ABSTRACT
Chimeric antigen receptor (CAR)-modified T-cells—that is, T-cells reprogrammed to target a particular molecule on cancer cells—are among the potential therapeutic approaches that are gaining favor worldwide, particularly for treating hematological malignancies. Ultimately, this infusion will change the immunotherapeutic landscape for the better by improving popular patient care applications and unlocking the ability to treat solid tumors and other challenging diseases. However, therapeutic efficacy may be affected by resistance mechanisms, antigen loss, suppressive tumor microenvironments (TMEs), altered T-cell trafficking, and metabolic competition. As new methods emerge to overcome the shortcomings of existing technologies, the field of CAR T-cell therapy is rapidly progressing, and a novel model known as dual-targeting CARs is now being researched. This model can facilitate the identification of several antigens and thus reduce the likelihood of tumor formation caused by antigen loss. To achieve and ensure the durability of T-cell therapy, methods that can alter tumors are also being investigated. The advent of CAR T-cell therapy has several potential benefits, including improved safety and efficacy, and it may also lead to personalized, adaptable cancer treatments. Innovations in this regard and can spark a much-needed shift in the medical industry, as they have the potential to augment or even replace the current healthcare system. This article outlines the potential benefits and risks of CAR T-cell therapy for cancer—a groundbreaking treatment option.
Key words: chimeric antigen receptor T-cell, immunotherapy, malignancy, personalized medicine
INTRODUCTION
Immunotherapy is a new cancer treatment method that has emerged as an alternative to traditional treatments such as radiation, chemotherapy, and surgery, which are often toxic and lack selectivity. Over the course of the last two decades, the primary focus has been on eliminating cancer through the utilization of the human immune system, and T-cells. Cancer cells that evade immune detection can also be determined and destroyed by T-cells. However, immunosuppressive factors and variations in antigens create obstacles for normal T-cells in the tumor surroundings. Considering this, initial research into chimeric antigen receptors (CARs) was conducted in the 1990s, forming the basis for the development of bulleted CARs that can detect specific cancer antigens generated by T-cells.[1–3]
CAR T-cells are T-cells that have undergone genetic modifications to produce the CAR molecule, which draws the T-cells to a specific antigen on a cancer cell, thereby tracking the cancer cell and subsequently killing the cancer cell . The key accomplishments of CAR T-cell therapy were first seen in projects involving leukemia, particularly acute lymphoblastic leukemia (ALL), and some lymphomas. These outcomes prompted the authorization of medicines such as Kymriah and Yescarta. Despite the significant advancements made in treating blood cancers, CAR T-cell therapy can be applied to solid tumors only after addressing a number of problems, including antigen heterogeneity and tumor microenvironments (TMEs). New CAR architectures and combination therapies are currently the focus of research for improvements in this area.[4] To date, the food and drug (FDA) has approved a number of CAR T therapies, and clinical investigations and improvements are ongoing with the goal of customizing treatments and improving efficacy while lowering toxicity.
