Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas

Abstract

Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CARs) 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 18/18 (100%) of osteosarcomas, 2/15 (13%) of rhabdomyosarcomas, and 7/35 (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 (MDSCs) 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.

Mechanisms of resistance to CAR T cell therapy

“…Several approaches to overcome this issue are under evaluation, including optimization of the preparative regimen before CAR T cell infusion 150,158 . Armoured CAR T cells that constitutively secrete pro-inflammatory cytokines as a mechanism to overcome local immunosuppression are a novel concept.…”

Monocyte heterogeneity and functions in cancer

“…Depletion of monocytes with CD44‐directed CAR T cells or clodronate liposomes prevented cytokine release syndrome . The efficacy of CAR T cell therapies can also be limited by concomitant induction of immunosuppressive myeloid cells in some cancers such as sarcomas . Co‐administration of all‐trans retinoic acid reduces the abundance of immunosuppressive monocytes in blood and enables antitumor immunity by sarcoma‐targeted CAR T cells .…”

Programming CAR-T cells to kill cancer

“…By contrast, T cells modified with CARs bearing 4-1BB costimulatory domains tend to expand and persist longer in vivo, have increased oxidative metabolism, are less prone to exhaustion, and have an increased capacity to generate central memory T cells 17,[44][45][46][47][48] . Whereas the vast amount of studies to date are based on CD28 or 4-1BB CARs, several other co-stimulatory domains are currently being evaluated (Table 1) 50,51 ; however, others reported opposite findings 52,53 . Expression of the 4-1BB ligand in CD28ζ -based CARs has also been shown to extend CAR-T-cell persistence, and is currently being tested in clinical trials 47 (NCT03085173).…”

“…It has been well established that solid tumours coerce non-transformed stromal and immune cells, such as myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), tumour endothelial cells (TECs) and regulatory T cells (T regs ), to support and maintain the tumour 97 . Importantly, these conditioned cells can directly suppress CAR-mediated antitumor effects in the tumour microenvironment 53 . In some cases, malignant cells can recruit these supporting cells to perform various functions, such as remodelling of the extracellular matrix (ECM), enhancement of angiogenesis and secretion of growth factors, and evasion of immune surveillance.…”