually have more mutations, and thus are more “visible” to the immune system. But these treatments haven’t always translated to other types of cancer. Is it also possible that by figuring out solutions for chordoma, which is a relatively hard-to-treat cancer, that this could also reveal insights that could be applied to the treatment of other cancers?

Joan Levy, PhD:

Yes, when it comes to mutations, I think chordoma is thought to be fairly silent at the genomic level, meaning that it doesn’t have as many mutations as say lung cancer or melanoma. So it would go into that class of cancers that are more difficult to treat with immunotherapy. However, as revealed at some of the recent cancer meetings, there are strides being made in how to treat some of these more immunotherapy-resistant tumors with different types of immune agents and through combination approaches. I’m encouraged that chordoma could fall into this class.

Additionally, chordoma is treated with radiation in many cases, and it’s been shown in a number of different cancers that radiation can make tumor cells more susceptible to immune attack and maybe even enhance the benefits of immunotherapy when used in combination.

And that’s why many of the trials in chordoma are exploring the combination of different types of immunotherapy and radiation, like the combination of brachyury vaccine and radiation as well as the combination of checkpoint immunotherapy and radiation.

Arthur N. Brodsky, PhD:

Along with you, I’m hopeful that some of these combination strategies will prove effective for patients with advance chordoma. At the very least, these trials should provide insights that can aid the development of novel strategies. So before we wrap up, I want to turn toward the future. With the launch of the collaboration between the Chordoma Foundation and CRI, what are your hopes for the research that we’ll be funding together and how do you hope that this will impact the chordoma field and potentially the treatment landscape for chordoma patients?

Joan Levy, PhD:

I think that the collaboration will enable many people in the chordoma research community who are interested in immunology and immunotherapy to really think about how they could translate some of the basic scientific findings to the clinic. And we hope to attract the great researchers in the Cancer Research Institute’s network to focus their time and talents on chordoma and even form collaborations with the chordoma research community to increase our understanding of immune biology in chordoma as well as advance immunotherapies to the clinic for chordoma patients.

It’s a particularly exciting time to do this because of the knowledge that’s been gained in other cancers that are more difficult to treat with immunotherapy. I think the investigators will be looking forward to this research opportunity to bring new therapeutics, like immunotherapy, to chordoma patients, especially those with advanced disease, who don’t have the systemic treatment options.

So, I’m hoping that this partnership will stimulate some really amazing collaborations and help advance research that leads to additional treatment options for chordoma patients.