Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy

Abstract

CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.

Chimeric Antigen Receptor-Modified T Cell Immunotherapy for Relapsed and Refractory Adult Burkitt Lymphoma

“…Large lesions, which are common in Burkitt lymphoma, prevent CAR T cells from infiltrating tumors, fully contacting and recognizing cognate antigens, and performing their antitumor functions ( 23 , 24 ). Besides, as shown in previous studies, the peak level of CAR T cell expansion is a significant predictor of clinical objective response ( 24 , 31 ). Burkitt lymphoma has similarities to both leukemia and solid tumors.…”

Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy

“…Identification of biomarkers associated with response or toxicity after CAR T cell therapy could enable earlier interventions to improve outcomes and provide novel mechanistic insights into response and toxicity. Immunokinetic measurements of total CAR T cell levels in LBCL have been performed in numerous studies 2,6,8,15,[47][48][49][50][51][52] and generally demonstrate inconsistent or weak correlations with response. In line with this, in 32 patients with LBCL receiving commercial axi-cel at our institution, we observed that neither flow cytometric nor qPCR-based measurement of CAR T cell expansion associated with clinical response or long-term disease control (Figs.…”

Predictive short/long-term efficacy biomarkers and resistance mechanisms of CD19-directed CAR-T immunotherapy in relapsed/refractory B-cell lymphomas

“…First, the association of active CAR-T-cell expansion with response was found in the ZUMA-1 trial (4), as the area under the curve of CAR-T-cell levels in responders was 5.4 times as high as the value in nonresponders (4). Several other studies confirmed this kind of association (10,58,62,63). In a representative study, patients were divided into weak expanders and strong expanders according to the peak blood concentrations of CAR-T cells (CAR-T-Cmax) (62).…”

“…According to the findings by Garcia-Recio and colleagues, high-risk aaIPI (≥2) indicated worse OS, while both high-risk IPI (≥3) and aaIPI predicted shorter PFS (78). Sylvain and colleagues revealed similar results that high-risk aaIPI indicated inferior PFS and OS (58). In addition to IPI, Gray and colleagues found that CRP ≥ 11 was a risk factor for survival at 1 year (P=0.019), while absolute lymphocyte count ≥ 0.50 at collection (P=0.043) and tocilizumab exposure (P=0.005) were protective factors (57).…”