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. 2023 Mar 14;7(5):744-755.
doi: 10.1182/bloodadvances.2021006563.

HLA-DR expression on monocytes and outcome of anti-CD19 CAR T-cell therapy for large B-cell lymphoma

Estelle Bourbon  1   2 , Pierre Sesques  1   2 , Morgane Gossez  2   3   4 , Jérémie Tordo  5 , Emmanuelle Ferrant  1 , Violaine Safar  1 , Florent Wallet  6 , Guillaume Aussedat  1   2 , Alizée Maarek  1   2 , Fadhela Bouafia  1 , Lionel Karlin  1 , Dana Ghergus  1 , Camille Golfier  1   2 , Hélène Lequeu  1 , Anne Lazareth  1 , Vérane Schwiertz  7 , Sébastien Viel  2   4   8 , Maryam Idlhaj  1 , Hervé Ghesquières  1   2   9 , Guillaume Monneret  2   3 , Emmanuel Bachy  1   2   9 , Fabienne Venet  2   3   4
Affiliations

HLA-DR expression on monocytes and outcome of anti-CD19 CAR T-cell therapy for large B-cell lymphoma

Estelle Bourbon et al. Blood Adv. .

Abstract

Despite their unprecedented success in relapsed/refractory (R/R) large B-cell lymphoma (LBCL), anti-CD19 CAR T cells are associated with significant toxicity, and more than half of patients relapse. As monocytes emerged as key players in CAR therapy, we sought to evaluate the evolution of HLA-DR expression on monocytes (mHLA-DR) before and after commercial anti-CD19 CAR T-cell infusion in a large cohort (n = 103) of patients with R/R LBCL and its association with adverse events and treatment response. Cy-Flu-based lymphodepletion (LD) upregulated mHLA-DR in 79% of the cases, whereas in 2l% of cases (15 patients), the mHLA-DR level decreased after LD, and this decrease was associated with poorer outcome. Low mHLA-DR at day minus 7 (D-7) (<13 500 antibodies per cell) before CAR T-cell infusion correlated with older age, poorer performance status, higher tumor burden, and elevated inflammatory markers. With a median follow-up of 7.4 months, patients with low mHLA-DR D-7 exhibited a poorer duration of response and survival than the higher mHLA-DR D-7 group. For toxicity management, tocilizumab was more frequently used in the low-mHLA-DR D-7 group. These data suggest that monocyte dysregulation before LD, characterized by the downregulation of mHLA-DR, correlates with an inflammatory and immunosuppressive tumor environment and is associated with failure of anti-CD19 CAR T cells in patients with R/R LBCL. Modulation of these myeloid cells represents a promising field for improving CAR therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: P.S. received honoraria from and served in advisory and consultancy roles for Janssen, Roche, Novartis and Kite/Gilead. E.F. received honoraria from and served in advisory and consultancy roles for Kite/Gilead, Janssen, and AbbVie. V.S. received honoraria from Roche. F.W. received honoraria from and served in advisory and consultancy roles for Novartis and Kite/Gilead. E. Bachy received honoraria from and served as a consultant for Gilead, Novartis, Roche, Amgen, Janssen, Sanofi, and AbbVie. H. Ghesquières received honoraria from and served in advisory and consultancy roles for Gilead Sciences, Celgene, Roche, Janssen, and Takeda. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Standardized measurement of HLA-DR expression on monocytes. (A) Monocytes are sorted according to their structure (SSC) and CD14 positivity. Among gated monocytes, the HLA-DR median fluorescence intensity (MFI) is measured and then (B) converted to the number of anti-HLA-DR antibodies bound per monocyte (Ab/c). FSC, forward scattered; MFI, median fluorescence intensity; SSC, side scattered.
Figure 2.
Figure 2.
Evolution of mHLA-DR values before and after anti-CD19 CAR T-cell infusion. (A) Individual patient time course showing the evolution of mHLA-DR levels during the first month after infusion. The bold trend curve is the cubic spline representation. (B) Violin plot showing the distribution of mHLA-DR at each time point for 1-year after infusion. The Wilcoxon matched-pairs test was used to calculate P values. The gray band delimits the 5th and 95th percentiles of normal values (ie, 13 500 and 35 200 Ab/c).
Figure 3.
Figure 3.
Comparison of biological markers according to mHLA-DR D7 before anti-CD19 CAR T-cell infusion. Biological markers included lymphocytes (A), monocytes (B), LDH (C), CRP (D), ferritin (E), IL-6 (F), TNFα (G), IFNγ (H), IL-2sR (I), and IL-10 (J). The Mann-Whitney U test was used to calculate P values.
Figure 4.
Figure 4.
Survival analysis according to mHLA-DR D7 before anti-CD19 CAR T-cell infusion. Kaplan-Meier curves for PFS (A) and OS (B). The log-rank test was used to calculate the P values.
See this image and copyright information in PMC

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