Deep myeloid cell profiling provides new insights into modulators of CAR T cell expansion in patients with pediatric solid tumors

Abstract Chimeric antigen receptor (CAR) T cells have shown remarkable results in hematological malignancies but limited efficacy in the setting of solid tumors. As myeloid-mediated immune suppression is known to play an important role in dampening antitumor activity, we hypothesized that myeloid cells impact CAR T cell expansion in patients with solid tumors. A phase I trial (NCT02107963) was performed to determine the feasibility and safety of administering 3rd generation GD2-CAR (GD2-CAR.OX40.28.z.ICD9) T cells in children and young adults with neuroblastoma and osteosarcoma. 76.9% of patients had stable disease by day 28, eventually all patients had disease progression. We stratified patients based on good versus poor CAR T cell expansion and evaluated peripheral immune profiles pre- and post-treatment by qPCR, ELISA, CyTOF, ATAC-seq, and RNA-seq. While A higher proportion of monocytes in pre-treatment apheresis was associated with poor CAR T cell expansion and CXCR3 expression on monocytes was the most robust marker of good CAR T cell expansion in this cohort. Longitudinal analysis demonstrated that CXCR3+ monocytes were low following treatment in both good and poor CAR T cell expanders, demonstrating a transition in myeloid populations in response to GD2-CAR T cell treatment. Together, these data suggest that GD2-CAR T cell administration is associated with changes in the myeloid cell compartment. This study provides evidence of novel myeloid-based pre-treatment biomarkers of CAR T cell expansion and rationale for the combination of CAR T cells with myeloid-modulating therapies as a strategy to improve outcomes for patients with solid tumors. Clinical trial supported in part by: Intramural Research Program, National Cancer Institute, NIH Clinical Center, National Institutes of Health. Scientific and financial support for the CIMAC-CIDC Network are provided through the National Cancer Institute (NCI) Cooperative Agreements: U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), U24CA224309 (to the Stanford University CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute). Scientific and financial support for the Partnership for Accelerating Cancer Therapies (PACT) public-private partnership (PPP).