A new arrival at University of Colorado Cancer Center tests a homegrown treatment for aggressive leukemia

A physician-scientist who last year joined the University of Colorado Cancer Center team will soon steer the first human trial of a homegrown novel chimeric antigen receptor (CAR) T-cell therapy for an aggressive, hard-to-treat form of leukemia.

Mathew Angelos, MD, PhD, an assistant professor in the CU Anschutz Department of Medicine’s Division of Hematology, says this is exactly the sort of work he came to CU Anschutz to do. “I’m very excited to have the opportunity to lead this and make it a successful project,” he says.

Starting early next year, Angelos will help lead a clinical trial of CART64, a form of personalized CAR T-cell therapy developed at CU, as a therapy for cases of acute myeloid leukemia (AML) that resist standard therapy.

If successful, it would be the first CAR T-cell therapy in the United States that targets the specific cells markers that CART64 will use. “We’re creating something from scratch here in Colorado that could fundamentally change how we treat myeloid diseases,” Angelos says.

The trial is backed by a $1 million grant from Blood Cancer United (formerly the Leukemia & Lymphoma Society). Angelos also has received funding supporting his work through the American Society of Hematology Scholar Award and is one of four recipients in the latest round of the National Comprehensive Cancer Network’s Young Investigator Awards.

A different disease

AML is the most common type of acute leukemia in adults, especially for those over age 65. AML starts in the bone marrow and can quickly move into the blood. It can spread to other parts of the body as well, including the lymph nodes, liver, spleen, and central nervous system.

The American Cancer Society projects that about 22,020 people in the United States will be diagnosed with AML this year, and that about 11,090 people will die from the disease.

A standard treatment for adult AML is a combination of drugs – hypomethylating agents and venetoclax, known as HMA/Ven therapy. But while this treatment helps many patients initially, most eventually relapse, with under half surviving beyond two years. In fact, the average overall survival for patients who relapse after HMA/Ven therapy is two to three months, Angelos says.

In recent years, CAR T-cell therapy has revolutionized treatment of stubborn cancers that resist other forms of treatment. “But CAR T cells for AML have just not worked very well,” Angelos says. “There’s a lot of biological reasons for that, but it comes down to the fact that AML is a different disease from other blood cancers.”

Promising lab results

For one thing, Angelos says, there’s more “heterogeneity” in AML compared to other blood cancers – variations that make it harder for CAR T-cell therapy to work well because the cancer cells don’t all present the same targets for therapy. He says that protocol designs in previous attempts to use CAR T-cell therapy against AML “used the same approach that we have for other diseases where CAR T cells are commercially approved, but for AML, we have to think differently.”

Previous research led by CU Cancer Center member Craig Jordan, PhD, a professor in the hematology division, pointed to a potential answer. Jordan and his group discovered that the same monocytic leukemic stem cells (m-LSCs) in AML that are resistant to HMA/Ven therapy also have a unique surface marker called CD64 that’s only minimally found on healthy cells.

Another cancer center member – M. Eric Kohler, MD, PhD, assistant professor of pediatrics in the Division of Hematology, Oncology and Bone Marrow Transplantation – and a fellow at the time, Haley Simpson, MD, PhD, led the engineering and preclinical studies behind development of CART64. Lab studies showed CART64 eliminating 100% of a line of leukemia cells within 18 hours, and animal-model results were also encouraging.

‘That got me hooked’

Angelos was exposed to biomedical research in a science class in high school in New York, followed by lab work as an undergrad at Duke University. “That got me hooked,” he says. “I liked thinking about ways we could engineer things to solve a medical problem.”

He then spent two years in a post-baccalaureate research program at the National Cancer Institute, where he was exposed to the search for new targeted therapies for cancer.

“What really struck me was that there were so many physician scientists, which was new for me,” Angelos says. “At NCI, their clinical research hospital is physically connected to where the basic science labs are, and these were MD-PhDs who were doing stuff in the lab that they were directly then putting into clinical trials. I was fortunate enough to be around these people and got plugged into seeing patients with them. That’s when I decided I needed to go to medical school to do this at a high level.”

