CAR T-Cell Therapy Continues to Spark Interest for Treatment of Patients With DLBCL

Nilanjan Ghosh, MD

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) continue to show benefit with chimeric antigen receptor (CAR) T-cell therapy, which has led to a number of new areas of investigation, but also additional challenges in administering treatment in patients appropriately, as well as in a timely manner.

The DLBCL treatment paradigm has seen promise with 2 FDA-approved CAR T-cell therapies. These include the approval of axicabtagene ciloleucel (Yescarta; axi-cel) in 2017 and tisagenlecleucel (Kymriah) in 2018 for the treatment of patients with relapsed/refractory large B-cell lymphoma, including DLBCL. Axi-cel is is indicated specifically following 2 prior therapies for those with DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma, while tisagenleceucel is indicated similarly for high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma after 2 or more lines of systemic therapy.

A Biologics License Application (BLA) was also submitted to the FDA with a Prescription Drug User Fee Act action date of November 16, 2020, to determine the potential approval of lisocabtagene maraleucel (liso-cel) as treatment of patients with relapsed/refractory large B-cell lymphoma following 2 prior lines of therapy. Despite encouraging data from the phase 1 TRANSCEND NHL 001 study, which included patients with DLBCL, the FDA was unable to complete its review in time due to the coronavirus disease 2019 (COVID-19). Travel restrictions brought on by the pandemic made the agency unable to complete an inspection of a third-party manufacturing facility in Texas during the current review cycle, and no new anticipated action date has been set.

The postponement of the FDA’s review of liso-cel was not the only influenced by the challenges that have been brought on by the COVID-19 pandemic. Physicians struggled with administering CAR T-cell therapy to patients with DLBCL, particularly in clinical trials due to new regulatory constraints, during the start of this pandemic.

In an interview with Targeted Oncology, Nilanjan Ghosh, MD, a hematologist and medical oncologist at the Levine Cancer Institute, Atrium Health, discussed the current challenges in using CAR T-cell therapy as treatment of patients with DLBCL and considers the next steps for this research.

TARGETED ONCOLOGY: In regard to CAR T-cell therapy, what are the biggest areas of unmet need in the DLBCL space?

Ghosh: CAR T-cell therapy has been a huge game-changer in an aggressive DLBCL. However, there are still many unmet needs. What comes to mind are those patients who are unfortunately relapsed after CAR T therapy or those who are refractory to CAR T therapy. The outcomes for most of these patients are quite poor, so that's the number 1 area of unmet need.

I think the second thing which an unmet need is is trying to improve on the toxicity of the CAR T therapy. It is associated with cytokine release syndrome (CRS) and neurotoxicity, and it is currently administered mostly in specialized centers, mostly transplant centers. If there is a way by which we can minimize the toxicity, the applicability of CAR T therapy will be more generalized, and more patients will benefit from it. Many things are being done in that regard, like earlier use of tocilizumab and steroids and also development of new CAR T treatments with less toxicity than the previous ones.

Another potential unmet need is the access to CAR T therapy. As I mentioned, it's being offered mostly in specialized centers, which limits the access to many other patients who may not be able to get there. In terms of access, also the time needed to get the CAR T therapy. There are many lags in that, so from the time a patient is diagnosed with the relapse to the time they get CAR T therapy would be several weeks, sometimes over a month. That can be a problem as this is not an off-the-shelf product, and it needs to be manufactured with patients. This is an aggressive disease, and so many times patients who have very aggressive disease may not be able to wait all that time until they get that CAR T therapy, so that's certainly an area of unmet need, and hopefully, that time duration can be decreased in the future.

TARGETED ONCOLOGY: How has the COVID-19 pandemic impacted the treatment of these patients?

