Expert Discusses Approval of First CAR T-Cell Therapy

James L. Ferrara, MD

The FDA’s recent approval of tisagenlecleucel (Kymriah) as the first chimeric antigen receptor (CAR) T-cell Therapy, marks a new era in oncology.

Tisagenlecleucel is specifically approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, based on phase II results from the single-arm, international ELIANA trial.

In the study, 63 patients received a single dose of tisagenlecleucel. The overall remission rate was 82.5% (95% CI, 70.9-91.0) in treated subjects. There were 40 patients (63%) who had a complete remission (CR) and 12 patients (19%) had a CR with incomplete hematologic recovery.

“Having the ability to genetically engineer a person’s lymphocytes and essentially weaponize them to kill these cells is a huge advance,” said James L. Ferrara, MD.

OncLive: Can you please provide some background on this CAR T-cell therapy?

In an interview with OncLive, Ferrara, a professor of hematology and medical oncology at the Icahn School of Medicine at Mount Sinai, discussed the significance of the FDA approving tisagenlecleucel as the first CAR T-cell therapy.Ferrara: This is a therapy for relapsed leukemia. If a type of leukemia does not respond to chemotherapy, which happens around 25% of the time, it’s very unlikely to completely respond to chemotherapy again. When we treat leukemia, it goes through different stages, like intensification and then maintenance. We use these different chemotherapy strategies to have many ways of poisoning the cancer cell, but cancer cells can become resistant to chemotherapy. Usually, the only therapy that works is bone marrow transplantation from a different donor where you have this part of immunotherapy called graft-versus-leukemia effects. If you relapse after bone marrow transplantation, you’re very likely to die because nothing has worked.

All lymphocytes have different ways of being activated; they have accelerators and breaks. This therapy has been engineered to completely remove the breaks and find the leukemia cells of a special receptor. It has worked remarkably for pediatric patients who are essentially doomed if they have not responded to all intensive chemotherapy forms and bone marrow transplantation.

Having the ability to genetically engineer a person’s lymphocytes and essentially weaponize them to kill these cells is a huge advance. In many ways, cancer cells are like zombie cells. They should die but they don't. This therapy can kill them when nothing else can.

What are your thoughts on the cost of the therapy?

Now that this has been approved, does this pave the way for other CAR T-cell therapies?

The therapy is complex and expensive but it is a huge advance that has taken decades of researchers investigating what the breaks are, how to take them off, how to make the target, and how to genetically engineer lymphocytes so that they don’t become cancerous themselves. It’s very high-tech, but the results are astonishing for these patients who have no options because their cancer has become resistant.Since the cost comes to around half a million dollars, it appears that only the elite will be able to afford it and that is not a good solution. I wish there was an answer to this issue. Everybody worries about the cost, and it is such a big advance that many can benefit from.Absolutely. As soon as researchers heard about the initial results 3 or 4 years ago, there is a big race going on to find the right target for these therapies. This therapy targets a protein called CD19, which is not specific to lymphocytic leukemia cells, as it’s on many B-lymphocytes, which makes antibodies.

Where do you believe the next area of research should be?

One negative side effect of this therapy is the patient loses their B cells that express CD19. The good news is that since it is only on B cells, we can replace the antibodies through a therapy called gamma globulin. These patients need to get an infusion once a month for the rest of their lives to help their immune systems by giving them antibodies but many patients do fine with this kind of therapy.It is likely that this therapy will extend to other subsets of leukemia and lymphoma. Solid tumors are more difficult because the protein targets are often expressed to some extent on other normal tissues, making it important to find the right target that has limited expression.

When the cancer cells are attacked, it causes a chain reaction between the target and the therapy itself which leaves cytokines, causing cytokine release syndrome and that is a problem that researchers are attempting to address. Those patients can get very sick and the practitioners must be alert to this because a patient can rapidly have a toxicity.

Is there anything else you would like to add regarding he significance of this?

There are antibodies that you can use to help prevent that or reduce the problems such as tocilizumab, which has been mentioned in the FDA approval. We need to get some experience with this therapy. It needs to be done in centers that have experience and that are particularly poised to deal with some of these side effects, but it is still a significant advance.I think what is so exciting is that it demonstrates the power of the immune system. This isn't chemotherapy, it is a new kind of cellular therapy. It's a proof of principle that this approach to cancer can be very effective. It's going to open whole new avenues of therapies for patients that we thought before were simply never going to be able to respond.