Made-in-Canada cancer therapy offers patients new hope

- Ottawa, Ontario

The National Research Council of Canada is developing new ways to create immunotherapies for cancer patients.

Some Canadians with aggressive B-cell leukemia or lymphoma cancers who do not respond well to existing treatments may now have new hope. Later this year, some cancer patients may be able to participate in clinical trials of a novel immunotherapy engineered by the National Research Council of Canada (NRC).

Immunotherapy, which harnesses the body's own immune cells to hunt down and destroy cancer cells, has shown promising results with much less toxicity than traditional treatments. This type of therapy has helped many people and is now being used to treat various types of cancer.

CAR T-cell therapies

One highly effective new form of immunotherapy is chimeric antigen receptor (CAR) T-cell therapy, or CAR-T therapy. This innovative treatment involves filtering out white blood cells from a patient's blood, introducing a synthetic gene and re-injecting the modified cells back into the patient.

CAR T-cell therapy uses a specific type of white blood cell called a T-cell, which has the ability to hunt down infected or cancerous cells in the body and destroy them. When T-cells are modified with a chimeric antigen receptor, they become CAR T-cell and gain new cancer-fighting powers.

The special CAR gene that is added to the T-cells encodes an antibody molecule that allows the CAR T-cells to recognize and bind to a specific protein on the surface of cancer cells, killing them but saving healthy cells. This selectivity makes CAR T-cell treatments much more effective with fewer side effects than chemotherapy.

Thousands of patients worldwide with previously incurable forms of leukemia and lymphoma have now undergone a type of CAR T-cell therapy known as CD19 CAR-T. In this treatment, the CAR T-cells include an antibody that recognizes and targets the CD19 protein found on some types of blood cancers. The majority of patients have responded well to CD19 CAR T-cell therapy, and many have even been cured.

The NRC's unique CAR T-cell therapy

"We have found new ways to rapidly identify antibodies that can be used to develop the next-generation of CAR T-cell therapies," says Risini Weeratna, Acting Program Director for the Cell and Gene Therapy (CGT) Challenge program at the NRC's Human Health Therapeutics Research Centre (HHT).

Risini Weeratna operating the flow cytometric cell sorter.

NRC researcher Mehdi Arbabi-Ghahroudi discovered and characterized a unique anti-CD22 antibody that is key to the NRC's CAR T-cell therapy. "This unique type of engineered single domain antibody, also called a nanobody, has superior properties over conventional antibody fragments," says Arbabi-Ghahroudi. "With it, the NRC's research team was able to create a new made-in-Canada CAR T-cell that can detect the CD22 protein on B-cell leukemia and lymphoma cells."

Targeting the CD22 protein is what allows the CAR T-cell therapy to work when treatments targeting other cancer proteins such as CD19 have not worked. This offers another chance at a successful treatment for relapsed pediatric and adult patients with certain blood cancers.

"This is the first CAR T-cell therapy designed and developed by the NRC, and we're working with a team of Canadian academic and clinical research scientists to bring it to clinical trials in 2023," adds Weeratna.

The NRC's CD22 CAR T-cell therapy is expected to enter clinical trials in late 2023 in Vancouver, Ottawa and Toronto. Two trials will run simultaneously. One will focus on pediatric and adult lymphoblastic leukemia and the other on lymphoma.

The clinical trials will be part of the Canadian-Led Immunotherapies in Cancer (CLIC) program founded by researchers at The Ottawa Hospital, BC Cancer and BioCanRx.

NRC manufacturing model accelerates hope

The United States Food and Drug Administration has approved 6 different CAR-T therapies, all for the treatment of blood cancers. While 5 of these have also received Health Canada approval, these therapies come with a hefty price tag and not all are reimbursed through provincial healthcare plans. Therefore, Canadian patients have very limited access to the therapies. Furthermore, all these therapies are manufactured outside of Canada with long wait times to access them. And most cancer patients don't have time to wait.

Scott McComb loading samples for high-throughput flow cytometric analysis.

"Our research focuses on developing more affordable and accessible CAR T-cell therapies," says NRC researcher Scott McComb, project lead for CAR-T development for blood cancers at the NRC. "There's no point in making fancy new therapies if Canadians can't access them."

He explains that the NRC is working with a consortium of Canadian researchers to establish a range of biomanufacturing facilities across Canada for manufacturing clinical CAR-T products under good manufacturing practices. Having the ability to deliver these types of therapies at Canadian hospitals and clinics could provide an attractive alternative for more direct and less expensive delivery of these therapies once they're approved. Each facility would be able to extract and modify patient T-cells on site to design personalized CAR T-cell therapies.

A key driver behind the success of this research is the NRC's Cell and Gene Therapy Challenge program, led by Risini Weeratna. This mission-oriented program provides targeted funding for investigators across Canada to collaborate with NRC scientists to achieve the ambitious goal of creating accessible and affordable cell and gene therapies for Canadians.

"The CGT program has had a revolutionary impact on our ability to deliver these therapies in Canada," says Weeratna. "We're not only innovating, but also helping to establish a whole ecosystem around cell and gene therapy." This means that, if the new therapies prove to be safe and effective in clinical trials, they will be more widely available across Canada without the high cost of the CAR T-cell therapies currently on the market.

Building on history

In the realm of biotherapeutics, the NRC has a long history of identifying new antigen and antibody sequences, modifying them and figuring out how to turn them into vaccine and/or antibody-based medicines. In the early 1980s, NRC researchers also developed the first meningitis vaccine, which helped to save countless lives by preventing the serious and often fatal bacterial disease. Later, the NRC created the world's first synthetic human proinsulin gene, which today is the basis for the medication used by almost all insulin-dependent diabetics.

"We fused the collective NRC knowledge of fundamental biology of immune cells and our expertise in the production of antibodies to create this new made-in-Canada CAR T-cell therapy," says McComb. "What we learn from our research into leukemia and lymphoma will also help us build breakthrough therapies for other diseases such as brain, pancreatic and lung cancer."

The NRC's leading role in bringing CAR T-cell therapy from the lab to the clinic builds on that leadership. Risini Weeratna sums up the exciting future ahead for the NRC's work in CAR T-cell therapies: "With our collaborative network of clinical and industry partners, we can continue the tradition of putting all the critical elements together to effect real change in how we treat cancer in Canada."

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