Axicabtagene Ciloleucel (Axi-Cel) Product Attributes And Immune Biomarkers Associated With Clinical Outcomes In Patients (Pts) With Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (Inhl) In Zuma-5.

Abstract Background: ZUMA-5 is a registrational Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL (follicular lymphoma [FL] and marginal zone lymphoma [MZL]). With a 17.5-mo median follow-up (Jacobson et al. ASH 2020. #700), 92% of pts responded (76% complete response [CR] rate). Pts with FL had lower rates of Grade ≥3 neurologic events (NEs; 15%) than pts with MZL (41%). Peak levels of key serum biomarkers were associated with Grade ≥3 NEs in pts with FL. Here we describe axi-cel product attributes and pharmacologic characteristics associated with clinical outcomes in ZUMA-5. Methods: Associations among product attributes, blood levels of CAR T cells and biomarkers, as well as CD19 expression in tumor biopsies at relapse (13 samples evaluable from 21 relapsed pts) were analyzed with methods described in Neelapu et al. New Engl J Med. 2017; Locke et al. Blood Adv. 2020. Pts with FL (n=124) and MZL (n=22) treated with axi-cel were included (median follow-up, 17.5 mo). Results: In pts with FL, ongoing response was positively associated with number of total infused CCR7+CD45RA+ T cells (P=.0044) and peak CAR T-cell levels (P=.0212). The association was maintained for number of CCR7+CD45RA+ T cells (P=.0065) and peak CAR T-cell levels (P=.0184) relative to tumor burden. CR also associated positively with these characteristics relative to tumor burden (P=.0217; P=.0383). In addition, ongoing response positively associated with peak levels of immune-modulating factor IFN-γ, inflammatory markers IL-6, SAA and CRP; homeostatic marker IL-2, and chemokine CXCL10. Relapse post-axi-cel in pts with FL was positively associated with higher pretreatment levels of regulatory T cell-related chemokines CCL22/MDC and CCL17, immune-modulating factors IL-10 and IL-16, and inflammatory markers IL-2Rα and TNF-α. Numbers of total infused CCR7+CD45RA+ T cells and peak CAR T-cell levels positively associated with Grade ≥2 cytokine release syndrome (P=.0398; P<.0001) and Grade ≥3 NEs (P=.0356; P=.0032) in pts with FL. Peak CAR T-cell levels were comparable in pts with FL and MZL. Compared with pts with MZL, pts with FL had numerically higher pretreatment levels of CCL17 and lower posttreatment levels of GM-CSF, IL-6, IL-10, IFN-γ, IL-2, CXCL10, and granzyme B. All evaluable tumor samples from pts with iNHL at relapse (12 FL; 1 MZL) retained CD19 expression. Conclusions: Results suggest that product composition and immune regulatory mechanisms, rather than target-related evasion, may influence the clinical activity of axi-cel in pts with FL. Differences in pre- and post-treatment levels of select disease and axi-cel-related biomarkers may contribute to differences in rates of severe NEs in pts with FL vs MZL. Citation Format: Vicki Plaks, Justin Chou, Lovely Goyal, Wangshu Zhang, Shruti Salunkhe, Alison R. Sehgal, Julio C. Chavez, Sattva S. Neelapu, Caron A. Jacobson, Mauro P. Avanzi, John M. Rossi, Adrian Bot. Axicabtagene ciloleucel (axi-cel) product attributes and immune biomarkers associated with clinical outcomes in patients (pts) with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT036.