Unanswered Questions Remain in DLBCL With Use of CAR T-Cell Therapies

Caron Jacobson, MD

Chimeric antigen receptor (CAR) T-cell therapy has made its impact on the treatment landscape of diffuse large B-cell lymphoma (DLBCL), with multiple CAR T-cell products under evaluation in this space. The interest in CAR T cells as treatment of patients with DLBCL was supported by findings from the phase 1/2 ZUMA-1 clinical trial, which ultimately led to the approval of axicabtagene ciloleucel (KTE-C19, axi-cel) in this patient population.

Considering the patient outcomes and survival benefits observed in the ZUMA-1 study, more research is needed to further improve upon the patient selection process for this therapy. Tumor mutational burden, for instance, has demonstrated itself as a clinical predictor of response, in which low tumor burden is associated with deeper and more meaningful responses with axi-cel in patients with DLBCL.

Another area of research in this paradigm is the role of bridging therapy. Real-world studies have demonstrated that bridging therapy may have a negative impact on patients with DLBCL who receive CAR T-cell therapy, but these studies also relied on classic chemotherapy as opposed to newer therapies that have become available and may provide better outcomes in this setting.

In an interview with Targeted Oncology, Caron Jacobson, MD, medical director of the Immune Effector Cell Therapy Program and physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discussed the data supporting use of CAR T-cell therapy as treatment of patients with DLBCL and some of the remaining questions in this space that need to be addressed as these cellular therapies advanced forward in the field.

TARGETED ONCOLOGY: Could you discuss the data for axi-cel from ZUMA-1?

Jacobson: This was a study of axicabtagene ciloleucel or axi-cel, which is a CD19-directed CAR T cell therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphomas, including DLBCL. These patients were all chemotherapy-refractory and so had no other standard effective treatment options. We know from historical studies that their median overall survival would have been expected to be on the order of about 6 months, and so with a single infusion of axi-cel on the Zuma one study, we saw responses in over 80% of patients and complete responses in over 50% of patients and following these patients. Now we have at least 3-year data, and we should expect to see 4-year data updated later this year. We can see that it's somewhere between 40% and 50% of patients maintain their response, so it's very promising, but that could potentially mean that they're cured with their single infusion of their CAR cells.

TARGETED ONCOLOGY: What current biomarkers do we have to kind of predict clinical utility with axi-cel?

Jacobson: There are some clinical predictors for better responses, and 1 thing we know for sure is that patients who have a lower tumor burden at the time that they get their therapy tend to have deeper and more meaningful responses.

Also, patients who don't seem to need bridging chemotherapy. Remember, to make an autologous CAR T-cell therapy, you have to collect the T cells from the patient, and then they undergo a manufacturing process, which takes about 2 to 3 weeks, while the patient's lymphoma is getting worse. Some patients need to get some bridging therapy in between, and we know that patients who have received bridging therapy tend to do worse than patients who haven't received bridging therapy, so I think tumor burden and need for disease control are 2 things that predict for worse outcomes. Identifying patients earlier and patients who have better disease control is important.

I think we're also learning a little bit more about the T cell product itself. There are certain compositions of the T cells that are collected that lead to more favorable responses. That really speaks to the way that both the disease interacts with the T cell with the patient's own T cells, but also their prior therapies may alter the composition of their T cells. I think we're only starting to understand that and starting to think about how that impacts decisions we make for patients in terms of prior therapies before CAR T-cell therapy.

TARGETED ONCOLOGY: What kind of bridging therapies do you typically use in clinical practice?

Jacobson: The data that shows that bridging therapy may be harmful largely comes from just classical chemotherapy. For most of the patients who received bridging therapy in the observational retrospective real-world series, at the time standard chemotherapy was the most commonly used bridging therapy largely because there wasn't much else to try.

We are typically giving what we've seen with bridging therapy and its impact on CAR T-cell therapy. If a patient needs a therapy, we are moving away from classical chemotherapy and moving towards either radiation therapy if a patient has a disease that's amenable to radiation, or some of the newer drugs like polatuzumab vedotin (Polivy), which is an anti-CD79b antibody-drug conjugate. That's been FDA-approved for relapsed/refractory large cell lymphoma, and it's delivered very targeted chemotherapy to the cancer cells and maybe doesn't put patients at risk for other things like infectious complications and things like that. We've been using a lot of that, I think, and other people are starting to use more ibrutinib (Imbruvica) and lenalidomide (Revlimid) both because they have activity in large cell lymphoma, but also because they do have some immunomodulatory properties that could make the CAR T cells work better when you eventually get them back to the patient.

TARGETED ONCOLOGY: What clinical predictors of neurotoxicity have we seen for axi-cel?

Jacobson: Tumor burden does tend to predict for worse neurologic toxicity, so patients with higher tumor burden tend to have a higher risk of developing grade 3 or higher neurologic toxicity. We also know that for patients who have early and high-grade cytokine release syndrome if that happens 1 to 2 days after their axi-cel infusion, it's more likely that 4 to 5 or 6 days later, they're going to have higher grade neurologic toxicity. Patients who have higher pretreatment inflammatory markers are also at increased risk so those are all things that we know before a patient comes in, puts us on a high on high alert, but they're not totally discriminatory. We still are surprised sometimes by patients we think would be low risk and then also patients we think would be high risk, who don't end up having significant neurologic toxicity, so we need better predictors for sure.

TARGETED ONCOLOGY: What message would you like convey to fellow oncologists in the field regarding the current state of CAR T-cell therapy?

Jacobson: I think that we've learned quite a bit. CD19 CARs are incredibly active, and they have been transformative. They have not only benefited patients with CD19 malignancies, but they have benefited the field as a whole as we understand how to apply this technology to other cancers that maybe don't have a CD19 target. I think we will improve upon outcomes in CD19-positive malignancies, for sure, but what we're learning right now is also going to translate into cellular therapies for a whole host of different kinds of cancers, many of which are in clinical trials right now and have the promise of hopefully transforming outcomes for more and more patients.

_​Reference

_{FDA approves axicabtagene ciloleucel for large B-cell lymphoma. News Release. FDA. October 25, 2017. Accessed November 5, 2020. https://bit.ly/3l1SEuf}