Abstract CT153: Pretreatment immunoscore and an inflamed tumor microenvironment (TME) are associated with efficacy in patients (Pts) with refractory large B cell lymphoma treated with axicabtagene ciloleucel (Axi-Cel) in ZUMA-1
Authors: Rossi John M. , Galon Jérôme , Chang Edmund , Perbost Regis , Scholler Nathalie , Turcan Sarah , Danan Corinne , Locke Frederick L. , Neelapu Sattva S. , Miklos David B. , Jacobson Caron A. , Lekakis Lazaros J. , Lin Yi , Ghobadi Armin , Milletti Francesca , Go William Y. , Bot Adrian 
Published: August 2019

Abstract
Background: Axi-cel is an FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In Phase 2 of ZUMA-1, the objective response rate was 83% (58% complete responses [CRs]) (Locke et al. Lancet Oncol. 2018). Previous work showed that pre-existing expression of immune-related genes (Immunosign® 21 with NanoString®) may be associated with response to axi-cel (Rossi et al. AACR 2018. #LB-016). This expanded post-hoc analysis includes novel analysis associating T cell density with efficacy.
Methods: Pts received a target dose of 2.0 × 106 CAR T cells/kg in ZUMA-1 (NCT02348216). Pretreatment (before conditioning) tumor tissues were analyzed by immunohistochemistry for density of T cell subsets (CD3+, CD8+). A prespecified bioinformatics algorithm was used to generate a numerical index (Immunoscore®; Galon et al. J Pathol. 2014) and analyses cutoffs. Higher Immunoscore® represents increased intra-tumor T cell infiltration. TME was evaluated for Immunosign® 21 and for additional myeloid- and dendritic cell-related genes. The association between Immunoscore®, CD3+, or CD8+ T cell density and CR was evaluated, as was the association of Immunoscore® with Immunosign® 21.
Results: Pretreatment tumor biopsy samples from 25 pts were analyzed (data cutoff Aug 11, 2017). Of pts with high Immunoscore®, 77% (7/9) had CR and 11% (1/9) were nonresponders. Of those with low Immunoscore®, 38% (6/16) were nonresponders and 50% (8/16) had CR. The pts in this category who achieved CR had a lower median pretreatment tumor burden by sum of product diameters. Overall, higher pretreatment Immunoscore® was associated with achievement of CR (P = .048). Pretreatment intra-tumor densities of CD3+ and CD8+ T cells separately quantified, were also positively associated with achievement of CR (P = .02 and .036 by t test). In addition, higher pretreatment Immunosign® 21 was associated with clinical efficacy. Values for Immunosign® 21 and Immunoscore® demonstrated 82% concordance (95% CI, 65-93; r2 = 0.451). Finally, TME gene expression analysis indicated a pan-inflammatory profile, including myeloid- and dendritic cell-related gene expression, in pts who achieved CR with higher Immunosign® 21 and Immunoscore®.
Conclusions: These results link pre-existing T cell involved lymphoma TME with clinical outcome in patients post axi-cel. They also suggest that factors intrinsic to tumor biology may influence CAR T cell efficacy through the immune microenvironment. In addition, this treatment modality may overcome an unfavorable TME in a subset of patients with low disease burden. Finally, these results support CAR T cell treatment optimizations designed to overcome an immune detrimental TME. John Rossi and Jérôme Galon contributed equally.
Citation Format: John M. Rossi, Jérôme Galon, Edmund Chang, Regis Perbost, Nathalie Scholler, Sarah Turcan, Corinne Danan, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, Francesca Milletti, William Y. Go, Adrian Bot. Pretreatment immunoscore and an inflamed tumor microenvironment (TME) are associated with efficacy in patients (Pts) with refractory large B cell lymphoma treated with axicabtagene ciloleucel (Axi-Cel) in ZUMA-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT153.