He completed a dual MD-PhD program at the University of Minnesota Medical School. “My graduate work was mostly looking at how we make lymphoid cells from stem cells, and it was very analogous to the field of CAR T cells that was growing at that time.”

Then came residency and a hematology-oncology fellowship at the Hospital of the University of Pennsylvania, a center known for developing early cellular therapies.

At Penn, “I was doing work engineering novel cellular therapies in the lab, and I also got keenly interested in the clinical side of doing those therapies,” Angelos says. “As I got more involved, I realized there was often a natural gap between the clinical and biological perspectives. My training allowed me to bridge that gap – understanding the underlying biology, the reasons a therapy might succeed or fail, and how we could refine these approaches to make them more effective.”

Coming to CU

Angelos’ training, he decided, equipped him to be “a translational person, bridging the gap between engineering treatments in the lab and putting them into people, and doing it in a logical manner, finding the right patients, the right disease, and the right product to make it work.”

He chose to come to CU Anschutz, he says, because it fit the “narrow set of things I was looking for. I wanted to see patients at least 50% of the time, and I wanted a program that had a very robust infrastructure in place to successfully implement cellular therapies, particularly ones that are coming out of the institution, taking work by people in the labs here and directly moving it into the clinic.”

Joining CU also meant a chance to work alongside CU Cancer Center member Dan Pollyea, MD, professor and interim division head of hematology. “He runs a renowned myeloid disease program here that rivals any other program nationally in terms of productivity and innovation that comes out of the institution. All my leukemia mentors thought Dan and his program were great and said I would get good clinical experience and do a lot of good trials in Colorado. So, it was kind of a no-brainer to come here.”

He also cites the Gates Institute, CU Anschutz’s translational institute supporting research in cell, gene, and regenerative therapies, as a big draw.

Hearing patients’ voices

The upcoming Phase 1 clinical trial, for which Angelos is principal investigator and wrote the protocol, will test CART64 in adult patients, focusing on safety and tolerable dosing. Angelos will work with CU Cancer Center member Terry Fry, MD, a professor of pediatrics and executive director of the Gates Institute, which is involved in the regulatory and biomanufacturing processes involved in the project.

As with other CAR T-cell therapies, Angelos and his collaborators at the Gates Institute will extract each patient’s own immune T cells, then engineer those cells in the lab to recognize and attack cancer cells with CD64 on their surface. They’ll grow millions of these modified cells, then infuse them into the patient.

Angelos and his team plan to recruit up to 18 adult AML patients at the CU Cancer Center whose cancer relapsed after HMA/Ven therapy. It’s expected that enrollment in the trial will take two to three years, largely because of the narrowly focused patient selection criteria being used. Angelos is looking for patients with low-level disease burden and a high risk of future relapse, rather than patients with high cancer burdens, a group that hasn’t responded well in past CAR T-cell trials.

After CART64 infusion, patients will be closely monitored for several months, with long-term follow-up extending for up to 15 years. Researchers will analyze blood and bone marrow samples to gauge how well the treatment works.

The trial will go to great lengths to “make sure that the patients’ voices are heard,” Angelos says. CU Cancer Center member Ajay Major, MD, MBA, an assistant professor of hematology, will oversee the gathering of “patient reported outcome” information during the trial, including how the therapy makes them feel. And Siri Lindley, an AML patient at the CU Cancer Center and a public speaker, will serve as a consulting patient advocate “to help us make sure the project is patient friendly,” Angelos says.

If the trial shows “good anti-leukemic activity,” he says, the study could expand as early as the second year, possibly adding trial enrollment locations.

Angelos says he’s thrilled, at an early point in his career, to be “designing a clinical trial in a thoughtful, logical way so it can make the most impact on people. If it’s successful, this could be something that other groups will look at and say, ‘How do we emulate this in our projects and protocols to have success in this space?’”