 Currently we have autologous CAR [chimeric antigen receptor] T-cell therapy in the third-line space for DLBCL [diffuse large B-cell lymphoma]. There are clinical trials ongoing investigating the question of CAR T therapy in the second-line setting compared with platinum-based salvage with or without an autologous stem cell transplant. We should have results from these studies in the next 12 months or so.

What’s tantalizing though is that the ZUMA-12 study showed us the proof of concept of first-line autologous CAR T therapy. These patients had initially been treated with chemoimmunotherapy with rituximab and CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and those patients who, on an interim assessment, had not achieved an adequate response could then go on to have an autologous stem cell harvest followed by CAR T therapy. That’s an important consideration for high-risk-patient groups in the first-line setting.

For patients who we think will have poorer outcomes, and these were identified based on response, we may be able to identify some patients at baseline who would be expected to have a worse outcome—for example, double- or triple-hit patients or 

-mutated patients and others. Of course, these patients have a better autologous harvest when we collect their cells prior to manufacture of a CAR T-cell product, which is enriched with more naїve cells and therefore a more favorable product characteristic. We know that they have very high response rates and complete remission rates. We also know that they have higher-peak CAR T expansion levels in the first month, and we know that they have a higher total area under the curve in the first month—2 parameters associated with response.

There are data confirming proof of concept of the approach of using CAR T therapy as part of first-line treatment in high-risk patients, and that’s the destination of travel. However, we’ve got a few steps to overcome before we get there. One of those is demonstrating superiority to conventional second-line therapy, based on the ongoing clinical trials for axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene, which is currently unlicensed in Europe.

In terms of the future landscape for autologous CAR T therapy, a number of developments of the product are underway. One of them is multitargeting to deal with CD19 escape or downregulation. Another has to do with manufacture and time to manufacture, and processes are also underway to reduce the time to manufacture to a couple of days. The third is really looking at allogeneic donor sources for CAR T therapies, and these are important areas of development where we’ve seen some early data presented at EBMT [European Society for Blood and Marrow Transplantation Annual Meeting] and at other conferences over the last year.

Videos

Amit Patel, BSc, MBBS, PhD, discusses currently ongoing clinical trials of CAR T-cell therapy in first- and second-line treatment settings and comments on potential developments on the horizon. 

Research on CAR T Therapy in Earlier Lines of Treatment 

 Optimal patient selection and sequencing are important considerations for potential CAR [chimeric antigen receptor] T candidates. If we think about patient selection, it’s important to remember that autologous CAR T-cell therapy is not high-dose therapy, so it is not the same as autologous stem cell transplantation and is also not the same as allogeneic stem cell transplantation. In other words, the lymphodepleting chemotherapy is not likely to cause significant organ impairment and is likely to be deliverable to patients who are much older and more comorbid than those patients who would not be otherwise suitable for autologous allogeneic stem cell transplant.

When somebody has either been refractory or has relapsed after first-line therapy, that’s the time to think whether somebody is likely to be a candidate for CAR T therapy. If they’re not a candidate for autologous stem cell transplant, then they will have second-line therapy but invariably will relapse. By that point, that patient at the earliest opportunity should be put on a CAR T treatment pathway. Arguably, that patient is already on a CAR T treatment pathway if they have relapsed or not responded to first-line therapy and are unable to be considered a candidate for autologous transplant.

For patients who have relapsed/refractory disease after first-line therapy who are potential autologous stem cell transplant candidates from a fitness perspective, those patients will go on to receive platinum-based salvage therapy. Unfortunately, half of patients will not respond to salvage and therefore will transition to an autologous CAR T therapy treatment pathway. For those patients who do respond, some patients will still end up not being able to go on to receive autologous stem cell transplant because either they can’t have peripheral blood stem cell harvest undertaken or undertaken in a timely manner such that they have disease that hasn’t relapsed within that time frame. Those patients will then end up moving to an autologous CAR T treatment pathway. You can see now that the majority of patients could be considered potential autologous CAR T patients in the relapsed and refractory setting for DLBCL [diffuse large B-cell lymphoma].

