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Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas
Adrienne H Long1, Steven L Highfill2, Yongzhi Cui2
1Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Abstract:
Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro However, in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+ sarcoma, despite effectively controlling GD2+ neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSC) that inhibited human CAR T-cell responses in vitro Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. Cancer Immunol Res; 4(10); 869-80. ©2016 AACR.
Insights
Chimeric antigen receptor (CAR) T-cell therapy shows promise for pediatric sarcomas. Combining GD2-CAR T cells with all-trans retinoic acid (ATRA) overcomes myeloid-derived suppressor cells, enhancing anti-tumor effects in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is effective against B-cell malignancies.
- Disialoganglioside (GD2)-specific CAR T cells show potential for neuroblastoma.
- The efficacy of GD2-CAR T cells in pediatric sarcomas requires further investigation.
Purpose of the Study:
- To evaluate the potential of GD2-CAR T-cell therapy for treating pediatric sarcomas.
- To investigate the mechanisms limiting GD2-CAR T-cell efficacy in sarcoma models.
- To explore combination strategies to enhance GD2-CAR T-cell therapy for sarcomas.
Main Methods:
- Assessed GD2 expression in osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma cell lines.
- Engineered third-generation GD2-CAR T cells (14g2a.CD28.OX40.ζ) for in vitro and in vivo studies.
- Utilized pediatric sarcoma and neuroblastoma xenograft models in mice.
- Investigated the role of myeloid-derived suppressor cells (MDSCs) in limiting CAR T-cell function.
- Evaluated the combination of GD2-CAR T cells with all-trans retinoic acid (ATRA).
Main Results:
- High GD2 expression was observed in osteosarcoma (100%) but was less frequent in rhabdomyosarcoma (13%) and Ewing sarcoma (20%).
- GD2-CAR T cells effectively lysed GD2+ sarcoma and neuroblastoma cell lines in vitro.
- GD2-CAR T cells failed to control sarcoma xenografts in vivo, despite efficacy against neuroblastoma xenografts.
- Sarcoma xenografts induced suppressive murine monocytic and granulocytic MDSCs that inhibited human CAR T-cell responses.
- ATRA treatment reduced monocytic MDSCs and partially diminished granulocytic MDSC suppressive capacity.
- Combined GD2-CAR T-cell and ATRA therapy significantly improved anti-tumor efficacy against sarcoma xenografts.
Conclusions:
- GD2-CAR T-cell therapy faces challenges in treating pediatric sarcomas due to MDSC-mediated suppression.
- Retinoids, such as ATRA, can overcome MDSC-induced suppression, making them a viable adjunct therapy.
- Combining GD2-CAR T cells with retinoids represents a promising strategy to enhance immunotherapy for solid tumors like pediatric sarcomas.
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