Armin Ghobadi, MD
With improvements to manufacturing processes, efficacy mechanisms, and locating better targets, physicians will be able to extend the reach of chimeric antigen receptor (CAR) T-cell therapy to more malignancies, said Armin Ghobadi, MD.
“CAR T-cell therapy is a really effective treatment, but we need to make it better in terms of efficacy and side effects,” said Ghobadi, assistant professor of medicine, Division of Medical Oncology, Washington University School of Medicine, Siteman Cancer Center. “Additionally, we know that it's really effective for hematologic malignancies, but we need to broaden the spectrum of disease that we go after.”
Currently, there are 2 FDA-approved CAR products on the market––tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta). Both products are approved for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after 2 prior lines of systemic therapy. Tisagenlecleucel also holds an indication in patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
Lisocabtagene maraleucel (liso-cel; JCAR017), predicts Ghobadi, is likely to be the next CAR T-cell product to join the market.
In an interview with OncLive®
during the 2018 State of the Science Summit™ on Hematologic Malignancies, Ghobadi discussed the evolution and expansion of CAR T-cell therapy in oncology and how to maximize its application across liquid and solid tumors.
OncLive: What did you cover in your presentation on CAR T-cell therapy?
Ghobadi: We spoke about the logistics of CAR T-cell therapy, how it works, and why it is revolutionary for patients with hematologic malignancies. We spoke about immune evasion and how the CAR T cell goes around cancer immune evasion. In terms of logistics, how we collect the white cells from a patient to local freezers and then send it to a good manufacturing process manufacturing facility.
Once they are sent to a treatment center, patients usually get lymphodepleting chemotherapy for 3 days, which is typically fludarabine and cyclophosphamide. After a couple days of rest, we infuse them in a way that is similar to blood transfusions. Then, we monitor them for side effects, mainly cytokine release syndrome (CRS) and neurotoxicity. We usually look at the response 1 to 3 months later.
This is a new platform of treatment that is going to revolutionize the way we treat cancer. It has already changed the way we treat patients with hematologic malignancies. As we know, it has been approved in high-grade B-cell lymphoma; there are 2 products that have been approved for that indication. Patients with relapsed/refractory high-grade B-cell lymphoma and pediatric and ALL in patients up to age 25 can get CAR T-cell therapy.
There are adverse events (AEs); CRS and neurotoxicity are the main AEs. The reason that those treatments are given in specific centers is because you need to have experience with managing those AEs. They are almost always reversible. You can treat them with a steroid using interleukin-6 or a receptor-blocking agent like tocilizumab (Actemra). With the combination of those agents, you can manage almost all of them.
Going from blood cancers to solid tumors is one of the more difficult things to tackle. We do have a clinical trial right now with CAR T cells in ovarian cancer. The science of it is evolving. In the next 5 to 10 years, we're going to have more preclinical data and hopefully early-phase clinical trials with effective CAR T-cell therapy for other cancers, such as solid tumors.
When we make CAR T cells, we have to wait. It usually takes about 3 weeks to produce the cells. A patient who needs CAR T-cell therapy has to wait around 4 to 6 weeks to receive it. What about coming up with a CAR T cell that we can give to the patient right away? That is the off-the-shelf or allogeneic CAR T cells. Using a T cell from a donor can cause graft-versus-host disease (GVHD), but there are modifications that we can make to eliminate the risk of GVHD. That includes getting rid of the T-cell receptor (TCR).
Then, you can use a normal donor, take the T cells out, make a CAR T cell, get rid of the TCR, and make an off-the-shelf CAR T cell. There are preclinical data on that approach, and a lot of people are working on that. Off-the-shelf CAR T cells are in early clinical trials. Usually 10% to 15% of patients cannot get CAR T cells because their disease progressed during that waiting time. Off-the-shelf CAR T cells [will overcome those hurdles].