Researchers with the National Research Council of Canada’s (NRC) Human Health Therapeutics Research Centre (HHT) are working in collaboration with partners across Canada to develop and test a new made-in-Canada CAR T-cell therapy that offers a new way to treat certain blood cancers.
According to Risini Weeratna, Program Director for the NRC’s Cell and Gene Therapy Challenge program, “the NRC’s specific contribution to this project is the creation of a nanobody-based chimeric antigen receptor with exceptional ability to engage T-cells to kill B-cell cancer cells.”
Confused? You aren’t alone. Cancer is a complex disease and fighting it takes a complex treatment. Let’s break it down.
The warrior: CAR T-cells programmed to kill cancer cells
To produce a CAR-T therapy, a patient’s blood is filtered through a machine to separate specific immune cells called T lymphocytes or T-cells from other blood cells. T-cells are then mixed with a virus that has been disabled so that it cannot cause illness. Instead, it carries a genetic instruction for the T-cells to make and display an artificial receptor on its surface called a chimeric antigen receptor (CAR). Millions of these CAR T-cells are grown in specialized manufacturing facilities and then sent back to the hospital for infusion into patients.
Imagine equipping T-cells with a powerful tool, much like installing a cutting-edge app on your phone. This tool includes a protein, called an antibody, that acts like a sensor, specifically designed to detect a certain protein found on the surface of cancer cells. Similar to how heat-seeking missiles zero in on their targets, these antibodies are highly precise in their aim. When they encounter the targeted protein on a cancer cell, they signal the T-cell to destroy it.
With this innovative approach, the antibody is integrated into what can be thought of as the rest of the "app"—a construct known as a CAR. Once the T-cells display the CAR, the antibody component identifies the cancer cell's protein target and triggers the T-cell to activate its killing mechanisms. These modified CAR T-cells are capable of eliminating many cancer cells. As they do so, they multiply within the body. After successfully destroying the cancer, most of these engineered T-cells will naturally diminish. However, a small number may stay present, acting as a kind of surveillance system, ready to respond if the cancer tries to return.
CAR T-cell therapies have helped leukemia and lymphoma patients worldwide by targeting the CD19 protein on cancer cells. However, the cancer cells can learn to adapt. In a bid to survive, cancer cells sometimes stop producing the CD19 protein, which causes treatments to stop working and the patient to relapse. To improve the efficacy of treatment, alternative strategies such as the hybrid CAR with 2 antibody domains recognizing 2 different proteins on cancer cells has been implemented.
The new target: CD22 protein
In 2019, the NRC and the Canadian-Led Immunotherapies in Cancer (CLIC) research program used the CD22 protein on cancer cells as an alternative target for when CAR T-cell therapies targeting CD19 are no longer working. This launched the Canada-wide collaboration to develop a new made-in-Canada CAR T-cell therapy targeting CD22.
A CAR T-cell therapy targeting the CD22 protein is not in itself unique. Others are in development around the world. However, one of the key challenges with this type of treatment is enabling the CAR T-cells to locate cancer cells that can be hidden in areas of the body that are extremely difficult to access. This is particularly true for blood cancer cells, where traditional antibody-based treatments are not always effective.
The NRC’s secret weapon: nanobodies
Mehdi Arbabi Ghahroudi, a researcher with HHT, has built a career studying particular type of antibodies called a single-domain antibodies or nanobodies.
The human body produces antibodies naturally. But, if you are looking for nanobodies, you will need to look to something taller, furrier and more likely to spit at you. That is because nanobodies are unique to animals called camelids. Camelids are part of the Camelidae family, which also includes camels, llamas and alpacas. Camelid nanobodies serve the same purpose as human antibodies: finding and killing off invading cells. However, compared to antibodies made in humans, these camelid nanobodies are much smaller. They have the ability to get into smaller nooks and crannies that conventional antibodies cannot access.
Arbabi Ghahroudi’s team identified and characterized a unique nanobody that uses ninja-like precision to find the CD22 protein on leukemia and lymphoma cells.
The NRC team used the ninja nanobodies to design a CAR that is extremely effective at recognizing and killing off cancer cells using the CD22 protein as a target.
The NRC’s CAR enabled the CLIC program to develop the world’s first clinical grade CD22 CAR T-cell therapy using nanobodies, in collaboration with The Ottawa Hospital, BC Cancer and BioCanRx. This exciting, publicly-funded, made-in-Canada, nanobody-based CAR T-cell therapy is expected to go through clinical trials in 2024.
Preparing the ninjas for future battles
The NRC continues to study nanobodies to find other ways to put their tiny size and ninja-like targeting skills to work. For example, teams are looking to develop CARs that target multiple proteins (CD22 and CD20) on cancer cells, which would improve the efficacy of treatments. They are also working to develop CAR T-cell therapies for hard-to-treat solid tumor cancers such as pancreatic, ovarian and lung cancers using nanobodies.
Read the article Molecular Therapy: Oncology for more information about this research.
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