Abstract
A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.
Highlights
Chimeric antigen receptor T cell (CAR T cell) therapy has shown significant efficacy in hematological malignancies [1,2,3]
Since most tumorassociated antigens (TAAs) are highly expressed on tumors and at lower levels on normal tissues, it is essential to consider the threshold of the stimulation to yield optimal specificity of chimeric antigen receptor (CAR)-redirected T cell activation since there is a risk that increasing the affinity of CARs will lead to serious adverse effects due to on-target, off-tumor recognition [37, 51]
We have shown that an oncolytic adenovirus expressing IL-2 and TNF-α enhanced the efficacy of mesothelin-redirected CAR T cells, which was associated with enhanced T cell infiltration to the tumor bed and reduced metastases [81]
Summary
Chimeric antigen receptor T cell (CAR T cell) therapy has shown significant efficacy in hematological malignancies [1,2,3]. The immunosuppressive TME contains multiple components including physical barriers, such as a dense extracellular matrix; dysfunctional epithelial cells; metabolic checkpoints, such as hypoxia and immunological barriers, such as immunosuppressive cytokines/molecules and immunosuppressive immune cells. To target such tumors effectively, multiple factors impacting efficacy and toxicity must be simultaneously addressed. In this regard, it is critical to deeply understand CAR T cell biology and multiple factors that can affect the therapeutic window of CAR T cell therapies. We discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms
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