David L. Porter, MD
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in the treatment of certain hematologic malignancies, including several types of large B-cell non-Hodgkin lymphomas (NHLs) and acute lymphoblastic leukemia (ALL). The U.S. Food and Drug Administration (FDA) has approved tisagenlecleucel in the treatment of relapsed or refractory pediatric and young adult ALL and axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell NHLs. CAR T-cell therapy has had less success in the treatment of patients with chronic lymphocytic leukemia (CLL), however. For example, tisagenlecleucel is providing most patients with advanced ALL with overall remission rates of more than 80% within the first 3 months of treatment,1 but just one-quarter of patients with CLL experience a durable response to the therapy. This is according to research by David L. Porter, MD, Jodi Fisher Horowitz Professor in Leukemia Care Excellence and Director, Cell Therapy and Transportation at the Abramson Cancer Center and -Perelman School of Medicine, University of Pennsylvania, and colleagues.2
However, a new study by Dr. Porter and colleagues has found that the addition of anti-CD19–directed CAR T-cell therapy in patients with advanced CLL who were receiving the tyrosine kinase inhibitor ibrutinib generated a sustained complete response rate of 43% and an overall response rate of 71%. Furthermore, 94% of patients had no evidence of CLL in their bone marrow, including a 78% minimal residual disease–negative response by deep sequencing of the immunoglobulin heavy chain locus, after 1 year of follow-up.3 The study included 19 patients, all of whom had received ibrutinib for at least 6 months prior to enrollment in the trial. During that time, none of the patients had achieved a complete remission. Eighteen patients are still alive.
The ASCO Post talked with Dr. Porter about why the combination of ibrutinib and anti-CD19–directed CAR T-cell therapy may be effective in eliciting durable responses in patients with progressive CLL and how combinations of targeted therapies and CAR T-cell therapy may change the standard of care for these patients.
Priming T Cells to Activate Them Against CLL
Why were patients in your clinical trial required to receive ibrutinib for 6 months prior to enrollment in the study?
The design of the trial was written based on preclinical data suggesting that patients with CLL who have had prolonged exposure to ibrutinib have healthier T cells—this would make CAR T cells more functional and more active against CLL. Based on these studies, patients had to have been on ibrutinib for at least 6 months prior to enrollment in the trial and had to have active disease. The patients were then required to remain on ibrutinib throughout the trial, including during the collection of their T cells, the infusion of their engineered CAR T cells, and the postinfusion follow-up.
Evaluating the Results
Please talk about your study results and the number of patients who achieved a complete remission on the combination therapy.
It is still early in our follow-up evaluation, but at the time we presented our findings during the 2018 American Society of Hematology Annual Meeting in December 2018, 6 of 14 patients (43%) who reached an evaluable milestone had a complete response, according to the International Workshop on Chronic Lymphocytic Leukemia response criteria guidelines, and another 4 patients had a partial response. So, the overall response rate was 71%.3
In total, 16 of the 18 patients have no evidence of leukemia in their bone marrow by morphology and/or flow cytometry, as of the latest follow-up.— David L. Porter, MD
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What is really exciting and interesting to us is that 10 of 11 patients who are now 1 year out postinfusion have maintained a complete morphologic remission in their bone marrow. Some of the patients could not be considered in strict complete remission because they still had lymph nodes or spleens that were slightly larger than normal. We did not have an opportunity to biopsy the slightly larger lymph nodes and don’t know whether those patients still have disease, but the fact that their marrow was clear of all disease was encouraging.
In total, 16 of the 18 patients have no evidence of leukemia in their bone marrow by morphology and/or flow cytometry, as of the latest follow-up.
Are the patients currently receiving maintenance ibrutinib?
Most are. The trial was not designed to assess the ability to stop ibrutinib. Our follow-up study will do that. We did have 6 patients discontinue ibrutinib at a median of 8 months, either because of toxicity or for various other reasons. One patient has experienced disease progression, and five patients have not.
How severe were the toxicities patients experienced with the combination of ibrutinib and CAR T-cell therapy?
There was no suggestion that the side effects from this combined therapy were more intensive compared with CAR T cells or ibrutinib therapy alone. As is common, most patients, 18 of the 19, did experience cytokine-release syndrome from the CAR T-cell treatment, but it was severe in only 3 patients, 2 of whom required tocilizumab.
What are you learning about why the combination of CAR T-cell therapy and ibrutinib appears to be effective in treating CLL?
