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

 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. 

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