Abstract
Chimeric Antigen Receptor T-cell (CAR-T) therapy is a transformative immunotherapy, particularly effective against hematological malignancies. By engineering a patient’s T-cells to express synthetic receptors targeting tumor-associated antigens, CAR-T combines the specificity of monoclonal antibodies with T-cell cytotoxicity. Over successive generations, CAR designs have incorporated costimulatory domains, cytokine support, and advanced signaling to enhance persistence and efficacy. The therapeutic process involves autologous T-cell isolation, ex vivo genetic modification, and reinfusion to selectively destroy cancer cells. Despite remarkable success in B-cell leukemias, lymphomas, and multiple myeloma, challenges such as cytokine release syndrome, neurotoxicity, antigen escape, and poor efficacy in solid tumors persist. Strategies like dual-targeting CARs, armored CARs, suicide switches, and synthetic circuits are being developed to improve safety and control. Future directions include universal allogeneic CAR-T cells, CRISPR-based multiplex editing, off-the-shelf platforms, and integration with checkpoint inhibitors, targeted agents, nanotechnology, and synthetic biology to optimize delivery and tumor infiltration.
Keywords
CAR-T cell therapy, Adoptive Cell Transfer, Cancer Immunotherapy, Cytokine release syndrome (CSR)
Introduction
Cancer, commonly known as a malignant tumor, arises from neoplastic tissues and can typically be described as a collection of modified cells that exhibit irregular, uncontrolled growth and have the ability to invade adjacent tissues and/or spread to nearby lymph nodes and/or distant organs[1] .For many years, conventional treatments like surgery and radiotherapy have been employed to address cancers; however, these approaches come with certain restrictions, particularly regarding side effects that often negatively impact the patient’s quality of life. The GLOBOCAN 2018 Cancer Incidence and Mortality Estimates, produced by the International Agency for Research on Cancer (IARC), reveal that lung cancer ranks as the most prevalent malignancy, making up 11.6% of all cancer cases, and is currently the leading cause of cancer-related deaths, followed by breast, prostate, colon, stomach, and liver cancers, among others [2]. In individuals with metastatic cancer, immunotherapy has demonstrated long-lasting anti-tumor effects. It has been demonstrated that patients with melanoma can fully recover with adoptive cell treatment (ACT). This is predicated on the idea that endogenous T cells may be genetically altered in vitro to target and kill tumor cells precisely. The tumor can then be eradicated by re-infusing the cells into the patient’s body. Several cancer types are now being treated with this strategy. The effectiveness of ACT and other immunotherapies is significantly influenced by the immunotargeting of mutant “neoantigens” expressed on tumor cells. Additionally, it implies that analyzing the genomes of malignancies would reveal possible antigens on all tumors, posing new opportunities and problems for ACT [3]. Cancer immunotherapy has revolutionized the treatment of cancers, with Chimeric Antigen Receptor (CAR) T cell therapy being a remarkable advancement, particularly in blood cancers. CAR T cells are a type of T lymphocyte derived from the patient that are genetically modified to produce synthetic receptors, allowing them to specifically target tumors without relying on MHC presentation [4]. While achieving success against targets such as CD19 in leukemias and lymphomas derived from B-cells, applying this success to solid tumors has been more challenging due to variations in antigens, immune suppression present in the tumor microenvironment, and the potential for on-target/off-tumor toxicity. To overcome these challenges, focus has turned to neoantigens—specific antigens unique to tumors that arise from somatic mutations and are exclusive to cancer cells [5]. In contrast to shared tumor-associated antigens (TAAs), neoantigens are exclusively found in cancerous tissues, which reduces the likelyhood of triggering autoimmune responses and improves the accuracy of T cell targeting. This attribute makes neoantigen-targeted CAR T cell therapy a highly promising approach for tailored cancer treatment. New platforms that combine next-generation sequencing (NGS) with bioinformatics prediction algorithms enable the swift identification of immunogenic neoantigens in specific tumors [6]. By utilizing scFvs or TCR-like constructs that identify neoepitopes, scientists have started creating CAR T cells specific to neoantigens that can precisely target distinct tumor mutations like KRAS^G12D or EGFR^Viii [7]. Without utilizing a major histocompatibility complex, this type of therapy’s primary benefit is its immediate identification and destruction of the tumor antigen [8]. Since they established the groundwork for CAR T cell therapy for the first time, Gross and his associates were regarded as its pioneers. “Chimeric T cell receptors with antitumor specificity will enable testing the feasibility of this approach in combating human tumors,” they said as they wrapped up their work, demonstrating the idea of genetically rerouting cytotoxic T lymphocytes to the tumor cells [9,10,11]
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Shruti Shinde
Corresponding author
Matoshri College of Pharmacy, Eklahare, Nashik, Maharashtra, India
Vaibhavi Jadhav
Co-author
Matoshri College of Pharmacy, Eklahare, Nashik, Maharashtra, India
Nilima Yadav
Co-author
Matoshri College of Pharmacy, Eklahare, Nashik, Maharashtra, India
Sampada Waghmare
Co-author
Matoshri College of Pharmacy, Eklahare, Nashik, Maharashtra, India
Shruti Shinde*, Vaibhavi Jadhav, Nilima Yadav, Sampada Waghmare, CAR-T Cells in Cancer Therapy: From Structural Blueprint to Clinical Barriers, Int. J. Sci. R. Tech., 2025, 2 (9), 22-37. https://doi.org/10.5281/zenodo.17066739
10.5281/zenodo.17066739
