Newer Approaches With CAR T Cells Explored in CLL


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“CAR T-cell therapy has changed our approach to the treatment of hematologic malignancies.”
— David G. Maloney, MD

Chimeric antigen receptor (CAR) T-cell therapy is a hot area of research and development in hematologic malignancies and, more recently, some solid tumors. Results have been particularly good in acute lymphocytic leukemia, and one or more CAR T-cell products may be getting close to approval by the U.S. Food and Drug Administration.

At the 2017 International Workshop on Chronic Lymphocytic Leukemia (iwCLL), David G. Maloney, MD, of Fred Hutchinson Cancer Research Center in Seattle, described his experience with CAR T cells in the treatment of CLL at his institution and other centers.1 “CAR T-cell therapy has changed our approach to the treatment of hematologic malignancies,” Dr. Maloney stated.

The first generation of trials used a CD19-directed antibody coupled to the T-cell receptor. The second-generation CAR T-cell therapy focused on adding co-stimulatory molecules (such as CD28 or 4-1BB) to make the genetically engineered T cell more active, Dr. Maloney explained.

“Third-generation molecules with more than one co-stimulatory molecule are being studied,” he noted. “There are different co-stimulatory molecules, but they have not been studied head to head.”

Selected CD19 CAR T cells are currently being studied in at least seven different centers. These CAR T-cell products differ in the choice of co-stimulatory molecule, virus vector, and lymphodepletion regimens. More recently, the Fred Hutchinson Cancer Center is using a fixed CD4:CD8 ratio for the CAR T cells, based on preclinical evidence that this approach is superior.

“The different CAR T-cell products are not identical. Do any of these factors make a difference? We don’t know, but you can’t generalize from one to the other,” Dr. Maloney told the audience.

CAR T Cells in CLL

The first reported clinical trial of CD19 CAR T cells for the treatment of relapsed or refractory CLL was conducted in 14 patients at the University of Pennsylvania.2 The overall response rate was 57%, with 4 complete remissions and 4 partial remissions. In vivo expansion of CAR T cells correlated with clinical responses. Evidence of persistent CAR T cells was found beyond 4 years in the first 2 patients who achieved complete remission. As of 2015, no patient in complete remission had relapsed. A few patients achieved minimal residual disease–negative status.

UPDATE ON CAR T-CELL THERAPY FOR CLL

CAR T cells are being studied in CLL, with high response rates and durable responses in some very high–risk patients with relapsed or refractory disease. Cytokine-release syndrome and neurotoxicity continue to be adverse events of concern. Researchers are exploring ways to manipulate CAR T cells, including a fixed ratio of CD4:CD8 cells.

In an effort to improve upon the potency of CD19 CAR T cells, Dr. Maloney and colleagues are studying a product called JCAR014 (CD19 CAR T cells with a fixed 1:1 composition of CD4/CD8 cells). A phase I/II study is currently ongoing to determine the feasibility of manufacturing JCAR014, its safety, CAR T-cell persistence and migration, as well as its efficacy in patients with advanced B-cell malignancies (including acute lymphocytic leukemia [n = 48], non-Hodgkin lymphoma [n = 64], and CLL [n = 24]).

“We picked this group of [CLL] patients because they are high-risk, relapse/refractory patients who progressed on ibrutinib (Imbruvica) and they have poor clinical outcomes. We thought this would be the best group to try to show that CAR T could make a difference,” he stated.

Early Results With JCAR014

Of the 24 patients with CLL, the median age was 61 years, the median number of lines of prior therapy was 5, 100% were treated with ibrutinib (Imbruvica); 19 (79%) were ibrutinib-refractory and 3 (13%) were ibrutinib-intolerant; 6 (25%) were refractory to venetoclax (Venclexta). A total of 23 patients (96%) had high-risk cytogenetics, 23 patients (96%) had extramedullary disease and were not candidates for allogeneic transplant, 14 patients (58%) had 17p deletion, and 16 patients (67%) had a complex karyotype.

Twenty-one patients (87%) received cyclophosphamide/fludarabine lymphodepleting chemotherapy; 18patients (75%) received a single cycle of CAR T cells, and 18 patients (75%) were treated as outpatients. Six patients (25%) received a second cycle for residual disease or relapse. Among the 21 patients who received cyclophosphamide/fludarabine, 19 were restaged at 4 weeks after JCAR014 infusion; in these patients, the overall response rate was 74%, and the complete response rate was 21%. The 16 patients who were ibrutinib-refractory were restaged at 4 weeks following infusion; of them, the overall response rate was 69%, and the complete response rate observed was 25%. Patients who had a lymph node response had longer progression-free and overall survival.

“Nonresponders do badly. We did not transplant responding patients,” Dr. Maloney told the audience.

“There is no free lunch with this treatment. You have a high probability of getting a marrow complete response but also the possibility of cytokine-release syndrome and neurotoxicity.”
— David G. Maloney, MD

Lessons Learned

One important lesson from this study was that expansion of CAR T cells is correlated with outcome. Proliferation of T cells generally correlates with disease burden, Dr. Maloney explained.

Six patients (25%) received tocilizumab (Actemra) and dexamethasone for cytokine-release syndrome and/or neurotoxicity.

“There is no free lunch with this treatment. You have a high probability of getting a marrow complete response but also the possibility of cytokine-release syndrome and neurotoxicity. With higher proliferation of T cells, the risk of both is increased. We need to find a sweet spot,” admitted Dr. Maloney.

The results to date of the phase I/II study show that JCAR014 plus cyclophosphamide/fludarabine lymphodepletion is a feasible approach, with a high level of antitumor activity as measured by bone marrow clearance on flow cytometry in 15 of 17 patients (88%) and by immunoglobulin heavy (IGH) sequencing in 7 of 14 patients (50%).

“Deep marrow clearance by IGH sequencing after JCAR014 provides early signs of durable responses, with 100% progression-free and overall survival,” he stated.

Moving Forward

Recent research suggests that ibrutinib may improve the outcome of CAR T-cell therapy. An ongoing clinical trial at the University of Pennsylvania is investigating this approach. The study includes 15 patients with partial remission or stable disease on ibrutinib for at least 6 months who failed to respond to 1 prior regimen. Complete responders to ibrutinib and patients with Richter’s transformation are excluded from this study.

Another approach is to use ROR1 as a target for CAR T cells. First-in-human trials of ROR1-positive, defined CD4/CD8 ratio, CAR T cells are being conducted at the Fred Hutchinson Cancer Research Center in patients with advanced ROR1-positive malignancies. Cohort A will include a total of 30 patients with relapsed or refractory CLL, mantle cell lymphoma, and acute lymphoblastic leukemia; cohort B will include a total of 30 patients with non–small cell lung and breast cancers. ■

DISCLOSURE: Dr. Maloney reported no conflicts of interest.

REFERENCES

1. Maloney DG: Anti-CD19 CAR-T cell therapy with defined T-cell subsets for ibrutinib-refractory CLL. 2017 International Workshop on Chronic Lymphocytic Leukemia. Presented May 15, 2017.

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.


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