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Chimeric antigen receptor (CAR) T-cell therapy represents a novel treatment for the management of several hematological malignancies, including large B-cell lymphoma (LBCL). Despite high clinical efficacy, treatment response and outcomes can be variable. Challenges faced include primary treatment failure, relapse, and significant toxicities, including cytokine release syndrome (CRS) and neurological events (NE) (e.g., immune effector cell associated neurotoxicity syndrome [ICANS]). The mechanisms underlying this variance in clinical response remain unclear, with no risk factors clearly identified among those commonly suspected (e.g., performance status, cytogenetic factors, and disease stage).
Here we summarize the results of two studies exploring factors that influence the efficacy and toxicity of CAR T-cell treatment with axicabtagene ciloleucel (axi-cel) for LBCL. Frederick Locke and colleagues provide findings from a comprehensive analysis of covariates and biomarkers not previously reported from the ZUMA-1 LBCL trial (published in Blood Advances, October 2020)1. Meanwhile, Qing Deng and colleagues present their findings on how transcriptomic and molecular features are associated with outcomes and efficacy (published in Nature Medicine, October 2020)2.
Samples and data from the multicenter phase I/II ZUMA-1 trial (NCT02348216) were used for the current analysis. Two-year results from this study have been reported previously on the Lymphoma Hub. In summary:
The factors most strongly associated with DR to CAR T-cell treatment are represented in Table 1. A higher expansion rate of product T-cells before infusion (doubling time) was correlated with greater in vivo CAR T-cell levels. The strongest positive correlate of DR was peak CAR T-cell levels normalized to pretreatment tumor burden, whereas high tumor burden and pro-inflammatory state were negatively associated with DR.
Table 1. Factors associated with DR1
CAR, chimeric antigen receptor; DR, durable response; IL-6, interleukin-6; LDH, lactate dehydrogenase; TB, tumour burden. |
||
Factor |
Probability of DR |
p value |
Peak CAR T-cells (cells/µl) |
Increased |
0.0159 |
Peak CAR T-cells/tumor burden (108cells/mm2) |
Increased |
0.0017 |
Higher baseline tumour burden |
Decreased |
0.0259 |
Increasing baseline ferritin (pg/mL) |
Decreased |
0.123 |
Increasing baseline LDH (pg/mL) |
Decreased |
0.0251 |
Increasing baseline IL-6 (pg/mL) |
Decreased |
0.0237 |
Increased number of infused CD8 cells, normalized to TB |
Increased |
0.0108 |
Increased number of CCR7+CD45RA+ T-cells infused |
Increased |
0.0301 |
Factors associated with increased risk of ≥ Grade 3 CRS and NE are represented in Table 2.
High tumour burden and proinflammatory state were positively correlated with an increased risk of significant toxicity.
Table 2. Tumor biomarkers correlated with increased risk of significant toxicities1
CCL2, C-C motif chemokine ligand 2; CRS, cytokine release syndrome; IL-6, interleukin-6; LDH, lactate dehydrogenase; NE, neurological events. |
||
Factor associated with toxicity |
Grade ≥ NE, p value |
Grade ≥ CRS, p value |
Baseline tumor burden (mm2) |
0.0164 |
Not significant |
Day 1 ferritin (ng/mL) |
0.062 |
Not significant |
Baseline LDH (pg/mL) |
0.0006 |
0.00275 |
Day 1 CCL2 (pg/mL) |
0.003 |
0.0774 |
Baseline IL-6 (pg/ml) |
Not significant |
0.0391 |
The authors identified several limitations, including:
A biological, observational study of 24 patients with LBCL (16 DLBCL, 6 tFL, and 2 PMBL) receiving standard of care axi-cel. Analyses included the following:
Primary end points were as follows:
CAR T-cell therapy continues to hold promise for patients with LCBL, both treatment naïve and those with refractory disease. Together, these studies confirm that the response to treatment and risk of side effects is affected by CAR T-cell infusion characteristics, tumour burden, host systemic inflammation at baseline, and molecular response to treatment. Large clinical trials are needed to validate these findings, and to determine if further product optimization and treatments such as immune modulation can improve outcomes and safety.
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