Alison R. Sehgal, MD, discusses the latest developments with CAR T-cell therapy in lymphomas.
Alison R. Sehgal, MD
Alison R. Sehgal, MD
The addition of CAR T-cell therapy to the lymphoma armamentarium continues to lead to encouraging outcomes for relapsed/refractory patients. However, a host of other strategies have come to the forefront, including adverse event (AE) management, potential widespread administration, and further CAR T-cell products emerging in the pipeline.
Such progress and research efforts have taken place following the FDA approvals of 2 CAR T-cell therapies for the treatment of patients with lymphoma. First, the FDA approved the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) in October 2017 as a treatment for adults with relapsed or refractory non-Hodgkin lymphoma.
Secondly, the FDA approved tisagenlecleucel (Kymriah) in May 2018 for use in adult patients with relapsed/refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after ≥2 prior lines of systemic therapy. Prior to this indication, tisagenlecleucel was first approved in August 2017 for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia.
In an interview with OncLive® during the 2019 State of the Science Summit™ on Hematologic Malignancies, Alison R. Sehgal, MD, a clinical assistant professor at the University of Pittsburgh Medical Center, discussed the latest developments with CAR T-cell therapy in lymphomas.
OncLive: What have we learned regarding CAR T-cell therapy over the last few years, which was discussed in your presentation?
Sehgal: The first topic is really for those not experienced with CAR T cells, so to review the structure of CAR T cells, how they are made, and how long [the process] takes. After that, I focused on [CAR T-cell therapy in] DLBCL; we reviewed the approved products for use. Then, we reviewed some of the major trials that led to those approvals, focusing on the response rates as well as the duration of response, and a little bit about at what time point the response rate really predicts long-term response.
This focused on the more recent Lancet paper that looked at axi-cel and the 3-month response rate—either a partial response or complete response—which translates into a long-term response. We also look at determinants of response, of which there are very few clinical variables, but also at the area under the curve of T-cell proliferation in the first 28 days. That’s been the main factor that has been associated with a durable response for people with DLBCL. Also, under that category, we looked at toxicity and how to recognize and manage it. The two main toxicities have been CRS and neurological toxicity.
Could you expand on the structure of CAR T-cell therapy and the manufacturing process?
There is a ligand binding portion that is targeting CD19 on the surface of the B-cell lymphoma. Then, there is also a transmembrane domain and then there are 2 stimulatory molecules, and there is a costimulatory domain—either CD28 or 4-1BB.
Patients who are thought to be eligible [for CAR T-cell therapy] come in and go through leukapheresis to collect their T cells. There is no mobilization ahead of time, so it differs from stem cell transplant in that way. After the T cells are collected, we send them to wherever they’re going to be manufactured, depending on which process we choose. Once they’re delivered to that facility, they are there for 2 to 4 weeks and allows for the growth of the T cells proliferation before they’re sent back to the institution. The patient then comes in, they receive 3 days of chemotherapy with fludarabine and cyclophosphamide, then they get a little break—anywhere between 2 to 7 days, dependent on the product.
Will there be a time that CAR T-cell therapy could be administered in the community setting?
I think that’s possible. And, I know that many people are interested in that, and it’s certainly a possibility. With the current product I’m not sure that that is going to happen in the short term, but it’s certainly long term—there has been efforts to make that happen.
Is the community setting something that perhaps these off-the-shelf CAR T-cell products could possibly have a larger role in?
The experience with the off-the-shelf CAR T cells and natural killer cells are limited but are exciting. It could certainly lead to faster use, but I’m not sure.
Could you discuss the journey that you’ve seen these 2 FDA-approved products through clinical practice?
It has certainly changed the way we view DLBCL, particularly in patients who relapse after autologous stem cell transplant (ASCT), who have resistant disease, and can’t achieve a remission to even proceed with ASCT. Therefore, rather than focusing on palliative care at that time for people who are fit enough to be eligible for CAR T-cell therapy, we certainly, or hopefully, maintain a curative approach. However, we are aiming to get them to a rather intensive therapy that we think could lead to long-term remission.
Lisocabtagene ciloleucel is another [CAR T-cell product] that’s moving through the pipeline. Are there any unanswered questions or next steps that should be taken with this agent?
We are all eager to see the durability of response; the toxicity rates have been explored a little bit and certainly appear favorable and so, that will be something that will be useful to see when the full data set is published.
What are the best practices of managing the CRS or neurotoxicity?
It depends on the severity of either of those syndromes. For CRS with axi-cel, most people get a fever, which is classified as grade 1 CRS and they can be managed supportively most of the time—often with Tylenol, fluids, or other antipyretics. If that fever worsens or persists, or if it escalates to someone developing hypotension or organ dysfunction, particularly pulmonary dysfunction, then we will often use an interleukin-6 receptor blocker, which is often effective.
If someone develops refractory CRS to both supportive care and tocilizumab (Actemra), at that point, we can reach for steroids and we can see that many centers are doing that with some frequency and with some of the real-world data that have been published. For neurologic toxicity, there is not of a role for tocilizumab unless there is concurrent CRS. Therefore, for those who develop more severe neurologic toxicity we have to move quickly to steroids.