Enhanced safety and efficacy of protease-regulated CAR-T cell receptors.
Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.
View details for DOI 10.1016/j.cell.2022.03.041
View details for PubMedID 35483375
Gene Editing to Enhance the Efficacy of Cancer Cell Therapies.
Molecular therapy : the journal of the American Society of Gene Therapy
Adoptive T cell therapies have shown impressive signals of activity, but their clinical impact could be enhanced by technologies to increase T cell potency and diminish the cost and labor involved in manufacturing these products. Gene editing platforms are under study in this arena to 1) enhance immune cell potency by knocking out molecules that inhibit immune responses; 2) deliver genetic payloads into precise genomic locations and thereby enhance safety and/or improve the gene expression profile by leveraging physiologic promoters, enhancers, and repressors; and 3) enable off-the-shelf therapies by preventing alloreactivity and immune rejection (Figure 1). This review will discuss gene editing approaches that have been most well studied in the context of human T cells and adoptive T cell therapies, summarizing their current status and near-term potential for translation.
View details for DOI 10.1016/j.ymthe.2021.10.001
View details for PubMedID 34673274
PET reporter gene imaging and ganciclovir-mediated ablation of chimeric antigen receptor T-cells in solid tumors.
Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. Additionally, the potential adverse effects of CAR T-cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene has previously been translated as a positron emission tomography (PET) reporter gene for imaging of T-cell trafficking in brain tumor patients. The HSV1-TK enzyme can act as a suicide gene of transduced cells through treatment with the prodrug ganciclovir (GCV). Here we report the molecular engineering, imaging, and GCV-mediated destruction of B7H3 CAR T-cells incorporating a mutated version of the HSV1-tk gene (sr39tk) with improved enzymatic activity for GCV. The sr39tk gene did not affect B7H3 CAR T-cell functionality and in vitro and in vivo studies in osteosarcoma models showed no significant effect on B7H3 CAR T-cell antitumor activity. PET/CT imaging with 9-(4-[18F]-fluoro-3-[hydroxymethyl]butyl)guanine [18F]FHBG of B7H3-sr39tk CAR T-cells in an orthotopic model of osteosarcoma revealed tumor homing and systemic immune expansion. Bioluminescence and PET imaging of B7H3-sr39tk CAR T-cells confirmed complete tumor ablation with intraperitoneal GCV administration. This imaging and suicide ablation system can provide insight into CAR T-cell migration and proliferation during clinical trials while serving as a suicide switch to limit potential toxicities.
View details for DOI 10.1158/0008-5472.CAN-19-3579
View details for PubMedID 32958548
Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model
2020; 9 (1)
View details for DOI 10.1080/2162402X.2020.1757360