Dual-Targeting CAR T-Cell Therapy: Implications for Relapsed or Refractory Large B-Cell Lymphoma
Key Clinical Summary
- Dual-targeting CAR T-cell therapy shows promise: Findings from the phase 2 ZUMA-14 trial suggest that combining axicabtagene ciloleucel (axi-cel) with rituximab may improve response durability by targeting both CD19 and CD20, potentially reducing antigen escape in relapsed or refractory large B-cell lymphoma (LBCL).
- Minimal residual disease (MRD) monitoring continues to evolve: Circulating tumor DNA (ctDNA)-based MRD assessment shows strong potential for guiding treatment decisions, although additional validation is needed before routine implementation following CAR T-cell therapy.
- Supportive care remains critical: Despite prolonged B-cell aplasia, no new safety signals were observed. Appropriate infection prophylaxis, intravenous immunoglobulin (IVIG) replacement when indicated, and patient education remain essential to safely optimize outcomes with CAR T-cell therapy.
In this interview, Paolo Strati, MD, associate professor at the University of Texas MD Anderson Cancer Center, discusses findings from the study titled “Axicabtagene ciloleucel in combination with rituximab for refractory large B-cell lymphoma: the phase 2, single-arm ZUMA-14 trial.” Dr Strati examines the potential role of dual-targeting CAR T-cell therapy in relapsed or refractory LBCL, including its implications for treatment sequencing, antigen escape, MRD monitoring, safety considerations, and the future integration of next-generation cellular therapies into clinical practice.
Paolo Strati, MD: My name is Paolo Strati. I'm an associate professor in the Department of Lymphoma-Myeloma and the Department of Translational Molecular Pathology at the University of Texas MD Anderson Cancer Center in Houston, Texas, where I serve as Deputy Section Chief for Indolent and B-Cell Lymphomas and one of the institutional CARTOX program leaders. My area of expertise is cell lymphoma, with a focus on follicular, marginal zone, and LBCL. I'm interested in immune therapies and cellular therapies for their treatments.
The ZUMA-14 study explored dual targeting of CD19 and CD20 using axi-cel plus rituximab in refractory LBCL. From a clinical pathways perspective, how do you see these findings influencing treatment sequencing and pathway design for patients at high risk of antigen escape after CAR T therapy?
Dr Strati: The findings from the ZUMA-14 trial are hypothesis-generating in regard to the current sequencing of treatments in LBCL. As a reminder, currently, autologous anti-CD19 CAR T are approved by the Food and Drug Administration (FDA) in second line for patients who are primary chemorefractory or for those who are chemosensitive but otherwise ineligible for a stem cell transplant. It can also be utilized in later lines of treatment.
The big competitor to CAR T cells for LBCL is currently represented by bispecifics. There are 2 anti-CD3, CD20 bispecifics currently approved by the FDA in LBCL, glofitamab and epcoritamab. Both are approved as a single agent in third line. However, when combined with chemotherapy backbone, mainly GemOx, can also be utilized in second line. So, the big question is how to sequence CAR T and bispecifics beyond frontline, understanding that this may change in the near future should CAR T or bispecifics move to earlier lines of treatment.
We know that about 30% of patients who receive CAR T will become CD19-negative at time of relapse. Those patients tend to maintain CD20 expression. So those are patients where we typically utilize bispecifics in second line. The big question is whether by utilizing bispecifics before CAR, in addition to potentially exhausting the T cells that we will collect for CAR in third line, whether subsequent relapses may be both CD19 and CD20-negative. That will be probably one of the scenarios that we will encounter in the not so distant future. Tt's hard to predict from now what the right treatment will be for those patients and multiple clinical trials are trying to address them.
The main take-home message from this trial regarding this big sequencing question is that if we try as early as possible to target both antigens, we may increase the overall efficacy of CAR T cells in second line and minimize chance of any relapse. Understanding the relapses that happen after a strategy targeting both CD19 and CD20 may be double negative and representing hence the big research challenge that I described earlier.
