Expert Discusses Latest CAR T-Cell Developments in Non-Hodgkin Lymphoma

David Maloney, MD, PhD

Results in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) suggest that chimeric antigen receptor (CAR) T-cell therapy should be used earlier in treatment, possibly after first relapse, said David G. Maloney, MD, PhD. Administration of these products in earlier lines of therapy could improve outcomes and reduce toxicity, he added.

“The most important thing about CAR T-cell technology is that it shouldn't be reserved just for relapsed/refractory patients who have failed everything,” said Maloney, medical director of Immunotherapy with Seattle Cancer Care Alliance. “Performance status is important. Tumor burden is important. If we can catch these patients early, we have a tremendous opportunity to improve outcomes and make the treatment safer.”

Physicians are interested in CAR T-cell therapy and targeted therapy for relapsed/refractory patients because response rates are low and prognosis is poor. The FDA has already approved the CAR T-cell therapy tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and adults with diffuse large B-cell lymphoma (DLBCL).

Moreover, axicabtagene ciloleucel (Yescarta) has been approved by the FDA for patients with relapsed/refractory DLBCL, DLBCL arising from follicular lymphoma, large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma following 2 or more lines of systemic therapy. If lisocabtagene maraleucel (liso-cel) is approved to treat B-cell NHL, clinicians will have 3 CAR T-cell products at their disposal.

“It is a really exciting time in the field,” Maloney said.

OncLive: What is the current state of treatment for DLBCL?

In an interview with OncLive, Maloney reviewed the latest developments with CAR T-cell therapy in patients with NHL.Maloney: DLBCL is a disease where we obviously try to cure it with chemotherapy and that can be remarkably successful in 60% to 70% of patients, but for those who don't go into complete remission or who relapse, then this becomes a life-threatening problem. Standard of care is salvage chemotherapy and, if you have responsive disease, autologous stem cell transplant. Unfortunately, with better therapies including R-CHOP, as the CORAL study showed, our success with transplant has gotten even lower. Therefore, people are very interested in the targeted therapies.

Thus far, it's been quite disappointing with the addition of new agents to our backbone of chemotherapy such as standard R-CHOP. You can add a bunch of drugs to it based on molecular profiling, and so far, the studies haven't panned out to be big winners. We are still awaiting results from some of these trials, but that's where we stand right now.

In the relapsed/refractory setting, patients were usually treated with palliative intent because we didn't have good options. With the advent of CAR T cells, we now have 2 commercially available products with a third on the way that show exciting response rates and, at least in some cases with 15 months’ follow-up, durable remissions in about 40% of patients.

Is CAR T-cell therapy becoming more widespread?

One of the more exciting presentations recently was the polatuzumab vedotin data in combination with bendamustine/rituximab. That seems to be another salvage or bridging therapy where you might be able to get people into a better response. If that's the case, you might be able to use it as a bridging therapy to get to CAR T cells. There are new exciting molecules on the way.There are 2 products currently approved: tisagenlecleucel and axicabtagene ciloleucel, both targeting CD19. A third [liso-cel] is on the way. These products are different. They have a CAR, but they have different costimulatory domains; 1 is CD28 and the other 2 are 4-1BB. That does cause some differences in the clinic.

These are autologous products. We collect T cells from the patient, then transduce them with a retrovirus—either a gamma virus or an antivirus. These genetically change the cells to express the CAR; they have all targeted CD19 so far. These cells are then given back to patient after lymphodepleting chemotherapy. These have led to very high response rates—up to 80% in 3 of the large phase II trials that have been done. The results led to FDA approvals for 2 agents.

What advice would you give to community oncologists and hematologists treating patients with DLBCL?

What are you working on right now in your lab?

The results are very exciting. These are refractory patients whom you wouldn't expect to have any meaningful response and for whom median survival is less than 6 months. Now we're seeing about 40% of patients staying in long-term, durable remissions with short follow-up. Most patients have been followed less than 2 years so far.Most of the clinical trials of CAR T-cell therapies treated patients with relapsed/refractory disease who really had no other options, and some prognostic markers are starting to come out. For example, patients with very high tumor burdens and high lactic acid dehydrogenase proliferative burden tend to have higher toxicity and less durable remissions. In early disease in which you don't have the option of stem cell transplant, those patients should be considered much earlier because the results seem to be better.We have about 18 different CAR T-cell therapy trials active in the Bezos Family Immunotherapy Clinic. We are studying CD19 CAR T cells, but also in other cancers, such as breast cancer and lung cancer. We have a CAR against ROR1 that's very exciting. We're attacking multiple myeloma with B-cell maturation antigen CARs.

What other updates are there with CAR-T cell therapy in NHL?

We are also trying to make CD19 CAR T cells work better. For example, we have trials with humanized CAR where the single chain Fv is a human antibody. We have trials where we're adding blocking antibodies such as PD-1/PD-L1 to make the CAR T cells less exhausted and have better persistence.For CAR T cells, we now have 3 products that are very, very interesting. The update on axi-cel with the recent New England Journal of Medicine publication shows a flat, durable response rate with around 42% of people staying in remission at 15 to 18 months. This was updated at the 2018 European Hematology Association Congress. Also, there and at the 2018 ASCO Annual Meeting, data suggested that patients earlier on in the treatment course or those with potentially less tumor burden might do better.

We are also learning more about escape mechanisms in that setting. In patients who relapse, there are 2 patterns reported. One is that some patients lose CD19 expression. In that case, a CAR T cell couldn't do anything further to get rid of that malignancy. In other cases, the tumor expresses a suppressive environment, such as PD-L1. That can interact with the receptor on the T cells and essentially turn them off. That would lead to interest in combination studies that are ongoing.

[There was the] JULIET trial [with tisagenlecleucel]. That is a different CAR. It has a slightly different toxicity profile, but it seems to allow outpatient administration in some case and seems to have encouraging results. The studies are different, and the patient populations are slightly different, so it's hard to compare them, but that's obviously what led to the FDA approval.

The third trial, TRANSCEND, from Celgene and Juno Therapeutics, is with liso-cel. In that setting, we have similar outcomes—high response rates and high CR rates—that certainly seem comparable, but surprisingly, there is a lower risk for severe toxicity. Grade 3 and above events of cytokine release syndrome (CRS) were seen in about 1% of patients, which is quite a bit less than what was seen in the other 2 products.

At the end of the day, hopefully we'll have 3 products approved. The efficacy will eventually be the major driving factor in the clinic—obviously, if one of them works better, that will lead to adoption of that product preferentially.

What is the take-home message about the state of CAR T-cell therapy?

Safety will be the next issue. Safety goes several ways. Number 1, not just how toxic is the regimen—amount of CRS and neurotoxicity—but also, what are the resource utilizations for giving these CARs to patients? With 1 or 2 years of follow-up, we will start to see that play out in the clinic as people will start choosing treatment based on patient populations and resource utilizations.We're trying to move CAR T-cell therapy up in patients. All 3 products have designed clinical trials taking on stem cell transplant, moving this up to the first relapsed setting in patients who fail standard R-CHOP chemotherapy within 12 months, for example. That’s a very poor outcome group from the CORAL study.

Each of these 3 products is being tested against standard of care, which is salvage chemotherapy and stem cell transplant. I would expect all 3 to win that kind of analysis based on what we've seen in the relapsed/refractory population. We still have to do the trials and there are crossover designs in all the studies where patients can go to a commercial product or get the treatment if they fail the standard of care. That is tremendously exciting to have these 3 trials ongoing.