Ongoing Efforts Seek to Refine, Expand CAR T-Cell Therapy

Brian Till, MD

The recent advances with chimeric antigen receptor (CAR) T-cell therapy in select hematologic malignancies have been exciting; however, more research is needed to move these treatments into an earlier treatment setting and drive down their costs, according to Brian Till, MD.

There are currently 2 FDA-approved CAR T-cell therapies: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (axi-cel; Yescarta). A third, lisocabtagene maraleucel (liso-cel; JCAR017), has shown promise in a phase I clinical trial.

In data from the multicenter TRANSCEND study, liso-cel demonstrated a durable complete remission rate of 46% at 6 months for patients with high-risk diffuse large B-cell lymphoma (DLBCL).

The multicenter TRANSCEND-NHL-006 study is determining the efficacy and safety of liso-cel in adult subjects who have relapsed from or are refractory to a single line of chemoimmunotherapy for aggressive B-cell non-Hodgkin lymphoma and are ineligible for hematopoietic stem cell transplant (NCT03483103).

The primary endpoint of the study is overall response rate, with a secondary analysis on patient-reported health-related quality of life. Till says these data are not yet available.

OncLive: You spoke about the current state of CAR T-cell therapy. What is important to highlight from your presentation?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Till, an associate member of the Clinical Research Division at Fred Hutchinson Cancer Research Center, and professor of medicine at the University of Washington, discussed the rapidly evolving field of CAR T cells.Till: In my presentation, I spoke about the role of CAR T cells, particularly in treating pediatric and young adults with ALL and in adults with DLBCL. I gave some background on how the CAR works. There have been some pretty exciting, recent multicenter data with CAR T cells.

What impact have tisagenlecleucel and axi-cel had on the landscape?

Beyond the 2 that are available, what other CAR T-cell therapies are in development?

The key message with using CAR T cells is that these are very high-risk patients who have relapsed disease and poor outcomes. CAR T-cell therapy has shown promising results. Some relapses do occur; but in general, if patients make it past 6 months or so, they will have durable responses. We need more follow-up to really understand this.It's still pretty early days. These agents have only been FDA approved for a short period of time, so there is a learning curve still attached to them. These agents are not widely available at every cancer center, but we're fortunate right now to have access to them [at Fred Hutchinson Cancer Research Center]. When we get into a situation where a patient has relapsed on standard treatment, we would refer in this direction [of CAR T-cell therapy]. Some of the common scenarios in which we're using this treatment are in DLBCL. These patients get their salvage therapy, and if they don't get a complete response we would put them on CAR T cells.Following on the heels of the 2 FDA-approved therapies, we have liso-cel. This hasn't been FDA approved yet, but it's in the middle of a clinical trial where we have seen promising data. It hasn't been fully reported yet, but the preliminary results look great. I can see an approval forthcoming at some point. There are other CAR T cells in development, as well. We have a CD20-targeted CAR that we're looking at. Other centers are looking at CD22-targeted CARs for patients with acute lymphoblastic leukemia.

What are your thoughts on combining checkpoint inhibitors with CAR T-cell therapy?

How do you see financial toxicity being addressed?

The trials we are working on at our institution are focused on lymphoma. We're participating in the TRANSCEND trial, which is a multicenter trial. All of the CAR T cells that are approved are from mouse samples. We're working on a fully human CAR T-cell product. We're also working on a CD19-targeted product that hopefully won't be as immunogenic. There is also work being done looking at targets other than CD19.It makes sense because we know atezolizumab (Tecentriq) is active in other diseases and it has an impact on the immune system. We don't quite know what the mechanisms of resistance are for patients who don't respond to CAR T cells. There are data from the University of Pennsylvania that suggested if you give a patient a PD-1 inhibitor, they might respond better to CAR T cells. It could be a good combination, but there are not enough data to confirm that PD-1 is the limiting step. It's worth the try, but we need to test it further.It's a great question and I'm afraid I don't have the answer. This is definitely something to consider. We are still trying to find our way in terms of insurance companies wanting or not wanting to pay. As more CAR T cells are approved, the increase in competition could drive down the cost. We probably haven't fully done an analysis here. A cost-benefit analysis is something that's important. It may be that the price tag is quite high, but if patients are being cured, they won't need future therapy. Perhaps it all balances out in the long haul. If we can move this treatment earlier on, that could save lots of money. We would just like for this to be a reasonable investment.