Cancer is a leading cause of death globally, with conventional treatments like surgery, radiation, and chemotherapy having significant drawbacks, particularly for patients with metastatic or recurrent disease. The past decade has seen advancements in targeted therapies and immuno-oncology, leading to the development of precision medicine. Antitumor immunotherapy, which modifies the immune system to fight cancer cells, has proven particularly promising. A key approach is engineering immune cells to express chimeric antigen receptors (CARs), redirecting them to target and destroy tumor cells. CAR-T cell therapy, using genetically modified T cells, has shown remarkable success in hematological malignancies, with high remission rates observed in multiple myeloma and B-cell leukemias/lymphomas using targets such as BCMA and CD19. However, applying this successful strategy to solid tumors presents unique challenges. Solid tumors are more complex than hematological malignancies, presenting obstacles such as poor T cell infiltration due to the immunosuppressive tumor microenvironment and the limited availability of tumor-specific antigens. In addition, CAR-T cell therapies are associated with side effects, including cytokine release syndrome (CRS) and on-target/off-tumor toxicities, which limit their therapeutic index. This necessitates the exploration of innovative strategies to overcome these limitations and improve the efficacy and safety of CAR-cell therapies in solid tumors. This review examines the current status, challenges, and potential of CAR-T, CAR-NK, and CAR-M cell therapies in treating solid tumors, highlighting the potential advantages of CAR-NK and CAR-M cells over CAR-T cells.

The literature review extensively covers clinical trials and preclinical studies investigating CAR-T cell therapy in solid tumors, focusing on various tumor-associated antigens (TAAs). Trials targeting IL-13Rα2 in glioblastoma, GD2 in neuroblastoma, ROR1 in lung and breast cancers, EGFR in various cancers, CEA in colorectal and other cancers, MSLN in ovarian and pancreatic cancers, and CD133 in hepatocellular carcinoma are reviewed. The review also examines clinical outcomes, noting the challenges associated with the heterogeneity of tumor antigens, antigen escape, limited tumor infiltration, and the immunosuppressive tumor microenvironment. The limitations of CAR-T cell therapy, including CRS and on-target/off-tumor toxicities, are discussed, setting the stage for exploring alternative immune effectors such as NK cells and macrophages.

This review article employs a systematic approach to gather information from peer-reviewed publications and clinical trial databases such as ClinicalTrials.gov. The authors searched for relevant studies using keywords related to CAR-T, CAR-NK, and CAR-M cell therapies, solid tumors, and specific tumor-associated antigens. Inclusion criteria likely focused on published clinical trials and preclinical studies with relevant data on efficacy, safety, and challenges of CAR-cell therapies in solid tumors. Data extraction included information on clinical trial design, patient characteristics, treatment parameters, clinical outcomes (response rates, progression-free survival, overall survival), and reported toxicities. For preclinical studies, the methodology likely included reviewing in vitro and in vivo studies assessing the efficacy and safety of different CAR-cell approaches. The review incorporates data from various sources to provide a comprehensive overview of the current landscape of CAR-cell therapy for solid tumors. The authors critically analyze the existing literature, identifying common themes, challenges, and areas requiring further research. They present the information in a structured format, organized by different types of CAR-cell therapy (CAR-T, CAR-NK, CAR-M) and specific TAAs.

The review highlights several key findings regarding CAR-cell therapies in solid tumors. Clinical trials of CAR-T cell therapy have shown varied success depending on the targeted antigen and tumor type. While some antigens (like CD19 in hematological malignancies) show high response rates, the success rate in solid tumors is significantly lower, often in the single digits. The challenges include the heterogeneity of tumor antigens, leading to antigen escape and tumor resistance. Limited infiltration of CAR-T cells into the tumor microenvironment due to the immunosuppressive nature of the TME is a significant hurdle. CAR-T cells often trigger severe side effects such as CRS and neurotoxicity, reducing the therapeutic window. The review presents several strategies to overcome these limitations, including the development of bispecific CAR-T cells targeting multiple antigens, the use of pooled CAR-T cell strategies, and the engineering of CAR-T cells to express chemokine receptors to enhance tumor infiltration. Armoring CAR-T cells to secrete immunostimulatory cytokines or to express dominant-negative TGF-β receptors to counteract the TME is also discussed. The review explores alternative effector cells like CAR-NK and CAR-M, highlighting their advantages: NK cells offer MHC-independent recognition, reduced risk of CRS and GvHD, and can be sourced from various sources for off-the-shelf production. CAR-M cells leverage the macrophages' ability to infiltrate the TME, remodel ECM, and act as antigen-presenting cells, but challenges remain in terms of efficient transduction and potential CRS. Combination therapies, such as combining CAR-cell therapies with chemotherapy, radiotherapy, oncolytic viruses, and immune checkpoint inhibitors, show promise in enhancing the efficacy of CAR-cell therapy.

The findings of this review underscore the complex challenges inherent in translating the success of CAR-T cell therapy in hematological malignancies to the treatment of solid tumors. The limitations of CAR-T cell therapies in solid tumors, such as inefficient tumor infiltration, antigen heterogeneity, and the immunosuppressive TME, necessitate innovative strategies to enhance their efficacy. The exploration of alternative immune effectors like CAR-NK and CAR-M cells presents promising avenues for overcoming some of the limitations associated with CAR-T cells. The findings suggest that combination therapies, leveraging the synergistic effects of different treatment modalities, may be crucial for achieving significant improvements in patient outcomes. The superior safety profile and off-the-shelf potential of CAR-NK cell therapy make it a viable alternative to CAR-T cell therapy. CAR-M therapy offers distinct advantages by utilizing the intrinsic properties of macrophages to infiltrate the TME and activate both innate and adaptive immune responses. Further research focused on optimizing CAR constructs, improving cell trafficking, overcoming TME suppression, and mitigating toxicities is needed to fully realize the potential of CAR-cell therapies for solid tumors.

CAR-cell therapy shows potential in treating solid tumors, but faces challenges such as limited tumor infiltration, antigen heterogeneity, and the immunosuppressive TME. CAR-NK and CAR-M cells offer potential advantages over CAR-T cells, requiring further research. Combination therapies, incorporating chemotherapy, radiotherapy, oncolytic viruses, and immune checkpoint inhibitors, are promising avenues for improving the efficacy of CAR-cell therapies. Future research should focus on addressing the limitations of CAR-cell therapy through innovative design, combination strategies, and application of Artificial Intelligence to improve manufacturing and prediction of clinical outcomes.

The review is based on the available literature and clinical trial data at the time of publication. The inclusion of clinical trials might be limited by the publication bias. The preclinical results may not always translate to clinical settings, and the long-term efficacy and safety of CAR-cell therapies still require further investigation. The review focuses primarily on the most studied TAAs and CAR-cell types, and there might be additional antigens or cell types that hold potential for improving CAR-cell therapies. The complexity of the tumor microenvironment and its influence on CAR-cell activity are only partially understood, and more research is needed to fully decipher these interactions.