In terms of patient selection, there is no upper age limit for this therapy because it’s not high-dose therapy; it’s an immune effector cell therapy. The chemotherapy is not limiting, and really it’s the ability to tolerate adverse effects, including cytokine release syndrome and neurotoxicity. We also know that in terms of patient selection, lower thresholds can be applied for renal function. For example, the EBMT [European Society for Blood and Marrow Transplantation] recommendation is a creatinine clearance of 30 mg/g. We also know that lower cardiac ejection fraction is tolerated, so the EBMT recommendation is also lower than what we would typically accept for autologous or allogeneic stem cell transplant.

It’s important to remember that these potentially nontransplant-eligible patients, of which there are lots in the relapsed/refractory setting, are candidates for autologous CAR T therapy. The other way I would think about this is really anybody who has DLBCL who failed first-line therapy should be considered for autologous CAR T therapy, and that consideration should be actively excluded if somebody is not suitable.

A key opinion leader in hematology and oncology shares insights on factors to consider for optimal patient selection and treatment sequencing, such as thresholds for tolerability, renal function, and cardiac ejection fraction. 

Optimizing Patient Selection for CAR T-Cell Therapy 

 Early referral to a CAR [chimeric antigen receptor] T center for autologous CAR T-cell therapy in the third-line space is critical. Unfortunately, patients who have relapsed/refractory disease in this setting are dying, and these patients need a rescue therapy given that they’ve already failed 2 lines of chemoimmunotherapy with or without radiotherapy in some cases. The time that the patient first becomes eligible based on their PET [positron emission tomography] scan after salvage therapy or on a biopsy after salvage therapy is when the clock starts, because that patient needs to have an apheresis procedure completed as soon as possible so that bridging therapy can start. When the patients have a manufactured product returned to site, that product needs to be infused into that patient after lymphodepletion at the earliest opportunity. Reducing the time between somebody being eligible for CAR T therapy and delivering it is a key metric in terms of efficacy and safety. We know that these patients are relapsed/refractory to chemoimmunotherapy, so more chemoimmunotherapy is not going to change the outcome of these patients who historically would have otherwise died.

In terms of bridging therapy approaches, it’s important to—at a very minimum—not allow the disease to progress any further. In other words, not to increase the tumor volume in that patient. The aim of bridging therapy is to achieve a response, and achieve the best response possible, to debulk the disease burden at the time of CAR T infusion. My advice would be as soon as the apheresis procedure has been completed, whether it’s on that day or the next day, those patients should commence bridging therapy immediately, and this should be meaningful bridging therapy.

For example, we tend to use a combination of rituximab, polatuzumab, and bendamustine, omitting bendamustine if they’ve had it previously. We combine this with radiotherapy if there is evidence of disease bulk, even if there are multiple sites involved. This combined approach, which is aggressive to try and debulk the total amount of tumor at the time of CAR T infusion, is what we would consider best practice globally. This does 2 things. It reduces the amount of tumor burden that’s there, and we know that the amount of tumor burden—whether it’s measured by total metabolic tumor volume, LDH [lactate dehydrogenase], or other markers of disease prior to CAR T infusion—is important from an efficacy and safety perspective. We know patients who have more disease on board might be expected to have a higher likelihood of developing cytokine release syndrome and neurotoxicity. So deliverability of CAR T-cell therapy after good bridging is what we now consider the standard of care.

Amit Patel, BSc, MBBS, PhD, discusses best practices for referring patients to CAR T centers earlier and provides advice on bridging therapy to debulk disease burden at the time of CAR T-cell therapy. 

Best Practices for Early Referral and Bridging Therapy 

Autologous CAR [chimeric antigen receptor] T-cell therapy has been a major advance in patients with DLBCL [diffuse large B-cell lymphoma] and is commercially available for patients in the third-line space who have relapsed/refractory disease. We have had 2 products available: axicabtagene ciloleucel and tisagenlecleucel. Tisagenlecleucel is a second-generation product with a 4-1BB costimulatory domain. The binding component, the thing that binds to CD19, is derived from FMC63. That binding domain is the same domain used for axicabtagene ciloleucel. This second-generation product has a CD28 intracellular signaling domain.

These 2 products have been available after single-arm pivotal clinical trials, the JULIET study for tisagenlecleucel and the ZUMA-1 study for axicabtagene ciloleucel. There are now a few years of follow-up in the real-world setting, and there are a number of real-world data sets evaluating the efficacy and safety of these 2 products. What’s been interesting is the real-world data have shown that the efficacy is similar to the pivotal clinical trials, and it’s important to remember that the real-world data for most therapies are typically not as good as the pivotal clinical trials. However, for CAR T-cell therapy, the opposite is true, and the real-world data are just as good despite including one-third to one-half of patients who would have not met inclusion criteria for the pivotal clinical trial. In other words, more difficult-to-treat patients are included, yet the efficacy signal is maintained.

