Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas

Adrienne H. Long, Steven L. Highfill, Yongzhi Cui, Jillian P. Smith, Alec J. Walker, Sneha Ramakrishna, Rana El-Etriby, Susana Galli, Maria G. Tsokos, Rimas J. Orentas, Crystal L. Mackall

Research output: Contribution to journalArticle

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 CD3z signaling domains (14g2a.CD28.OX40.z) 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.

Original languageEnglish (US)
Pages (from-to)869-880
Number of pages12
JournalCancer immunology research
Volume4
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Long, A. H., Highfill, S. L., Cui, Y., Smith, J. P., Walker, A. J., Ramakrishna, S., El-Etriby, R., Galli, S., Tsokos, M. G., Orentas, R. J., & Mackall, C. L. (2016). Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer immunology research, 4(10), 869-880. https://doi.org/10.1158/2326-6066.CIR-15-0230