Abstract
Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.
Highlights
Chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient
Fitzgerald et al have reported that 92% of acute lymphoblastic leukemia (ALL) patients treated with an anti-CD19 chimeric antigen receptor (CAR) T cell therapy experienced a CRS and 50% of these patients developed grade 3–4 symptoms that could have resulted in death[7]
Each of the strategies to regulate a CRS below will be seen to rely on the ability to rapidly change the number of bispecific adapters that mediate engagement of a CAR T cell with its malignant target
Summary
Chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. CAR T cell therapies involve the genetic engineering of a patient’s T cells to express a chimeric antigen T cell receptor (CAR) that can redirect the cell to kill an antigenexpressing cancer cell. In this strategy, a single-chain variable fragment (scFv) that recognizes a tumor antigen is fused to the exoplasmic domain of a T cell receptor to enhance engagement of the T cell with the cancer cell. While the aforementioned response rates have justifiably generated considerable excitement, use of these genetically engineered T cells to treat human cancers has introduced challenges associated with control of the CAR T cell’s activity. The molecular mechanisms driving a CRS are not fully understood, it has been established that the uncontrolled
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