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1015 High Levels of Circulating Granulocytic Myeloid-Derived Suppressor Cells (G-MDSCs) Predict Failure of CD19-Targeting CAR-T Cell Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 703. Cellular Immunotherapies: Basic and Translational: Evaluating Strategies to Enhance Cellular Immunotherapies
Hematology Disease Topics & Pathways:
Research, Translational Research, Clinical Research, health outcomes research
Monday, December 11, 2023: 4:30 PM

Eugenio Galli1*, Alessandra Battaglia2*, Marco Fossati3*, Ilaria Pansini4*, Silvia Bellesi5*, Alexia Buzzonetti3*, Nicole Zampetti3*, Stefan Hohaus4,5*, Andrea Bacigalupo, MD5, Patrizia Chiusolo4,5*, Simona Sica4,5*, Andrea Fattorossi3* and Federica Sorà, MD4,5*

1Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
2Dipartimento di Scienze della vita e sanità pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
3Cytometry Facility, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
4Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
5Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy


The mechanisms of resistance to CAR-T cell therapy may depend on the physical and biological characteristics of the tumor itself, on CAR-T cells in terms of efficiency and fitness, or on the microenvironment. Myeloid-derived suppressor cells (MDSCs) play a crucial role in hematological tumors, promoting immunosuppression and tumor progression. Their presence hampers the anti-tumor immune response, posing challenges for effective therapeutic interventions. The predictive role of myeloid-derived suppressor cells (MDSCs) of monocytic and granulocytic origin (M-MDSCs and G-MDSCs, respectively) in the context of CAR-T cell therapy is largely unknown.

Aim and methods

Our aim was to quantify circulating M-MDSC and G-MDSC in patients (n=26) receiving approved CAR-T cell products for high-grade B cell lymphoma or acute lymphoblastic leukemia.

Whole blood samples were collected at enrolment (time point 1), after leukapheresis (time point 2) and just after Cy/Flu lymphodepletion (time point 3). Stringent criteria for multicolour flow cytometry identification of M-MDSC (CD14/HLA-DR/CD124/CD11b/CD45 and light scattering) and G-MDSC (CD15/CD11b/CD66b/oxidized low-density lipoprotein receptor -1, LOX-1, /CD45 and light scattering) were used. Blood samples were examined immediately after collection to prevent artefactual G-MDSC changes.


M-MDSC number, although very variable between patients, remained essentially constant from time point 1 to time point 3 in each individual (range 1.2-947 cells/ml at the latest time point) and was not associated with a higher risk of relapse.

Conversely, G-MDSC number, which was extremely low at time points 1 and 2, markedly increased at time point 3 (range 1.5-85.5 cells/ml). According to our preliminary data, at time point 3, mean G-MDSC were 39.3, 44.5, and 12.3 cells/ml in tisacel, axi-cel and brexu-cel, respectively. Mean G-MDSC were significantly lower in patients treated to receive brexu-cel (Figure 1).

Responses were evaluated one, three, and six months after receiving CAR-T cells infusion. As we aimed at finding if G-MDSC could predict prognosis, we set a cut-off value of 30 G-MDSC/ml at time-point 3 (immediately after the completion of lymphodepletion); overall, approximately 35% of the patients had G-MDSC >30/ml at that moment. Kaplan-Meier survival analysis revealed that G-MDSC >30/ml at time point 3 associated with a higher risk of relapse, with a PFS of 80% vs 10% six months after CAR-T infusion (p= 0.0002) (Figure 1).

The sudden appearance of G-MDSC following the lymphodepletion is likely to reflect emergency granulopoiesis that favors an increased release of G-MDSC to the bloodstream and may be ideally customized with a tailored lymphodepletion.


In conclusion, here we show that the high circulating levels of G-MDSC induced by the lymphodepletion are associated with a lack of response to CAR-T cell therapy, thus representing a promising predictive biomarker of CAR-T cell therapy efficacy and possibly a hypothetical point of intervention for ameliorating CAR-T efficacy.

Disclosures: No relevant conflicts of interest to declare.

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