Abstract
T cells engineered with chimeric antigen receptors (CAR) have demonstrated its widespread efficacy as a targeted immunotherapeutic modality. Yet, concerns on its specificity, efficacy and generalization prevented it from being established into a first-line approach against cancers. By reviewing challenges limiting its clinical application, ongoing efforts trying to resolve them, and opportunities that emerging oncotherapeutic modalities may bring to temper these challenges, we conclude that careful CAR design should be done to avoid the off-tumor effect, enhance the efficacy of solid tumor treatment, improve product comparability, and resolve problems such as differential efficacies of co-stimulatory molecules, cytokine storm, tumor lysis syndrome, myelosuppression and severe hepatotoxicity. As a promising solution, we propose potential synergies between CAR-T therapies and cold atmospheric plasma, an emerging onco-therapeutic strategy relying on reactive species, towards improved therapeutic efficacies and enhanced safety that deserve extensive investigations.
Highlights
Adoptive cell therapy (ACT) takes advantages of the immune system by transfusing back one’s own genetically engineered T cells or cancer-cognate lymphocytes that identify and attack malignant cells or foreign invasions [1]
This paper identifies challenges faced by chimeric antigen receptors (CAR)-T therapies limiting their wide applications, reviews ongoing efforts circumventing such problems, and highlights opportunities brought by such promising technologies to academia and clinics (Table 1)
We found previously that Cold atmospheric plasma (CAP) could selectively kill triple negative breast cancer cells, and this type of breast cancers is featured by high cancer stemness [90], implicating the functionality of CAP in targeting cancer stem cells; and such a property can be used to rewire lineage switch caused by CAR-T cells against CD19 for prolonged therapeutic efficacy and reduced recurrence rate
Summary
Adoptive cell therapy (ACT) takes advantages of the immune system by transfusing back one’s own genetically engineered T cells or cancer-cognate lymphocytes that identify and attack malignant cells or foreign invasions [1]. Four types of immune cells are typically used to confer such clinical features, i.e., engineered peripheral blood T lymphocytes expressing T cell receptors (TCRs) or chimeric antigen receptors recognizing tumors (CARs), tumor infiltrating lymphocytes (TILs) expanded ex vivo, and T cells specific to viruses [3, 4] (Figure 1). TCR must match the human leukocyte antigen (HLA) immune type of the patient genetically before achieving any functionality. CARs do not require antigen processing and presentation and are more broadly applicable to HLA-diverse clinical cohorts This brilliant idea of transforming T cells into a “living” drug gave birth to the CAR T-cells, whose clinical activity was confirmed in various types of diseases including diffuse large B-cell lymphomas [23]. This paper identifies challenges faced by CAR-T therapies limiting their wide applications, reviews ongoing efforts circumventing such problems, and highlights opportunities brought by such promising technologies to academia and clinics (Table 1)
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