Evidence that macrophages can play a role in accelerating corrosion in CoCrMo alloy in total hip replacement (THR) interfaces leads to questions regarding the underlying cellular mechanisms and immunological responses. Hence, we evaluated the role of macrophages in corrosion processes using the cell culture supernatant from different conditions and the effect of wear particles on macrophage dynamics. Monocytes were exposed to CoCrMo wear particles and their effect on macrophage differentiation was investigated by comparisons with M1 and M2 macrophage differentiation. Corrosion associated macrophages (M CA macrophages) exhibited upregulation of TNF-α, iNOS, STAT-6, and PPARG and down-regulation of CD86 and ARG, when compared to M1 and M2 macrophages. M CA cells also secreted higher levels of IL-8, IL-1β, IL-6, IL-10, TNFα, and IL-12p70 than M1 macrophages and/or M2 macrophages. Our findings revealed variation in macrophage phenotype (M CA ) induced by CoCrMo wear particles in generating a chemical environment that induces cell-accelerated corrosion of CoCrMo alloy at THR modular interfaces.

Corrosion at modular junctions of total hip replacement (THR) remains a major concern today. Multiple types of damage modes have been identified at modular junctions, correlated with different corrosion characteristics that may eventually lead to implant failure. Recently, within the head-taper region of the CoCrMo retrieval implants, cell-like features and trails of etching patterns were observed that could potentially be linked to the involvement of cells of the periprosthetic region. However, there is no experimental evidence to corroborate this phenomenon. Therefore, we aimed to study the potential role of periprosthetic cell types on corrosion of CoCrMo alloy under different culture conditions, including the presence of CoCrMo wear debris. Cells were incubated with and without CoCrMo wear debris (obtained from a hip simulator) with an average particle size of 119 ± 138 nm. Electrochemical impedance spectroscopy (EIS) was used to evaluate the corrosion tendency, corrosion rate, and corrosion kinetics using the media after 24 h of cell culture as the electrolyte. Results of the study showed that there was lower corrosion resistance (p < 0.02) and higher capacitance (p < 0.05) within cell media from macrophages challenged with particles when compared with the other media conditions studied. The potentiodynamic results were also in agreement with the EIS values, showing significantly higher corrosion tendency (low E corr ) (p < 0.0001) and high I corr (p < 0.05) in media from challenged macrophages compared with media with H 2 O 2 solution. Overall, the study provides in vitro experimental evidence for the possible role of macrophages in altering the chemical environment within the crevice and thereby accelerating corrosion of CoCrMo alloy.

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&lt;.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.