The study discussed the potential role of ctDNA-based MRD monitoring in predicting relapse after CAR T-cell therapy. How close are we to integrating MRD surveillance into standardized lymphoma pathways, and what barriers remain in terms of reimbursement, assay standardization, or workflow implementation?
Dr Strati: In terms of generating data, supporting the reliability of ctDNA and MRD assays in LBCL, we're getting close. At least for patients who receive chemotherapy as treatment, data are quite strong to the extent that we have a large, randomized phase 3 trial now offering treatments to patients with LBCL while in complete remission, but MRD positive at the end of chemo.
Before I dive more into this, I would like to recap what MRD assays have been available for patients with LBCL. We started with something as simple as quantitative polymerase chain reaction (qPCR). We moved to clonoSEQ, then CAPP-Seq, and more recently, PhasED-Seq, which has represented the most sensitive and specific MRD assay available for LBCL with the ability to detect 1 molecule of circulating tumoral DNA out of a million, much higher sensitivity as compared to qPCR.
So as for PhasED-Seq, data in terms of association between MRD negativity at the end of chemo, event-free survival and relapse-free survival are quite strong. A recent Journal of Clinical Oncology publication pulled multiple trials utilizing chemo for laryngeal cell lymphoma. The data is convincing enough that we may, in the near future, also have FDA support for utilization of PhasED-Seq for treatment decisions for patients with chemotherapy-treated LBCL.
We may not be that close yet for patients who receive CAR. We do have promising data with PhasED-Seq after autologous anti-CD19 CAR T cell products in LBCL in association with relapse-free survival. But the data don't look as robust as for chemotherapy-treated patients. This may be due to the dynamic of these different treatment types. Typically, patients who are MRD-positive at the end of chemotherapy or MRD-negative at the end of chemotherapy will stay as such. It doesn't matter at what time point after the end of treatment you measure MRD by PhasED-Seq. But treatments that are more dynamic, such as CAR T may take a longer time to kick in. Patients who are MRD-positive 30 days after CAR, if you just give it time, it may become MRD negative subsequently. So that's still an open question. And that's why when it comes to utilization of MRD, including PhasED-Seq after CAR, we may not be as close yet.
As for the second part of your question, as clinicians we all know that it's also important to have regulatory approval but also financial support for reimbursement. In order to get there, it's important to have certified assays and being able to demonstrate the reimbursement is valid. So, there are ongoing efforts. The smaller company that created PhasED-Seq has been acquired by a larger company. There's now more experience with reimbursement and financial support through regulatory agencies. In the near future, we may get to that point, especially for patients with LBCL who receive chemotherapy as a frontline treatment.
The study found longer-lasting B-cell suppression but no major increase in severe infections or new safety concerns. How should oncology teams weigh the potential for better long-term responses against the added monitoring and supportive care needs for these patients?
Dr Strati: This is always a big dilemma in clinical research overall and specifically in lymphoma where in doing more and trying to achieve more efficacy, we may generate more toxicity. And of course, it makes biological sense that by targeting both CD19 and CD20, both antigens that are expressed not only on lymphoma cells, but also on non-tumoral B cells, we may induce deeper and more durable B-cell aplasia. That was the case in this case. However, there are a few things to keep in mind. And the data from ZUMA-14 were very reassuring to this extent.
First, in most of the patients B-cell aplasia is not total, and sometimes residual B-cells still have good function. And even if they don't, as the main function of B cells is really generation of immunoglobulins. we do have a way to artificially support that through administration of IVIG.
But also we must remember that B cells are not the only component of the immune system. We have T cells whose function and number recover over time after lymphodepleting chemo. Yet immunity, including natural killer (NK) cells and macrophages, which aren’t impacted much by lymphodepleting chemo or CAR, remains intact and should be able to help patients in terms of defense from infections.
No matter what, all patients who receive CAR T, if they are neutropenic, typically with absolute neutrophil count (ANC) less than 1000 or 2000, should receive prophylactic antibacterial and antifungal antimicrobials. And those who have a CD4 count less than 200, usually at least for the first year, should receive antiviral prophylaxis and anti- pneumocystis jirovecii pneumonia (PJP) prophylaxis. And usually for IgG levels less than 400, IVIG should also be provided.
