Chimeric antigen receptor T cell therapies have demonstrated their potential in chronic lymphocytic leukemia. However, the dysfunction of T lymphocytes inherent in the disease, in particular the reduction in proliferative and cytotoxic capacities, limits the effectiveness of this approach, according to an expert.

Concomitant treatment with ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who were receiving lisocabtagene maraleucel (liso-cel; Breyanzi) resulted in measurable effects on both chimeric antigen receptor positive (CAR+ ) and on endogenous T cells, both of which are linked to improved efficacy, according to translational analyzes from the ongoing TRANSCEND CLL 004 study (NCT03331198) that were presented at the 2021 Annual Meeting of the Society for Immunotherapy of Cancer (SITC).1

Data from a gene set enrichment analysis showed that there was a positive enrichment of gene sets related to cell proliferation, metabolism, and interferon response, as well as a negative enrichment of sets of genes associated with inflammation. “These results suggest that ibrutinib may potentiate the efficacy of liso-cel therapy in patients with relapsed/refractory CLL,” said study lead author Jerill Thorpe, principal investigator at Bristol Myers Squibb. , during a virtual presentation at the meeting.

CAR T-cell therapies have demonstrated their potential in CLL. However, Thorpe noted that the T-cell dysfunction inherent in CLL, including reduced proliferative and cytotoxic abilities, limits the effectiveness of this approach. Preclinical data have shown that ibrutinib improves liso-cel function independent of its antitumor effects.2

The Phase 1 TRANSCEND CLL 004 trial is evaluating the efficacy and safety of liso-cel monotherapy or concomitant ibrutinib in patients with relapsed/refractory CLL. More recently, in data presented at the International CLL Workshop, the combination was associated with a manageable safety profile for patients with relapsed/refractory CLL or small lymphocytic lymphoma.3

At a median follow-up of 17 months, no Grade 5 adverse events or Grade 4/5 cytokine release syndrome (CRS) or neurological events were reported. Of the 23 evaluable patients, CRS events of all grades occurred in 18 patients (78%), of whom only 1 (4%) had CRS grade 3. Neurological events of all grades were reported in 7 patients ( 30%) and 4 of them (17%) had grade 3 events. Eleven of these patients (48%) required tocilizumab (Actemra) and/or corticosteroids.

Efficacy results showed an overall response rate of 95%, which included a complete response (CR) rate of 59% and a partial response (PR) rate of 36%. Additionally, patients who received liso-cel 100 × 106 CAR T cells had a more pronounced CR (61%) and PR rate of 29%, compared to 50% and 25%, respectively, for those who received 50 × 106 CAR T cells.

At the 2021 SITC Annual Meeting, researchers presented data from translational analyzes of those who received liso-cel alone (n=16) or plus ibrutinib (n=19) from the trial. The pharmacokinetics of Liso-cel was evaluated by flow cytometry.

Other data showed that gene set enrichment analyzes through characteristic gene sets demonstrated that endogenous CAR+ and T cells had similar expression profiles in response to ibrutinib in patients in this study. Data showed that at peak CAR+ T cell expansion, increased expression of pathways was associated with T cell proliferation and metabolism, as well as decreased expression of pathways related to inflammatory signaling . Additionally, Thorpe noted that ibrutinib treatment resulted in increased liso-cel expansion and reduced serum IL-6.

An independently derived ibrutinibresponse CLL genetic signature score was increased and maintained over time in endogenous CAR+ and T cells after the liso-cel/ibrutinib combination, but this was not the case with liso-cel alone. Additionally, a higher ibrutinib gene signature score in CAR+ T cells at peak concentration was linked to an increased likelihood of undetectable minimal residual disease in bone marrow and peripheral blood, regardless of treatment arm. . When ibrutinib score was higher in endogenous T cells at 2 months, post-treatment was linked to longer progression-free survival (PFS) (P =.0012).

Additional findings showed that a genetic signature of T-cell exhaustion was significantly reduced and associated with improved PFS with liso-cel alone and in combination with ibrutinib. However, Thorpe cautioned that the small sample size of the analysis must be considered when interpreting the ibrutinib gene expression score and gene signature data related to gene depletion. T cells. “Work is underway to extend this analysis to a larger cohort,” Thorpe said. Additionally, a lower CAR+ T cell depletion score after 1 month of treatment (≤0.8 vs >0.8) was related to longer PFS (P =.01).

THE REFERENCES

1. Thorpe J, Rytlewski JA, Gillenwater HH, et al. Simultaneous ibrutinib improves T-cell function in patients with chronic lymphocytic leukemia (CLL) treated with lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T-cell therapy. Presented at: 2021 Society for Immunotherapy of Cancer Annual Meeting; November 10-14, 2021; Washington DC.

2. Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of a chimeric anti-CD19 antigen receptor T cell therapy, lisocabtagen maraleucel in combination with ibrutinib or acalabrutinib. J Immunother. 2020;43(4):107-120. doi:10.1097/CJI.0000000000000307 3. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: Phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory CLL/LLS. Presented at: 2021 International Workshop on Chronic Lymphocytic Leukemia; September 17-20, 2021; virtual.