CAR T-Cell Therapy vs Bispecific Antibodies: Picking an Approach in R/R DLBCL

Marie Hu, MD

CAR T-cell therapies and bispecific antibodies have transformed the treatment landscape for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), and several factors contribute to decisions on when to select between the two modalities, according to Marie Hu, MD.

“Overall, we've come a long way since the first CAR T-cell [therapies] were approved. Now, with newer indications into earlier lines, the goal is to try to be able to collect the healthiest T cells so that we can have a good product,” Hu said in an interview with OncLive^® following an OncLive State of the Science Summit™. “The other thing we're just trying to work on as a field is to better manage supportive care, reduce risk of infections, and find new ways to try to reduce the risk of cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS].

In the interview, Hu discussed a head-to-head debate that she partook in on the topic of CAR T-cell therapy vs bispecific antibodies for the treatment of relapsed/refractory DLBCL; highlighted the differences, similarities, pros, and cons associated with these novel treatment approaches; and expanded on access to such therapies.

Hu is a hematologist-oncologist and an assistant professor of medicine in the Division of Hematology, Oncology and Transplantation, at the University of Minnesota Medical School in Minneapolis.

OncLive: What were the key takeaways from the debate you participated in regarding bispecific antibodies vs CAR T-cell therapy in relapsed/refractory DLBCL?

Hu: Joseph Maakaron, MD, [of the University of Minnesota], and I participated in a head-to-head debate on CAR T-cell therapy vs bispecific antibodies for relapsed/refractory DLBCL. I [argued for] the CAR T-cell therapy and Dr Maakaron [argued for] bispecific antibodies.

There are a lot of advantages for both [treatment types]. When I went through the CAR T-cell therapy data, we talked about the CAR T-cell process and how it's a bit more intensive up-front with 1 to 2 months of close monitoring. [However, CAR T-cell therapy] is a 1-time therapy that's over and there's no maintenance therapy required. If patients are in remission, they go on surveillance, and we continue monitoring for other complications.

I presented some data on the initial pivotal trials that led to the third-line approval [of different CAR T-cell therapies, including the phase 1/2 ZUMA-1 trial (NCT02348216) evaluating axicabtagene ciloleucel (axi-cel; Yescarta), the phase 2 JULIET trial (NCT02445248) evaluating tisagenlecleucel (Kymriah), and the phase 1 TRANSCEND-NHL-001 trial (NCT02631044) evaluating lisocabtagene maraleucel (liso-cel; Breyanzi)], as well as the [phase 3] trials that led to second-line approval [the ZUMA-7 trial (NCT03391466) of axi-cel, the BELINDA trial (NCT03570892) of tisagenlecleucel, and the TRANSFORM trial (NCT03575351) of liso-cel].

Across the board, the overall response rates were quite high [in these various studies]. However, it seems like the overall cure rates or 2-year progression-free survival rates are settling out around 40% for all the products, which is still a substantial portion of patients that we're curing who previously had difficult-to-treat disease. I also presented a little data showing that we have more and more data for CAR T-cell therapy in high-risk subgroups, including double- and triple-hit lymphomas, as well as central nervous system lymphoma. We have collectively started to see more data [for these high-risk populations].

For Dr Maakaron's side, he presented data on CD20 x CD3 bispecific antibodies that are approved. Overall, they do have high response rates, and they have less toxicity in terms of CRS and ICANS. CRS and ICANS are usually pretty mild [for bispecific antibodies] at grade 1 and 2, and only a short hospital stay [is required] for some of the initial doses for those agents. The [treatment] schedule is a bit more ongoing. The initial ramp-up can be quite a few weeks in a row, and then it spaces out. Eventually, [bispecific antibodies are given] every 3 to 4 weeks for up to a year for some of the products, or indefinitely until disease progression for some of the other products.

Overall, CAR T-cell therapies and bispecific antibodies represent a big advance in the lymphoma field, and we're lucky to have both options, especially since they have different targets.

What patient factors do you look at when choosing between a bispecific antibody and CAR T-cell therapy?