In my experience, and based on real-world experience type of data, as long as antibacterial, antifungal, antiviral, anti-PJP prophylaxis, and hypogammaglobulinemia support are provided to the right patients and patients are compliant, no matter how strong the B-cell aplasia that is generated, patients should be well-protected from infectious complications. This also speaks to the fact that in our study, despite the B-cell being more pronounced with a combination of rituximab to axi-cel, the infections rates were lower than what we observed in ZUMA-1. This was based on the fact that these trials happened at different times. When ZUMA-1 was run initially, we didn't know what the potential infection complications of CAR were, but with time we learned what they look like, what the right management is, and patients have been educated to be more compliant.
As long as we have a consistent approach to preventing infections and patients are properly educated to be compliant with those, we can aim for a higher efficacy and still have acceptable toxicity.
As newer dual-targeting CAR T-cell therapies move through development, do you see them becoming part of standard treatment pathways for aggressive B-cell lymphomas, and what challenges could that create for oncology practices and treatment centers?
Dr Strati: There is promise for dual-targeting CAR. There are a couple or more of autologous anti-CD19 and CD20 CAR T-cell treatments that are moving to large, randomized phase 3 trials, and the efficacy data are quite consistent. We see higher CR rates and with longer follow-up, I'm sure we will see also more durable remissions.
One additional element to keep in mind is that some of them also have a quicker manufacturing, which is currently translating into more effective phenotype of T cells. As long as T cells are more naive and more central memory, less antigen prime, they tend to have more durable activity and more antitumor activity. The increasing utilization of dual-targeting CAR will translate into higher efficacy and potentially even less toxicity. The phenotype I just described also tends to be associated in clinical trials with lower rates of cytokine release syndrome (CRS) and neurotoxicity. So, I believe the approval in second-line or beyond of using dual-targeting CAR in LBCL is around the corner, based on ongoing large, randomized phase 3 trials.
As to how this will impact community oncologists, for patients who live in the community, sometimes it may be hard to relocate to an academic center to be able to receive CAR. It's important for referring centers to educate patients and share with them the curative potential of CAR. For mono-targeting CAR, autologous anti-CD19 CAR, we now have 5-year follow-up, at least for 2 of them, and there is improvement in overall survival for 1 of them. However, we can’t make the same statement yet for other treatments that can be more easily accessed in the community, including bispecifics.
Currently, the penetration of CAR treatment in the community is still very limited. There is an ongoing effort from the Foundation for the Accreditation of Cellular Therapy (FACT) to try to accredit as many CAR T-only sites as possible, even if a stem cell transplant is not provided. I believe community oncologists should still be aware of the curative potential that CAR and dual-targeting CAR may provide. As such, they can educate patients to consider the referral to an academic center or wherever needed, even if it means relocating to another city to be able to receive treatment that may be potentially curative.
Do you have any final thoughts or takeaways that you'd like to leave with our audience?
Dr Strati: The ZUMA-14 is more of a hypothesis generating trial. This trial has demonstrated that trying to target 2 antigens, in this case CD19 and CD20, is safe and may translate into better efficacy. This was not a randomized trial. The sample size was small and the median follow-up was about 2 years, not 5. So, there needs to be a longer follow-up before making any statement that these higher CR rates are also durable. But the study supports the idea that the upcoming dual-targeting CAR may be safe in terms of infectious complication from B-cell aplasia and may translate into higher efficacy.
While we prepare for the near future, we must also start thinking of the far future. This entails allogeneic instead of autologous products that are maybe non-T-cell–based cellular treatments, including NK cells or macrophages. As we learn to engineer better, these immune products, including in vivo CAR or CAR that are able to resist alloreactivity, we may be able to get away from lymphodepleting chemo. And this will, with time, move more cellular treatments from the academia to the community oncology. I hope that we will see that in the not-too-distant future.
