In-Vivo Induced CAR-T Cell for the Potential Breakthrough to Overcome the Barriers of Current CAR-T Cell Therapy

Abstract

Chimeric antigen receptor T cell (CAR-T cell) therapy has shown impressive success in the treatment of hematological malignancies, but the systemic toxicity and complex manufacturing process of current autologous CAR-T cell therapy hinder its broader applications. Universal CAR-T cells have been developed to simplify the production process through isolation and editing of allogeneic T cells from healthy persons, but the allogeneic CAR-T cells have recently encountered safety concerns, and clinical trials have been halted by the FDA. Thus, there is an urgent need to seek new ways to overcome the barriers of current CAR-T cell therapy. In-vivo CAR-T cells induced by nanocarriers loaded with CAR-genes and gene-editing tools have shown efficiency for regressing leukemia and reducing systemic toxicity in a mouse model. The in-situ programming of autologous T-cells avoids the safety concerns of allogeneic T cells, and the manufacture of nanocarriers can be easily standardized. Therefore, the in-vivo induced CAR-T cells can potentially overcome the abovementioned limitations of current CAR-T cell therapy. Here, we provide a review on CAR structures, gene-editing tools, and gene delivery techniques applied in immunotherapy to help design and develop new in-vivo induced CAR-T cells.

Nanotheranostic Strategies for Cancer Immunotherapy

“…To address these drawbacks, next-generation CAR-T cells and CAR-NK cells have been engineered to improve the treatment outcomes. [53][54][55][56][57][58] Although they show promise, the success rates of such therapies have been relatively low and hampered by several challenges. For example, the overall response rate (ORR) of ipilimumab (anti-CTLA-4) for treatment of non-small-cell lung cancer (NSCLC) was reported to be 30%, with 2.4% of the patients experiencing a complete response.…”

“…To address these drawbacks, next‐generation CAR‐T cells and CAR‐NK cells have been engineered to improve the treatment outcomes. [ 53–58 ]…”

Nanoparticles targeting hematopoietic stem and progenitor cells: Multimodal carriers for the treatment of hematological diseases

“…In this context, in vivo CAR-T cell induction mediated by NPs encapsulating CAR-genes and gene-editing tools have shown promising results in the treatment of leukemia. In situ programming of autologous T-cells with the help of NPs could avoid the safety concerns of allogeneic T cells and reduce systemic toxicities ( Xin et al, 2022 ).…”

Potential roles of hyaluronic acid in in vivo CAR T cell reprogramming for cancer immunotherapy

“…Individualized approach with a complex and labor intensive manufacturing process and the requirement of accredited GMP laboratories to control and ensure the quality of the products lead to a costly treatment course that limits the accessibility of several patients [4,6]. In addition, cytokine release syndrome could occur up to 25% of patients after receiving ACT, leading to multiple organ failures, neurologic disorders, or severe immune reactions [7,8]. To address these limitations, a novel concept of in situ or in vivo programming of CAR T cells has been introduced in which CAR constructs are administered to patients, allowing de novo genetic modification, expansion, and then attack tumor cells [4,6].…”

“…4,6 In addition, cytokine release syndrome could occur up to 25% of patients after receiving ACT, leading to multiple organ failures, neurologic disorders, or severe immune reactions. 7,8 To address these limitations, a novel concept of in situ or in vivo programming of CAR T cells has been introduced in which CAR constructs are administered to patients, allowing de novo genetic modification, expansion, and then attack of tumor cells. 4,6 Due to this 'off-the-shelf' approach, individualization can be overcome, and the products can be manufactured in a large batch and delivered to a large number of patients.…”