Benefits and barriers of newly approved CAR-T therapy for leukemia: A discussion with Dr. Elizabeth Jaffee

By John J. Murphy, MDLinx
Published September 4, 2017

Key Takeaways

The FDA has approved the first gene therapy for use in the United States. The one-time treatment, named Kymriah (tisagenlecleucel), is a genetically-modified autologous T cell immunotherapy for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

The chimeric antigen receptor (CAR) T cell therapy was developed by investigators at the University of Pennsylvania and in collaboration with Novartis. In a multicenter clinical trial of 63 patients with B-cell ALL, the overall remission rate was 83% within 3 months of treatment.

It's an historic achievement, but it's not one without limits or precautions.

In this interview, cancer immunotherapy researcher Elizabeth M. Jaffee, MD, President-Elect of the American Association for Cancer Research, puts the therapy into perspective as both an important medical advance and as a mere first step into a new frontier of fighting cancer.

Elizabeth M. Jaffee, MD, President-Elect of the

American Association for Cancer Research

MDLinx: This was announced as the first approved CAR T cell therapy and the first approved gene therapy. How would you characterize the importance of these accomplishments?

Dr. Jaffee: There are several reasons why this is a big advance in our field. The first, of course, is that it is the first approved gene therapy—we're introducing a gene into the patient's own T cells to supercharge them so they can react against the B cell-specific antigen.

But, importantly, this is a major advance because it's a new therapy that is specifically targeting acute lymphoblastic leukemia, a very serious and deadly pediatric cancer. These are patients—children and young adults under 25—with no other options. Without this therapy, most of them would have died within weeks to a month or two. Instead, this therapy now is causing complete remission in more than 80% of those who have this bad disease and are resistant to all other therapy. Eighty percent—that's huge. And about 62% will probably be cured of their leukemia.

It's also a major advance in cellular therapy. It shows that we can technologically alter T cells in favor of fighting cancer. Although I don't think this is going to happen in other cancers within the next year or two, it is a proof of principle that we now have technology and we can start to apply that technology to better understand how to use it against other cancers. So, even though it's a niche type of therapy right now for a very small group of people, this is still a huge advance.

But now we have a lot of work to do to figure out how to move this from this small group of patients, who are benefiting, to a larger group.

Also, one of the challenges is that this therapy works by depleting not just the cancerous B cells, but by depleting all B cells. B cells typically produce antibodies to fight infection, but unfortunately B cells occasionally become cancerous and become a leukemia. So to treat the leukemia, the CAR T cell therapy depletes all B cells. But people can live without their B cells. It's not easy—we have to monitor them for early infection and treat them with large doses of antibiotics or try to replace their antibodies—but the reality is that patients can live good lives.

MDLinx: You mentioned that 83% of patients who received treatment achieved complete remission within 3 months. Do you know if there was any indication or explanation why the remaining 17% did not go into remission?

Dr. Jaffee: I don't know why 17% did not go into remission, but I suspect that either the antigen wasn't expressed or it was expressed but the leukemia quickly lost its expression and just developed other proteins that allowed it to continue to maintain its cancerous state. So even though we've given back T cells to these patients, it wasn't enough to do the job. That's the hypothesis right now and, in fact, that's the hypothesis for why only 62% have had long-term responses.

Resistance is another problem that eventually does happen, and there are some studies that suggest that resistance may help explain why not everybody who receives this therapy stays in remission.

MDLinx: In the study, 49% of patients experienced grade 3 or 4 cytokine release syndrome (CRS). Can you briefly describe this syndrome, and how it can be managed?

Dr. Jaffee: Cytokine release syndrome happens when you supercharge a T cell—when you get it very activated—and it releases a lot of cytokines as a way to mediate its response. That's its effector function. But because these T cells are so supercharged, they're not easily regulated and the body doesn't have natural ways of downregulating all these cytokines being produced, so it gets out of control initially. Then you have a high level of these cytokines in the bloodstream, which can cause all sorts of hemodynamic changes—like hypotension and capillary leak syndrome—that could put the patient at risk of death acutely.

But we have do drugs that can prevent them from dying. In fact, a major mediator of these symptoms is an immunosuppressive drug, Actemra (tocilizumab), which was approved for expanded indication alongside Kymriah. It inhibits the receptor for the cytokine IL-6, and so ameliorates those symptoms of cytokine release syndrome.

MDLinx: What are the barriers for this treatment for use in other blood cancers, or for solid tumors?

Dr. Jaffee: One barrier for other cancers is that we need to find what their antigens are. For acute lymphoblastic leukemia, we know we're targeting a B cell-specific antigen. But as far as knowing what to target in other cancers, both blood and solid tumors, we don't know what those antigens are—we don't know what the immune system sees in the cancer versus in the normal tissue.

Solid tumors present an even greater challenge. With a leukemia, the cells are in the blood. They're not in a mass that has protective mechanisms to prevent the activated T cells from getting in and killing the cancer. But that is the challenge with solid tumors. To get the CAR T cells into the mass effectively, we'll likely need to combine them with checkpoint inhibitors—the other approved immunotherapy for cancer. What checkpoint inhibitors do is they "take off the brakes" in the tumor mass that prevent the T cells from fully functioning. So, with checkpoint inhibitors, CAR T cells could get into the mass and kill the cancer. Of course, this presupposes that we know the antigen of that cancer.

MDLinx: What are the very next cancers that will likely have approvals for this kind of treatment?

Dr. Jaffee: CAR T cell therapy is now being studied in ovarian cancer. That may have a decent chance because ovarian cancer is kind of in between a solid and a liquid tumor, in the sense that the cells get into the peritoneal fluid. Investigators are now targeting a T-cell antigen that I identified, mesothelin, which is overexpressed by 50% of ovarian cancers. It's being targeted because it's mostly cancer specific—very few normal cells express mesothelin. These cancers include ovarian cancer, as I mentioned, as well as mesothelioma, some lung cancers, and pancreatic cancer. In fact, I discovered it in the context of pancreatic cancer initially, and then others started working on it in those other cancers.

But again, there's a lot of work that needs to be done before this treatment is really something that's going to be generally available.

About Dr. Jaffee: Elizabeth M. Jaffee, MD, is President-Elect of the American Association for Cancer Research (AACR), as well as Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD, and Associate Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. She is chair of the National Cancer Advisory Board for the National Cancer Institute and was co-chair of the recent FDA-AACR Regulatory Science and Policy Workshop on combination therapies in immuno-oncology.

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