Ghosh: Initially when the pandemic started, we thought that this would affect not just CAR T therapy but also our transplants. There was a lot of uncertainty. We didn't know how long the pandemic would last. It came like a wave, a lot of acute cases and filled up a lot of hospital beds. As more time went on, we got back to a "new normal," I would say. I don't think it can ever be normal, but it's the way things are so at this point in time, it is not currently affecting our delivery of therapy, both on clinical trials, as well as on standard of care. Even during the early days of the pandemic, we did our best to accommodate our patients who weren't getting standard of care CAR T therapy.

It did affect CAR T therapy delivery on clinical trials because of many of the regulatory constraints. Fortunately, in the last few months, those have been lifted, and most of the CAR T studies have been up and accruing again. However, there was certainly a period of several months when approval of patients on a call to CAR T-cell therapy clinical trials was extremely limited. Fortunately, that's been overcome.

TARGETED ONCOLOGY: A BLA is under review with the FDA for liso-cel as treatment of patients with large B-cell lymphoma. Could you discuss the data supporting the potential approval of this therapy as well?

Ghosh: This study has now been published in Lancet, and I think the key main takeaways from the study are the high response rate, the objective response rate of 73%, and complete response rate of 53%. The important thing, again, is for patients to achieve a complete response. The median progression-free survival is not reached, and the median overall survival is not reached. Patients who get a partial response have a much shorter median progression-free survival and overall survival, so the efficacy is certainly excellent.

I think the big thing with the study was a lower incidence of CRS and neurotoxicity. That's an important thing. All grade CRS was 42%, and all grade neurotoxicity was 30%. The important point is that the highest rates, so grade 3 or higher, CRS and neurotoxicity was low. I believe the grade 3 or higher CRS was just seen in a handful of patients like 2% or 3%, and neurotoxicity was also in the 10% range. What that does is it gives you the delivery of a CAR T product, which can achieve high efficacy and low toxicity. It's not that we don't have to be vigilant about CRS and neurotoxicity, we do have to do that, but with the lower incidence, the applicability of that becomes higher.

Subsequent studies have shown that this product has been used a lot in the outpatient setting as well. There was another study, which is not yet published, but it was presented in both the American Society of Clinical Oncology (ASCO) [2020 Virtual Scientific Program] and European Hematology Association (EHA) [annual meeting], whereas about half the patients were able to get this product as an outpatient. That increases the applicability, and the earlier use of tocilizumab and steroids also help overall in lowering some of the severe toxicities in general with CAR T cell therapies.

In the TRANSCEND study, the tocilizumab use was certainly seen, and it was in the 10% range for CRS. The other thing, which is a little different from the other approved products, at least 1 of them, is that the median time to onset of CRS is a bit longer, around 4 or 5 days.

TARGETED ONCOLOGY: What are the implications of these data and where do you see this CAR T-cell therapy impacting this patient population the most?

Ghosh: Typically, most people who use axi-cel, they are used in an inpatient setting. The reported CRS and neurotoxicity with axi-cel is higher. This is not a head to head comparison, so this is not a randomized comparison, but I think this is what we have, right now; individual single-agent trials, and we are left with comparing them, which is not a fair thing to do. However, I think we have a general sense of both. Axi-cel has data now from clinical trials like ZUMA-1, as well as large real-world data, which is published in Journal of Clinical Oncology.

Axi-cel is mostly given in the inpatient setting, while liso-cel can be given both inpatient and outpatient, so I think that's a huge thing. That increases the applicability, as I discussed before, The lower risk of severe CRS and neurotoxicity also increases the applicability, so we are seeing better toxicity, and at the same time, we are not really compromising efficacy. I think that's a very important thing.

Now, there are still some differences. In terms of liso-cel, the median time to make liso-cel is longer than the median time to make axi-cel, so if someone has a very rapidly growing disease, in that situation, sometimes it is difficult to give any CAR T therapy, but certainly, if you have to wait even longer, then you may have to go with a product where the median time to make the cells is shorter than the other product. I think, eventually, when it comes down to choosing between products, it's the comfort of the site using the product. Second is it's looking at the details about toxicity, efficacy time to manufacturing, and those kinds of thing. Another thing which we don't seem to discuss that much is, once a product goes from clinical trial to commercial manufacturing, how smooth is that transition? How can the company make this almost seamlessly and cater to the demand of the product without any further delays and sort of mimic almost what was done in the clinical trial. I think those are those are important things, and that will allow us to help choose between the different products.

