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Carlos HF Chan, MD, PhD, Receives 2022 SSO Clinical Investigator Award

Carols ChanThe SSO Clinical Investigator Award was introduced in 2007 to recognize early-to-mid-career investigators with a record of peer-reviewed funding, and to support further clinical cancer research. SSO’s research grant program is made possible through generous donations to the SSO Research and Education Fund. Since its inception, the award has granted more than $4 million to 39 recipients. The title of the 2022 award-winning proposal, presented by Carlos HF Chan, MD, PhD, is “Clinical Translation of New Immunotherapy-based Concepts in Patients with Peritoneal Metastasis.” SSO recently spoke with Dr. Chan about his research.

Thank you for your time today, Dr. Chan. Let’s start by having you tell me a little about yourself, your training, and how you chose your specialty.

I completed my general surgery training at McGill University in Montreal, Canada, followed by the complex surgical oncology fellowship at Dana-Farber Cancer Institute in Boston, MA, where I spent time at both Massachusetts General Hospital and Brigham and Women’s Hospital. That’s when I became interested in studying and treating peritoneal metastasis of gastrointestinal and pancreatic cancers. Available treatment for peritoneal metastatic disease is very limited. So, I wondered what could be done to improve patient outcome.

When I started my research lab in 2016 at the University of Iowa where I am currently a tenured associate professor, I wanted to know what makes certain cancers grow in the peritoneum and why some patients experience better treatment outcome than others. I began by investigating the immune system in the peritoneal cavity of patients with peritoneal metastatic disease originated from the gastrointestinal tract. It turns out that the immune cell population within the peritoneal cavity varies from patients to patients. The microenvironment is in general very immunosuppressive making it an interesting target for novel immunotherapeutic drug development, since current immunotherapy with checkpoint blockade is not a treatment of choice for most of these patients.

We also don’t know enough about the direct effects of chemotherapy on the peritoneal immune system. Most of what we learned so far came from research done on ovarian cancer over the past few decades. While we can extrapolate a good amount of acquired scientific knowledge, gastrointestinal cancer, especially pancreatic cancer, is a different beast. I wondered if there might already be an existing treatment or drug that would change the peritoneal immune microenvironment from an immunosuppressive to activated state. That’s when I met with Dr. Jessie Au who is leading a research team to develop a polymeric microparticle loaded with the chemotherapy agent, paclitaxel, that has the ability to penetrate and destroy peritoneal tumors. After successful preclinical animal studies, they received FDA approval for human clinical trials. But they needed surgeons who can bring this new drug formulation to clinical trial. That’s when I decided to step in and move this drug into clinical trial.

My specific question was whether these Tumor Penetrating Microparticles (TPM) could induce an immune response in the peritoneal cavity. A great deal of research studies exists on chemotherapy-induced immune responses in cancer, but the majority of these studies show the immunogenic effects are quite short-lived. To leverage the anti-cancer immunity, we need something that can produce a sustained effect on the immune system. If we can change the tumor microenvironment and activate the immune system using these TPMs, we can move to the next phase of this study which would combine TPMs with immunotherapy.

When you refer to slow release, what period of time does that actually cover?

For this study we need to look at the pharmacokinetics and pharmacodynamics of these particles, how these drugs travel through the peritoneal cavity, how much ends up in the blood, and how much actually gets inside the peritoneal tumor. Based on our mathematical models, we calculated a period of roughly around 100 days.

We’ve learned from animal studies the way these particles penetrate and destroy tumors and slowly release chemotherapy. They have unique penetrating properties that other drugs do not offer. This is a localized therapy (as opposed to systemic) introduced through the abdominal cavity, which is quite a different approach. When you can directly access the tumor and penetrate it with these particles, you can achieve a localized effect. We believe there is a high probability of inducing an immune response by treating peritoneal tumors with chemotherapy. However, because the immune responses are so short-lived, we have yet to see any long-term effects. I think the key is to apply constant pressure to the tumor through a slow-release treatment.

How far along is your research? Have you enrolled any patients?

We did experience pandemic-related delay so we have only enrolled one patient in this study to date. We expect to enroll 15 to 30 patients during this phase 1 trial. Once we demonstrate the feasibility of this study, we can move on to phase 2. We plan to enroll patients with peritoneal metastasis for whom standard therapy is not working. They could have any type of cancer—pancreatic, colon, gastric, ovarian cancer or mesothelioma.

How is the chemotherapy agent you are using different?

The active chemotherapy agent we are using is Paclitaxel, a drug that has been used to treat tumors in the peritoneal cavity. The novelty of TPM is that these particles have specific polymer composition such that one part releases the drug rapidly as soon as the particles hit the body temperature and the other slow-release part releases the drug slowly. This way patients would receive a quick-onset, fast-release dose, followed by the controlled-released drug for the next 100 days. This drug was designed under the direction of Dr. Jessie Au, a cancer pharmacologist with 20+ years of grant support from the National Cancer Institute. TPM is produced by the National Center for Advancing Translational Science (NCATS), so it is not commercially produced. It could cost nearly $1,000,000 to produce one batch of TPM. NCATS is sponsoring the drug portion for our clinical trial. If everything goes as planned, we can finish the treatment part of this study in two years and determine the best dosage.

How were you able to partner with NCATS?

I was lucky to get involved because Dr. Au initially was partnering with some other well-known surgeons. As you would imagine, they were very busy and she couldn’t get the study off the ground. It happened that I was looking for what she had to offer. Originally, I was supposed to be one of the study sites. When the other surgeons weren’t able to participate, we became the only study site for enrollment. NCATS is pleased because they can finally take this newly developed, tumor-targeting formulation to patients.

I am grateful to Dr. Au and NCATS for making my research possible. I also want to thank SSO for its generous funding and for understanding the potential of my study that holds for advancements in treatment and patient outcomes. Finally, I’d like to thank the University of Iowa Holden Comprehensive Cancer Center. Without my team and institutional support, I would not be able to complete this work. From infrastructure to research and development, it takes a large research team to make this trial possible.

When do you hope to have everything completed and what are next steps?

If everything goes as planned, we can finish the treatment part of this study in about two years, at which point I’d like to take this research further. I’d like to be able to determine the optimal dosage for individual patient based on a model-informed drug development (MIDD) approach along with Dr. Au. This is important because each patient has variable abdominal cavity size and stiffness, tumor burden and distribution, and cancer types, and all these variations could potentially affect regional drug delivery. MIDD, we offers the ability to personalize the drug dosing based on these variables.

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