Sex bias is well documented in autoimmune diseases, cancer and immune responses to infectious agents. Here, we investigated if pre-treatment risk factors that influence the survival of B-cell non-Hodgkin lymphoma (NHL) patients after anti-CD19 CAR T-cell therapy are sexually dimorphic. We measured pre-leukapheresis tumor burden (lactate dehydrogenase levels), C-reactive protein (CRP) and serum cytokine and chemokine concentration in 67 B-cell NHL patients treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Association of relative abundance of each factor with progression-free survival (PFS) and overall survival (OS) was analyzed in male and female patients together, or only within the male cohort or only within the female cohort. No differences in PFS or OS or in pre-treatment tumor burden, CRP and cytokine/chemokine levels were observed between male and female patients undergoing axi-cel or tisa-cel therapy. However, within the male group, patients with higher pre-treatment tumor burden and greater relative abundance of CRP and pro-inflammatory cytokines and chemokines conferred greater risk of poor progression-free survival (PFS) and/or overall survival (OS). In contrast, within the female group, patient survival was largely agnostic to variations in tumor burden, CRP and cytokine/chemokine abundance. Specifically, higher relative abundance of IL-6, IL-8, IL-27, TNF-α, Eotaxin-1, MIP-1β and MCP-1 was associated with poor PFS and/or OS after CAR T-cell therapy within the male group, whereas higher IL-27 and IFNα2 abundance was associated with better PFS and poorer OS, respectively, within the female group. Our data suggest that biological sex may modulate the impact of baseline risk factors on survival outcomes of CAR T-cell therapy in B-cell NHL.

B.T.H. has received research funding from Takeda; Consultancy, Honoraria, Research Funding from Genentech, Karyopharm, Celgene, Abbvie, Pharmacyclics, Beigene, AstraZenica, Kite, a Gilead Company, BMS; Consultancy, Honoraria from Novartis.

This study was funded by VeloSano Bike to Cure, Cleveland Clinic Center of Excellence in Lymphoid Malignancies Research, and Taussig Cancer Institute.

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This study was approved by Cleveland Clinic Institutional Review Board and conducted in accordance with the declaration of Helsinki

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