Background: Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved for patients (pts) with relapsed/refractory LBCL after ≥2 prior systemic therapies. In the pivotal ZUMA-1 study, pts with high pretreatment (preTx) TB (estimated by sum of product diameters [SPD]) had lower peak CAR T-cell expansion normalized to TB and less frequent durable response rates vs pts with low TB ( < 30% vs > 60%, respectively; Blood Adv. 2020;4:3268). The number of CD8⁺ and CCR7⁺CD45RA⁺ product T cells infused and favorable immune contexture in preTx TME were also associated with axi-cel response (Blood Adv. 2020;4:3268; Galon et al. ASCO 2020. #3022). As potential barriers to axi-cel efficacy are not fully elucidated, we systematically analyzed preTx TME characteristics, including myeloid-related biomarkers and product attributes, to identify such challenges in ZUMA-1 pts with high TB. Methods: Samples from evaluable pts in ZUMA-1 Phase (Ph) 1 and Ph2 Cohorts (C) 1–3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). PreTx immune TME was analyzed by multiplex immunohistochemistry (n = 18) and gene expression analysis (n = 30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell product characteristics and other covariates were evaluated as previously described (Blood Adv. 2020;4:3268). Correlative analyses of these covariates with clinical outcomes were performed by Wilcoxon or Kruskal-Wallis test. Median TB (by SPD) from ZUMA-1 Ph1 and Ph2 C1+2 was used as a cutoff for high ( > 3721 mm²) vs low (≤3721 mm²) TB. Durable response refers to pts in ongoing response at time of data cutoff. Results: PreTx immune TME features related to suppressive myeloid-related activity, most notably ARG2, TREM2, and IL-8 gene expression, were elevated in pts who failed to respond or relapsed without documented loss of CD19 expression. ARG2 and TREM2 levels in preTx biopsies were negatively associated with CD8⁺ T-cell density. Pts with high TB who achieved durable response had low preTx ARG2 and TREM2 levels in TME and enhanced CAR T-cell expansion after axi-cel compared to pts with high TB who relapsed. High ratio of T-cell to suppressive myeloid cell markers (T/M ratio) in preTx biopsies associated positively with CAR T-cell expansion (peak and peak normalized to TB) and durable response in pts with high TB. Conclusions: Axi-cel may overcome high TB in pts with a favorable immune TME alongside robust CAR T-cell expansion. Favorable immune TME is characterized by reduced suppressive myeloid cell activity (low ARG2 and TREM2 expression) and increased T/M ratio. These data suggest possible actionable strategies to overcome high TB in the context of CAR T-cell therapy. [JC and VP contributed equally] Clinical trial information: NCT02348216