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4607 Enhancing CAR-T Therapy in CLL By Modulating the Immunosuppressive Tumor Microenvironment: A Novel Approach with Significant Therapeutic Potential

Program: Oral and Poster Abstracts
Session: 641. Chronic Lymphocytic Leukemia: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Monday, December 9, 2024, 6:00 PM-8:00 PM

Angimar Uriepero Palma, MD, MMSc1*, Melanie Mediavilla Varela, pH.D2*, Maria Elena Marquez, Ph.D3*, Wael Gamal2, Mohammad Ammad-ud-din, MD4*, Pablo Oppezzo, Ph.D5*, Eva Sahakian, PhD6* and Javier Pinilla-Ibarz, MD, PhD7*

1Department of Internal Medicine, Jefferson Einstein Hospital, Philadelphia, PA
2Immunology/Immune-Oncology, Moffitt Cancer Center, Tampa, FL
3Research Laboratory On Chronic Lymphocytic Leukemia. Institut Pasteur De Montevi, Montevideo, URY
4Department of Hematology/Oncology, Moffitt Cancer Center, Tampa, FL
5Institut Pasteur De Montevideo, Montevideo, URY
6Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
7Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL

BACKGROUND: Adoptive cell therapies have revolutionized the treatment paradigm for B-cell neoplasms, including acute lymphoblastic leukemia and non-Hodgkin lymphomas. However, in chronic lymphocytic leukemia (CLL), lower response rates are observed for anti-CD19 chimeric antigen receptor T cell (CAR-T) therapies. This therapeutic failure is mainly attributed to the profound T-cell exhaustion seen in CLL and the highly suppressive tumor microenvironment (TME). Here, we present a novel approach to improve CAR-T therapy by targeting the alarmin S100-A9. This protein plays a pivotal role in the TME of solid tumors and other hematologic malignancies by promoting the accumulation of myeloid-derived suppressor cells (MDSCs). We recently demonstrated that S100-A9 contributes to activating inflammatory pathways in B-CLL cells. We hypothesize that S100-A9 inhibitors could indirectly potentiate T cell fitness by decreasing chronic inflammation and modulating the CLL TME, ultimately leading to lower T cell exhaustion and suppression.

METHODS: Flow cytometry assessed S100-A9 expression in B-CLL cells in the peripheral blood (PB) and bone marrow (BM) of 20 CLL patients. Nurse-like cells (NLCs) were obtained using PBMCs from individuals with CLL. MDSCs were differentiated from the BM of Eµ-TCL1 mice and treated in vitro with an S100-A9 inhibitor. To evaluate the in vivo immunomodulatory effect of targeting S100-A9, C57BL/6 were injected with splenocytes from Eµ-TCL1 mice and treated with the oral S100-A9 inhibitor, tasquinimod (TasQ). T cells were isolated from the spleen of TasQ-treated and control mice, activated with CD28/CD3 beads, transduced with the CAR construct, and then injected into Eµ-TCL1 mice with established disease. All immunophenotyping analyses were performed using a BD FACSymphony cytometer.

RESULTS: Significantly higher S100-A9 expression was found in B-CLL cells from the patient’s BM compared with PB. Additionally, NLCs and myeloid and T cell co-stimulatory signals enhanced S100-A9 expression in leukemic lymphocytes. S100-A9 was expressed in neoplastic B-CLL cells and in MDSCs from CLL patients. Similar to previously shown in multiple myeloma and several solid tumors, in vitro treatment with the S100-A9 inhibitor, TasQ decreases PD-L1 and Arginase 1 expression in MDSCs derived from the BM of CLL-bearing mice. To evaluate the in vivo effect of TasQ, adoptive transfer Eµ-TCL1 mice were treated with this oral inhibitor or vehicle for four weeks. TasQ-treated mice showed more prolonged survival, less accumulation of MDSCs, and fewer patrolling monocytes in the spleen. Additionally, T cells were skewed toward a predominant naive and central memory phenotype in the TasQ group. Given the immunomodulatory benefits of S100-A9 inhibitors, we evaluated whether T-cells from TasQ-treated mice can be an excellent source to build more efficacious CAR-T cells. Notably, CAR-T cells manufactured from TasQ-treated T cells expanded faster in vitro and maintained their central memory phenotype after one week of expansion. Likewise, TasQ-treated CAR-T cells lasted longer in the PB of adoptive transfer Eµ-TCL1 mice. They could control CLL progression more effectively than CART manufacture from vehicle-treated mice.

CONCLUSION: Our study demonstrates that targeting S100-A9 decreases the suppressive TME in CLL. This finding makes S100-A9 inhibitors promising candidates for bridge therapy to improve T-cell fitness and enhance the effectiveness of CAR-T therapy.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH