Cancer immunotherapy has significantly advanced cancer treatment, but even combined immune checkpoint inhibition offers suboptimal long-term survival rates. While Sipuleucel-T was the first cellular therapy approved for cancer, it had limited adoption. CAR T-cell therapy, however, has gained significant traction since its approval in 2017, offering a new treatment option for various malignancies. This review explores the limitations of current immunotherapies, emphasizing the need for innovative treatments like CAR T-cell therapy. It delves into the mechanism of action, clinical data (particularly focusing on anti-CD19 CAR T-cell therapy for B-lymphoid malignancies), toxicity profiles, and the potential of this therapy for common epithelial cancers. The review is especially relevant considering the rise of advanced immunotherapy beyond checkpoint inhibitors.

The review extensively examines the successes and limitations of contemporary cancer immunotherapy approaches, primarily focusing on immune checkpoint inhibitors like ipilimumab and pembrolizumab. It analyzes their efficacy and survival rates in various cancers (melanoma, renal cell carcinoma, non-small cell lung cancer, cholangiocarcinoma, and urothelial carcinoma), highlighting the limitations of checkpoint inhibitors due to their non-antigen-specific nature and associated toxicities (autoimmune reactions, neurologic toxicities, type 1 diabetes). The literature also covers challenges in identifying predictive biomarkers for response to immunotherapy, including the role of PD-L1 expression and tumor mutational burden (TMB). The authors discuss resistance mechanisms to checkpoint inhibitors, suggesting the need for combined strategies targeting multiple checkpoints or disrupting tumor immune evasion mechanisms. The review further discusses adoptive T-cell therapy (ACT) as a form of passive vaccination, showcasing its successes and limitations in treating advanced melanoma, particularly focusing on the challenges of obtaining tumor-infiltrating lymphocytes (TILs) and the need for extensive in vitro culture.

This is a review article; therefore, there is no original methodology. The authors systematically reviewed the existing literature on CAR T-cell therapy, focusing on its applications in hematological malignancies and selected solid tumors. They synthesized information from clinical trials, preclinical studies, and other relevant publications to comprehensively present the current state of the art in CAR T-cell therapy and its future directions. The review focuses on the biological principles of CAR T-cell technology and the clinical outcomes for various cancer types. The paper discusses the design of CAR T cells, including the generation of first- to fourth-generation CAR constructs, with specific attention to the use of single-chain variable fragments (scFvs), transmembrane domains, intracellular signaling domains (CD3ζ, CD28, 4-1BB), and the inclusion of cytokines. The authors also discuss advanced CAR T-cell designs, including logic-gated cellular control and multi-target CARs. The manufacturing process of clinical-grade CAR T cells, employing viral vectors (lentiviruses, gamma-retroviruses) and non-viral gene-editing technologies (CRISPR/Cas9), is described. Different T-cell subsets as potential substrates for CAR expression (CD4, CD8, alpha/beta, gamma/delta T cells) are also discussed. Furthermore, the review details the clinical toxicities associated with CAR T-cell therapy, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), allergic reactions, and tumor lysis syndrome. The management strategies for these toxicities are also outlined.

The review highlights the remarkable success of CAR T-cell therapy targeting the CD19 antigen in various B-cell malignancies, including acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and multiple myeloma. The authors present data from pivotal clinical trials demonstrating high response rates and survival benefits with approved CAR T-cell therapies such as tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel. However, the absence of large-scale, randomized controlled trials is noted. The review also discusses the challenges and limitations of applying CAR T-cell therapy to solid tumors, emphasizing the importance of careful antigen selection to minimize on-target off-tumor toxicity. The limited ability of CAR T cells to effectively penetrate the tumor microenvironment in solid tumors is also highlighted. The review presents data from several clinical trials using CAR T-cell therapy for selected solid tumors, including neuroblastoma (anti-GD2 CAR T-cells), hepatocellular carcinoma (anti-glypican-3 and anti-CD133 CAR T-cells), and pancreatic adenocarcinoma (anti-mesothelin CAR T-cells). These studies showed variable levels of clinical activity, with some demonstrating objective responses and disease control, while others showed limited efficacy. The potential of loco-regional CAR T-cell administration is also discussed, as a strategy to reduce systemic toxicity and enhance efficacy. The use of a caspase-9 suicide switch in CAR T-cell constructs to control toxicity is also presented. Finally, the review explores the promise of combination therapies, such as using CAR T-cell therapy in conjunction with immune checkpoint inhibitors (e.g., anti-PD-1 therapy), to potentially enhance therapeutic outcomes in solid tumors.

The findings of this review underscore the transformative potential of CAR T-cell therapy, especially in hematologic malignancies. However, the significant challenges in translating this success to the treatment of solid tumors are clearly outlined. The need for improved strategies to overcome the limitations associated with antigen selection, tumor penetration, and systemic toxicity is evident. The discussion highlights the crucial need for larger, randomized controlled trials to definitively establish the clinical benefits of CAR T-cell therapy in solid tumors and to better understand the optimal treatment strategies, including the role of lymphodepleting chemotherapy and the use of combination therapies. The success seen in neuroblastoma, particularly with the inclusion of a caspase-9 safety switch, suggests a path forward for improving the safety profile of CAR T-cell therapies targeting solid tumors. The exploration of loco-regional delivery strategies offers a promising approach to enhance efficacy and reduce systemic toxicity.

CAR T-cell therapy has revolutionized the treatment of B-cell malignancies, although the lack of comparative studies necessitates further research. While promising in some solid tumors, particularly neuroblastoma, its efficacy in common epithelial cancers remains limited, with challenges in antigen selection, tumor penetration, and toxicity management. Future research should focus on refining CAR T-cell design, exploring combination therapies with other immunotherapies, and optimizing delivery methods to improve the clinical impact of this technology in solid tumors. The use of safety switches and loco-regional delivery may be particularly valuable avenues to pursue.

This review is based on the existing literature and does not include original research. The interpretation of results is limited by the lack of large-scale, randomized controlled trials, especially for solid tumors. The heterogeneity of clinical trials and patient populations across studies can also impact the generalizability of the findings. The rapid evolution of CAR T-cell technology also makes it challenging to present a completely up-to-date overview.