The first thing would be the FDA label. Right now, the bispecific antibodies are restricted to after 2 lines of treatment, and for CAR T-cell therapy, 2 of the products [axi-cel and liso-cel] are approved as second-line treatment if patients are high risk, primary refractory, or relapsed within 12 months of their initial therapy. We have been seeing a lot of referrals for that indication since those got approved. If [patients are] in that category after only 1 line of treatment, then they'd only be eligible for CAR T-cell therapy, and we offer CAR T-cell therapy to lot those patients.

After 2 lines, we offer patients both, and a lot of it has to do with whether they can go through the more intensive 30-day monitoring period that’s required for CAR T-cell therapy. [This includes] relocation and having a 24-hour caregiver for 30 days, which can be a barrier for some patients. [If these barriers are present], often we will use a bispecific antibody in that case.

[Deciding between these treatments] also depends on if patients can wait for the time it takes to manufacture the CAR T cells. If they need to be treated right away, then sometimes, a bispecific antibody—since it's off the shelf—can be started within a couple of weeks.

Otherwise, in terms of comorbidities and age, a lot of patients are eligible for both—more than you would expect.

As CAR T-cell therapy has moved into earlier lines of treatment, what considerations need to be made as far as sequencing and safety?

We try to be cognizant of prior treatment [patients] receive immediately before apheresis. For the most part, most traditional chemotherapies, immunotherapies, and antibody-drug conjugates can be washed out within 2 weeks before apheresis, as long as the lymphocyte count looks good. The [prior treatments] that we try to avoid are bendamustine [Bendeka], fludarabine, or other agents that can deplete T cells. If patients did end up having [one of these agents as the most recent treatment], we would try to wait longer to make sure they have a good CAR T-cell product, and we might have to use something else in the meantime before we move on to CAR T-cell therapy.

However, most patients do not receive [agents that deplete T cells] in the first line. Right now, [first-line therapy is] mostly [comprised of] R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone], polatuzumab vedotin-piiq [Polivy], R-CHP, or R-EPOCH [rituximab, toposide phosphate, vincristine, cyclophosphamide, doxorubicin hydrochloride, and prednisone]. If we’re considering CAR T-cell therapy in the second line, there usually aren’t too many issues [with prior therapies].

Since the introduction of CAR T-cell therapy, have there been any ways that the manufacturing and treatment processes have improved?

There have been a lot of improvements in the availability of manufacturing slots, as well as the turnaround times for the products. In the very beginning, we used to have to fight for 1 or 2 apheresis slots a month. However, now [these slots are] pretty much immediately available; it takes 1 or 2 weeks to get insurance approval and get everything lined up. Most of the products are turning around within 3 to 5 weeks. Some of them are on the shorter end, and some on the longer end.

For the actual administration, right now, at our center, we can administer tisagenlecleucel completely as an outpatient [procedure], as long as the patients don't have too significant of a disease burden or other major comorbidities. We're hoping to transition the other products [to outpatient treatment] as well, especially the ones where CRS or ICANS is low or delayed. If the median time [to onset of CRS or ICANS] is 9 days, then it doesn't make sense to keep them in for 7 days, discharge them, and then they have to readmit them. That has been in process, and it's been helping to reduce the burden on the health care system overall.

Is there any ongoing research with CAR T-cell therapy that has caught your eye recently?

A couple of things that we're excited about include allogeneic products, either CAR T cells or CAR natural killer cells, where the products are available immediately off-the-shelf and you don't have to go through the apheresis and the waiting period for patients who urgently need to be treated.

I talked about targets other than CD-19, which is the only target [of currently approved CAR T-cell therapies]. Investigators are looking at CD22 [as a potential target], and we're going to be opening a trial soon for a BAFF receptor–directed CAR T-cell therapy.

Additionally, there was a new manufacturing platform at the ASH Annual Meeting a couple of years ago called the T-Charge™ platform, where they try to reduce the manufacturing time to less than 2 days. Not only does that shorten the time that patients need to wait, but the goal is to improve the T-cell quality.

CAR T-cell therapy is branching into other disease groups [beyond] just lymphomas or even solid tumors. We are participating in CAR T trials for lupus and autoimmune disorders, which is a new, ongoing area of research.