As mentioned previously, I think prolonged exposure to ibrutinib may make a patient’s own T cells healthier and lead to a generation of more active and functional CAR T cells. We have also found that prolonged exposure to ibrutinib may make CLL cells a better target for the CAR T cells. We think it is a combination of both factors.
Evaluating the Best Candidates for Combination Therapy
Your earlier study of CAR T-cell therapy alone in patients with relapsed and refractory CLL found that only about one-quarter achieved a complete remission. Based on your latest research, should all eligible patients with advanced CLL be considered for this treatment?
If our recent study results hold up in longer follow-up, that may indicate the combination of ibrutinib plus CAR T-cell therapy may lead to a much higher response rate. It is also important to note that although complete response rates from CAR T-cell therapy alone occur only in a minority of patients with CLL, those who respond tend to have sustained remissions, so relapses are unusual.
However, we think the combination of ibrutinib plus CAR T-cell therapy may significantly increase the likelihood of achieving a complete response in more patients. With longer follow-up, we hope to see that the remissions are sustained. It may be that the most effective way to use CAR T-cell therapy in patients with CLL is in combination with ibrutinib.
Are you planning to study the combination of ibrutinib and CAR-T cell therapy in a larger number of patients with CLL?
Yes, we do plan to study this treatment in a larger cohort of patients with CLL. We also hope to determine through follow-up biopsies whether patients who have achieved complete remission in their bone marrow but have slightly enlarged residual lymph nodes still have disease. Furthermore, we are going to test whether we can stop ibrutinib once patients achieve a remission to see whether those remissions are sustained.
Prolonged exposure to ibrutinib may make a patient’s own T cells healthier and lead to a generation of more active and functional CAR T cells.— David L. Porter, MD
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We hope to learn the impact of continuous ibrutinib and its effect on CAR T cells to sustain complete remissions. Although ibrutinib is generally well tolerated, it may be associated with a long list of side effects, and many patients discontinue the drug because of toxicity. Ibrutinib tends to cause significant gastrointestinal toxicity, including cramping and diarrhea; it also can increase the risk of atrial fibrillation and has antiplatelet effects, which makes patients prone to bleeding.
In addition, right now, ibrutinib is expensive, and there are many patients who suffer significant financial hardship because the drug is given as long-term therapy. It’s not just expensive in the short term, it is a many-year therapy that can impact patients’ financial security long term. For these reasons, we think it would be beneficial to have a protocol that would allow patients to have a limited course of ibrutinib and not have to use it as a prolonged therapy. We are hoping to launch a study to determine the effects of short-term ibrutinib on patients.
Prolonging Remission in Patients With Advanced Disease
Are there other targeted therapies that appear to be effective in combination with CAR T-cell therapy in CLL? What other studies are you planning?
We are starting to test CAR T cells with checkpoint inhibitors in both CLL and in lymphoma to see whether checkpoint inhibitors can increase activation of CAR T cells. We also hope to launch a trial for patients who have been receiving ibrutinib for a long period and may have achieved T-cell benefits but are either progressing or are at risk of progressing on ibrutinib;
It may be that the most effective way to use CAR T-cell therapy in patients with CLL is in combination with ibrutinib.— David L. Porter, MD
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these patients have acquired an ibrutinib resistance mutation in their CLL cells and so might be excellent candidates for CAR T-cell therapy before they experience rapid disease progression on ibrutinib.
This is a rapidly evolving field, and enormous progress has been made. The use of CAR T cells targeting CD19 has produced dramatic results. For CLL, the goal is to improve remission rates and prevent disease progression in patients with advanced disease. It is also critical to identify other targets for different malignancies, so that CAR T cells can be applied effectively to other diseases. ■
DISCLOSURE: Dr. Porter is a patent owner with royalty payments from Novartis; has received research support from Novartis; honorarium for advisory board participation from Novartis, Kite Pharma, Incyte, Humanigen, and Glenmark; honorarium for DSMB participation from Immunovative Therapies; salary and stock/options from Genentech/Roche (spouse employment).
REFERENCES
1. Maude SL, Laetsch TW, Buechner J, et al: Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378:439-448, 2018.
2. Porter DL, Hwang WT, Frey NV, et al: Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139, 2015.
3. Gill SI, Vides V, Frey NV, et al: Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows high response rate. 2018 ASH Annual Meeting. Abstract 298. Presented on December 2, 2018.