The thing that’s more heartening is that the real-world data show us that the safety of CAR T therapy is better in the real world compared with the pivotal clinical trials, in terms of both cytokine release syndrome and neurotoxicity but also other safety parameters. That’s speaking to the fact that these therapies are delivered within specifically designated CAR T centers as part of allogeneic stem cell transplant programs. There is now a critical mass of expertise and concentration of expertise in these centers that has led to these excellent outcomes.

The EBMT [European Society for Blood and Marrow Transplantation] symposium highlighted that the long-term follow-up available from the pivotal clinical trials relating to tisagenlecleucel and axicabtagene ciloleucel showed durability of response. This is a onetime therapy for patients who have relapsed/refractory DLBCL in the third-line space. After this onetime therapy, we know that 30% to 40% of patients will remain in response in the longer term, up to 4 years and that 40% to 50% of patients will remain alive in the longer term. That’s been very important. The long-term data have also shown us that immune reconstitution and full recovery are also an expectation, particularly for patients followed up with after axicabtagene ciloleucel in the pivotal clinical trial. So we know from the pivotal studies that their initial responses seen are durable, they don’t require further therapy, and the patients recover after this therapy in terms of the immunity.

Real-world data have shown us that across the globe, whether the consortia that collected the data were based in the United States, in the United Kingdom, or anywhere in Europe, the patients treated with both axicabtagene ciloleucel and tisagenlecleucel expect to have similar outcomes to those presented in the pivotal clinical trials in terms of efficacy. But what’s important is that the safety in the real world has been shown to be better than in the pivotal clinical trials. That’s important to underline because the real-world data show us the safety of this complicated, autologous, personalized, patient-derived cell product is not only logistically possible to deliver but also able to deliver it in a very safe manner in a safe environment. The inclusion of patients who would not have met the pivotal clinical trial criteria in the real world, 30% to 50% depending on the product, is also very important to highlight, making sure that patient access and broad applicability of those findings have been demonstrated.

A key opinion leader in diffuse large B-cell lymphoma provides a historical perspective on third-line options for CAR T-cell therapy and shares insights on both clinical trial and real-world data. 

Options for CAR-T Therapy in the Third-Line Setting

My name is Amit Patel. I’m a consultant in cellular therapies and stem cell transplantation. I work at The Christie NHS Foundation Trust in Manchester [in England], and I lead the cellular and CAR [chimeric antigen receptor] T-cell program.

There is an ongoing patient need for patients with relapsed/refractory diffuse large B-cell lymphoma. Patients in this category either will have primary refractory disease to frontline therapy, typically on CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. A percentage of patients will have advanced-stage disease, or they will have had a response to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or other frontline therapies and then relapsed. This is the relapsed/refractory patient population we’re talking about. They will go on to receive second-line therapy, and if they’re transplant eligible, then they will go on to have a platinum-based salvage regimen. If they’re not, then they will go on to have other potential regimens.

The patients who either don’t respond to salvage therapy, or who relapse after salvage therapy and a transplant, will then be eligible for CAR T therapy. CAR T therapy is available in the third-line space for relapsed/refractory diffuse large B-cell lymphoma. Before we had CAR T therapy, these patients would unfortunately have had a limited survival potential with very few patients surviving more than a few months and small numbers surviving out to a year. CAR T therapy has been able to rescue patients who would have otherwise died and achieve a progression-free survival between 30% and 40% with an overall survival of 40% to 50%, with long-term data out to around 4 years.

An expert in hematology oncology, Amit Patel, BSc, MBBS, PhD, reviews the unmet needs for patients with relapsed/refractory diffuse large B-cell lymphoma.

Amit Patel, BSc, MBBS, PhD, The Christie NHS Foundation Trust

Articles

Research on CAR T Therapy in Earlier Lines of Treatment

Optimizing Patient Selection for CAR T-Cell Therapy

Best Practices for Early Referral and Bridging Therapy

Options for CAR-T Therapy in the Third-Line Setting

Unmet Needs in Relapsed/Refractory DLBCL