Female Sex Effect on Anti-CD19 CART Cell Therapy for Relapsed/Refractory B-Cell Lymphoma: A Grupo Español De Trasplante y Terapia Celular (GETH-TC) Study
Authors: Fabbri Nicole , Peña Marta , Barba Pere , Iacoboni Gloria , Kwon Mi , Bailen Rebeca , Perez-Simon Jose A. , Delgado Javier , Lopez Corral Lucia , Martin Lopez Ana Africa , Hernani Rafael , Ortiz-Maldonado Valentin , Martinez-Cibrian Nuria , Guerreiro Manuel , Sanz Jaime , Caballero Gonzalez Ana Carolina , Sancho Juan-Manuel , Yanez San Segundo Lucrecia , Chinea Anabelle , Sanchez-Pina Jose , Perera Alvarez Maria Del Mar , Rius-Sansalvador Blanca , Sureda Balari Anna Maria , Mussetti Alberto 
Published: December 2023

Introduction
Recent studies have shown the potential implication of sexual disparity on the immune system, emphasizing the significant roles of androgens and estrogens in immune cell function and their potential implications for immune responses and antitumor immunity. Anti-CD19 CART therapy is a new immunotherapy pillar for patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). However, this treatment has major limitations, including high individual variability with life-threatening toxicities, antigen escape, poor tumor infiltration, T cell exhaustion, and an immunosuppressive microenvironment. The underlying mechanisms responsible for these issues remain unknown and may potentially involve sex-based differences. To date, no studies addressed sex differences in CART therapy.
Methods
Data from consecutive patients with R/R LBCL from the Grupo Español de Trasplante y Terapia Celular (GETH-TC) who received commercial anti-CD19 CART infusion between November 2018 and December 2022 were retrospectively collected from electronic medical records at 12 Spanish institutions. Patients were divided by sex into two groups for analysis and stratified by patient/disease characteristics and CART cell product. A t-test comparison between the two cohorts was performed. The primary endpoint was comparing 1-year progression-free survival (1y-PFS) between the groups. Secondary endpoints were overall survival (OS), relapse incidence/progression of disease (RI/POD), non-relapse mortality (NRM), cytokine release syndrome (CRS) and immune-effector cells associated neurotoxicity (ICANS) cumulative incidence. Patient sex variable was added into the Cox Proportional-Hazards model for a multivariate analysis for each endpoint in addition to all the variables which were statistically significant in univariate analysis (α=0.05).
Results
A total of 479 patients received anti-CD19 CART infusion. Among them, 185 patients (39%) were female and 294 patients (61%) were male. No statistically significant differences were found in patient, disease and CART characteristics between the two cohorts ( Table 1). At 1-year post-infusion, PFS and OS were 39% (95% confidence interval [CI]: 34-44%) and 57% (95% CI: 51-62%), respectively. ( Fig. 1). On multivariate analysis, female sex had a favorable impact on 1-year PFS (HR=1.33; 95% CI: 1.01-1.75, p=0.04) but not on OS. A subset analysis on females revealed no significant differences in outcomes based on pre and postmenopausal age (p=0.23), with a fixed cut-off at 50 years. The 1 year RI/POD and NRM rates were 56% (95% CI: 52-60%) and 5% (95% CI:3-7%), respectively. Female sex was significantly associated with a lower RI/POD at one year (HR=0.68; 95% CI:1.10-1.96, p=0.01) but not with NRM. Regarding safety, the 1-month cumulative incidences of CRS grade ≥2 and ≥3 were 47% (95% CI: 41-53%) and 11% (95% CI:7-15%), respectively, without statistically significant correlation to female sex in univariate and multivariate analysis. However, the 1-month cumulative occurrence of ICANS grade ≥2 (28%, 95% CI: 26%-30%) and ≥3 (16%, 95% CI: 14%-18%) were significantly associated with female sex in univariate analysis (p&lt;0.01 and p=0.02, respectively), with a trend towards significance in multivariate analysis (HR=1.4; 95% CI: 0.99-1.2, p=0.06 and HR=1.48; 95% CI:0.90-2.44, p=0.12).
Conclusions
In this retrospective analysis we compared for the first time the clinical outcomes of female and male patients who received anti-CD19 CARTs for R/R LBCL. Our findings suggest that, in a real-world setting, female sex is linked to improved survival outcomes, lower relapse rates, and a tendency toward higher neurotoxicity. This observation, without disparities in female outcomes based on pre and postmenopausal age, could suggest that such effect is potentially related to androgens and not to estrogens-dependent mechanisms on T cells. Sex differences, possibly related to hormonal mechanisms, should be further investigated to discover newer therapeutic mechanisms to increase the efficacy of adoptive cell therapies.