Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell-Treated Mice
Marie-Louise Sentman1, Joana M Murad2, W James Cook1
1Center for Synthetic Immunity and the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.
Abstract:
Targeting cancer through the use of effector T cells bearing chimeric Ag receptors (CARs) leads to elimination of tumors in animals and patients, but recognition of normal cells or excessive activation can result in significant toxicity and even death. CAR T cells based on modified NKG2D receptors are effective against many types of tumors, and their efficacy is mediated through direct cytotoxicity and cytokine production. Under certain conditions, their ligands can be expressed on nontumor cells, so a better understanding of the potential off-tumor activity of these NKG2D CAR T cells is needed. Injection of very high numbers of activated T cells expressing CARs based on murine NKG2D or DNAM1 resulted in increased serum cytokines (IFN-γ, IL-6, and MCP-1) and acute toxicity similar to cytokine release syndrome. Acute toxicity required two key effector molecules in CAR T cells-perforin and GM-CSF. Host immune cells also contributed to this toxicity, and mice with severe immune cell defects remained healthy at the highest CAR T cell dose. These data demonstrate that specific CAR T cell effector mechanisms and the host immune system are required for this cytokine release-like syndrome in murine models.
Insights
CAR T cell therapy shows promise for cancer treatment but can cause toxicity. This study reveals that specific CAR T cell effector mechanisms and host immune cells are crucial for cytokine release syndrome-like toxicity in mice.
Area of Science:
- Immunology
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T cell therapy offers potent anti-tumor activity but faces challenges with toxicity due to potential off-tumor recognition and excessive activation.
- CAR T cells engineered with modified NKG2D receptors demonstrate efficacy against various tumors via cytotoxicity and cytokine release.
Purpose of the Study:
- To investigate the mechanisms underlying the potential off-tumor toxicity of NKG2D-based CAR T cells.
- To understand the contribution of CAR T cell effector molecules and host immune cells to toxicity.
Main Methods:
- Administration of high doses of activated CAR T cells (NKG2D or DNAM1 based) in murine models.
- Analysis of serum cytokine levels (IFN-γ, IL-6, MCP-1) and acute toxicity.
- Assessment of the role of effector molecules (perforin, GM-CSF) and host immune cells in toxicity.
Main Results:
- High-dose CAR T cell injection led to increased serum cytokines and acute toxicity resembling cytokine release syndrome (CRS).
- Toxicity was dependent on perforin and GM-CSF effector molecules within CAR T cells.
- Host immune cells were essential for the observed toxicity, as mice with immune defects remained healthy.
Conclusions:
- Specific CAR T cell effector mechanisms, particularly perforin and GM-CSF, are critical drivers of CRS-like toxicity.
- The host immune system plays a significant role in mediating CAR T cell-induced toxicity.
- These findings highlight the need to consider both CAR T cell intrinsic factors and the host environment for safe and effective CAR T cell therapy.