TARGETED ONCOLOGY: What is the most important message regarding CAR T cells in DLBCL at this time?

Ghosh: I think the most important message would be that CAR T-cell therapy can be a life-changing therapy for patients with relapsed/refractory aggressive B-cell lymphoma. It is very crucial to have this access to this therapy, so for patients who do not have direct access to CAR T-cell therapy, there needs to be a network where they can get connected to a science center where CAR T-cell therapy is offered. There also needs to be a rapid referral process where if it takes weeks to make a referral, and then another several weeks to get clearance, financial clearance, and then several other weeks to get CAR T-cell therapy, I'm afraid many patients with very aggressive lymphoma would not get this therapy, which could potentially get them long-term emissions. How we can shorten that process and how we can have this very good treatment delivered to patients in need is a very big challenge. That's something that the community needs to work on to get that access to patients.

I think that is the most important thing, and secondly, just to remind everyone that it's a one-time treatment. Yes, there are acute toxicities, but the death from the toxicities is getting low, so I think there's a there's this thought out there that it's a very toxic therapy. Yes, patients can lend up to it in ICU, they can get severe CRS, they can get neurotoxicity, but that all happens mostly in that acute period after the CAR T-cell therapy. The CRS and neurotoxicity is not something, which lingers on for a long time. If managed well, the mortality from these toxicities is extremely low. Mostly this is managed by specialized centers, so when the patient is done with this one-time treatment, and they go back to their referring physicians and follow long-term, there are some things which have to be managed like cytopenias and low hemoglobulin levels, but there's no maintenance therapy. There is nothing. If they are getting a complete remission early on, and they maintain it for 3 to 6 months, then they can hit long-term missions. We don't have 5-year data or 10-year data, but for patients who are refractory, if they continue to be in remission, my hope is some of them can be cured. We'll see as we get 5- and 10-year data eventually, but this is a very promising treatment for patients. I hope that more and more patients with relapsed/refractory aggressive lymphoma can get access to this.

TARGETED ONCOLOGY: Where do you see the role of CAR T cells expanding in the DLBCL landscape down the line?

Ghosh: There's an expanding role of CAR T-cell therapy in general in oncology, and it's a very exciting time for immunotherapy. It is currently approved for patients who have had 2 or more prior therapies in DLBCL, but there are efforts to move in even earlier in the process. We do know that there are some patients who have primary refractory disease, and if they get second-line treatment, often that doesn't work. If you try to do CAR T after that, it may be a little too late, so the whole idea is to try and see if in select groups of patients if we can move this treatment upfront. There are some treatments and some trials for this; 2 or 3 studies with the 3 different products are looking at comparison of autologous transplant with CAR T-cell therapy after failure, firstly in therapy, so that's something we would look for. There's also the pilot study for liso-cel, where we looked at CAR T-cell therapy application with liso-cel after failure of 1 line of therapy in DLBCL and similar aggressive B-cell lymphomas for patients who may be poor candidates for transplant. That data were presented at ASCO and EHA, and we had very good response rates with that as well and good safety data.

Any treatment that’s very effective in the late relapsed setting naturally moves up to the second line, and then maybe eventually to select patients in the frontline setting. The other things which are being done in research is to see if there could be ways in which we can improve on the outcomes. We had started this discussion by asking about unmet needs, and we mentioned relapse to start with. We are working on adding other things after CAR T to see if we can improve on the response rates or lower the relapse after CAR T because that's certainly an area of so many strategies to look at that as well. Looking at immunomodulating agents, checkpoint inhibitors, and other treatments to see if we can improve on that. This is a very exciting field. Lots of patients have benefited from this, and we hope this continues.