CAR-T cell therapy offers hope when standard treatments fail

Patient Stefany Dupont

The Ottawa Hospital plans to launch clinical trials with revolutionary therapy for blood cancer patients who are out of options.

Stefany Dupont sits cross legged on the hospital bed hooked up to an IV machine.

“I come every month to get immunoglobulin– it’s an immune system boost because the therapy I received last September called CAR-T therapy is very new and very promising,” said Stefany. “But the only side effect for me is that I need this immunoglobulin because it wiped out all my normal B cells [which create antibodies to fight infection].”

The 22-year-old was first diagnosed with acute lymphoblastic leukemia (ALL) when she was 13.

Children with leukemia are given a strict chemotherapy protocol that effectively cures more than 90 percent of patients. Unfortunately, this was not the case with Stefany.

She was in remission for five years but, in 2010, her leukemia came back. She was 18, so began receiving treatment at The Ottawa Hospital.  A regimen of chemotherapy was followed by a hematopoietic bone marrow stem cell transplant in October 2015. Stefany, however had another relapse a year and a half later. Adults with leukemia who relapse after a transplant have less than a 10 percent chance of survival.

Dr. Natasha Kekre

“Stefany was unlucky enough to relapse within two years of her transplant,” said Dr. Jill Fulcher, Stefany’s doctor, who specializes in malignant hematology, and is a clinician-investigator at The Ottawa Hospital. “But her leukemia came back with a blast and she was very sick. Palliative management was all we had to offer patients with ALL who relapsed so soon post-transplant.”

Dr. Fulcher and fellow colleague Dr. Natasha Kekre, a hematologist, associate scientist at The Ottawa Hospital, and assistant professor at the University of Ottawa, knew that clinical trials using this CAR-T cell immunotherapy had amazing results in children and adolescents with leukemia and blood cancers, putting many into long lasting remission.

The success of these trials led the US Food and Drug Administration to approve two CAR-T cell therapies: one in August, the other in October 2017. The treatment has not yet been approved by Health Canada, so the therapy is not offered in Canada – yet.

However, there was an option of CAR-T cell therapy at the Children’s Hospital of Philadelphia where clinical trials had been run with great success. The hospital’s clinical trial was still accepting patients with ALL up to 25 years of age. Stefany was eligible to participate.

“To get Stefany well enough to go to Philadelphia for CAR-T cell therapy was a struggle. She was very sick and we had to gain adequate control of her leukemia for her to be well enough to safely make the trip there,” said Dr. Fulcher, who is also an assistant professor at the University of Ottawa.

CAR-T cell therapy is a relatively new treatment for ALL patients. The therapy uses the patient’s own immune cells, known as T-cells, to treat their cancer. T-cells play a critical role in the immune system by killing abnormal cells, such as cells infected by germs or cancer cells.

Donate NowWith this treatment, blood is taken from the patient and the T-cells are separated out. The cells are then genetically engineered using inactive viruses to produce synthetic molecules on their surface called chimeric antigen receptors, or CARs. Over several weeks, these modified T cells multiply in the laboratory into hundreds of millions before being infused into the patient’s blood stream.  The CAR-T cells further multiply in the patient’s body, then begin recognizing and killing the cancer cells.

“We’ve seen dramatic responses in patients who normally have a 10 to 20 percent long term survival rates with standard therapies. The short-term response rate with CAR-T cells has been 70 to 80 percent,” said Dr. Kekre. “That’s why Stefany, who had a bad disease that didn’t go away with chemotherapy, got referred for the trial.”

“CAR-T therapy is very promising, but it is still very new,” said Dr. Harold Atkins, a hematologist-scientist who is working with Dr. Kekre to bring CAR-T trials to The Ottawa Hospital. “More clinical trials are needed, particularly to study the long-term effects.”

Dr. Atkins and Dr. KekreHowever, data from the Children’s Hospital of Philadelphia is promising. They have patients who are in remission five years after treatment.  And patients who are still in complete remission at the six-month stage are likely to have long term survival.

Stefany was able to go to Philadelphia and had a CAR-T cell infusion in September 2017. At her first three-month assessment, she had a bone marrow biopsy that showed she was still in remission. Positive news that meant the treatment was working.

Three months later after getting the all clear that her leukemia was in remission, Stefany went to Australia. She scheduled her trip between her monthly immunoglobulin infusions.

“After the sixth month waiting time, I went to Australia, from January 10 to February 7,” said Stefany. She visited Sidney, Brisbane, Melbourne, and went scuba diving at the Great Barrier Reef and hang-gliding over the shores of Byron Bay. It was a wonderful break after the intensive treatment.

“It is a really good sign that Stefany remained in remission six-months after CAR-T cell therapy,” said Dr. Fulcher. “Without this therapy, she definitely would not be with us today.”

For patients, like Stefany, who are extremely sick and out of options, CAR-T cell therapy offers hope, which is why Dr. Kekre is leading the charge to bring CAR-T cell immunotherapy to The Ottawa Hospital. A pharmaceutical company-led trial will begin recruiting patients at the hospital within the next few months. The Ottawa Hospital will be among the first hospitals in Canada to participate in these trials. CAR-T therapy may also soon be available in Canada, outside of clinical trials, as Health Canada is expected to approve the first version of the therapy in the fall of 2018.

But this will still just be the beginning of the CAR-T story. Researchers at The Ottawa Hospital, working with colleagues across Canada, have designed a “made-in-Canada” version of CAR-T therapy, which will provide access for Canadian patients to CAR-T cells using Canadian science and expertise.

“We are making our own Canadian CAR-T cell program. The CAR-T cells will be slightly different than those made in the States,” said Dr. Kekre. “Because they are considered experimental, they will only be available as part of a clinical trial.”

This trial could begin recruiting patients in 2019. It will be open in Ottawa and Vancouver with CAR-T cells being manufactured for the trial in Ottawa and Victoria.

CART-T cells

CAR-T therapy needs to be individually manufactured for each patient, using a patient’s own cells combined with large amounts of highly pure virus to deliver the CAR gene. The Ottawa Hospital’s Biotherapeutics Manufacturing Centre is ideally positioned to manufacture this kind of therapy because it already produces viruses for other kinds of clinical trials in cancer patients. This facility, pioneered by Dr. John Bell, presents the opportunity to produce the viruses needed for CAR-T therapy. 

“With our unique manufacturing facility, our expertise in clinical trials and our world-class cancer and hematology programs, The Ottawa Hospital is ideally positioned to lead the way in developing the next generation of CAR-T therapy,” said Dr. Rebecca Auer, Director of Cancer Research at The Ottawa Hospital and associate professor at the University of Ottawa.

Dr. Kekre said patients with ALL, lymphoma, and other blood cancers could benefit from this treatment. The hope is that one day CAR-T cell therapy may also be a treatment for a variety of cancers, such as breast and colorectal, that have solid tumours. It is through translational clinical trials conducted at The Ottawa Hospital that innovative treatments for more cancers will be discovered. 

Organizations such as BioCanRx, the Canada Foundation for Innovation, and the Government of Ontario have supported The Ottawa Hospital’s CAR-T research and the Biotherapeutics Manufacturing Centre, but additional funding is essential to make this program a reality.

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