CAR T-cell therapy is revolutionizing cancer treatment because of its targeted specificity, enhanced T-cell activation, and potential to improve outcomes for cancers as aggressive as glioblastoma. This therapeutic approach facilitates accurate tumor identification and tumor death while sparing healthy tissue, specifically by genetically modifying CAR T-cells to detect particular antigens on cancer cells, thus allowing for customized treatment options. It works by signaling regions in such a way that immune cells are activated and being proliferating. CAR T-cells persistent in the body enable prolonged surveillance against tumor recurrence, thereby yielding the desired treatment results. CAR T-cells can also be adapted through genetic engineering to counter some cancer mechanisms that create an immunosuppressed TME. This can optimize CAR T-cell activity against tumors that would otherwise evade immune killing though other cell-intrinsic methods. Dual-targeting CARs have been designed to improve the efficacy and safety of immunotherapy against cancer, marking a sophisticated advancement in CAR-T cell therapy.[5]
CAR T-cell therapy has shown significant success in treating hematologic malignancies by targeting antigens such as cluster of differentiation 19 (CD19) and CD22. However, single-target approaches often face challenges such as antigen escape, wherein malignanT-cells downregulate or lose the targeted antigen, leading to relapse. Dual-targeting CARs can address this limitation by targeting multiple antigens simultaneously. A phase-one trial utilizing AUTO3, a bicistronic CAR T-cell therapy targeting both CD19 and CD22, showed promising results in relapsed/refractory large B-cell lymphoma (LBCL). This therapy demonstrated high efficacy and tolerable safety profiles, especially when combined with programmed cell death protein 1 (PD-1) blockade, and also achieved durable remissions by mitigating antigen escape mechanisms.[6]
In a study where pediatric ALL patients were treated with cotransduced CD19/CD22 CAR T-cells, 83% of patients achieved negative remission of measurable residual disease (MRD) within two months, with no antigen-negative relapses observed after one year. The event-free survival rate was 60% at 12 months, underscoring the potential of these CAR T-cells to enhance long-term outcomes.[7] By simultaneously targeting CD19 and CD22, dual-targeting CARs reduce the risk of relapse due to antigen loss, which is a significant issue with single-antigen CAR therapies. Dual-targeting strategies may also enable more robust tumor eradication through the synergy that arises between two antigenic targets frequently coexpressed on malignanT-cells. Further optimization of dual-targeting constructs, such as incorporating checkpoint inhibition or novel antigen combinations, could further improve response rates and durability. Studies are ongoing to identify the best constructs and combinations for different malignancies.[8] Further developments in genetic engineering methods produces next-generation CAR T-cells with enhanced efficacy and the potential for combining treatments that can improve the outcomes of cancer therapy at different types and stages. These cells have demonstrated success in treating hematologic cancers, with encouraging early results against solid tumors.
DEVELOPMENT OF CAR T-CELLS
CARs are intended to enhance T lymphocytes' ability to recognize and combat cancer cells. The majority of the extracellular domain of a CAR T cell is obtained from the variable sections of designed antibodies that target cancer cells in specific, exclusive areas. This domain is usually formed as a single-chain variable fragment (scFv) in which an antibody's heavy and light chains are connected by a polypeptide chain and share an antigen adhesion affinity. Anti-CD19 scFvs attach to the B-cell surface protein CD19, making them effective for treating B-cell malignancies such as leukemias and lymphomas. The most crucial factor in this regard is scFv selection, which affects CAR specificity and cancer cell binding. The hinge region of CAR T-cells connects the extracellular and transmembrane domains, altering the CARs' location for optimal antigen binding. This area contains a short peptide sequence that can vary in length and composition and affect CAR functioning. The hinge flexibility of CARs allows them to contact target antigens on tumor cells at multiple orientations. Research has shown that hinge length affects T-cell activation and activity, making it crucial for the success of CAR T-cell therapy.[9] However, the transmembrane domain anchors the CARs in the T-cell membrane so that they can be orientated correctly to carry an effective signal when antigen contact occurs. A well-designed transmembrane domain ensures that CARs are properly positioned to send activation signals to the T-cells, triggering the immune response needed to target and eliminate cancer cells. After attaching to the target antigen, CAR T signaling domains activate T-cells. The CD3 chain then transmits the T-cell activation signals, triggering cellular responses such as memory formation, cytotoxicity, and proliferation. CD28 and 4-1BB (CD137) are costimulatory domains that boost T-cell survival and activation. CD28 first activates T-cells and then boosts their proliferation, while 4-1BB increases T-cell growth and in vivo persistence. Adding costimulatory domains can boost T-cell efficiency and lifespan, which allows for overcoming the immune evasion capacity of tumors and fight cancer.[8–10]
The manufacturing process of CAR T-cell therapy presents several challenges, particularly in terms of scalability and cost-effectiveness. CAR T-cell production is highly individualized, and T-cells have to be extracted, genetically modified, and expanded for each patient. This limits the scalability of the process and increases turnaround times. Large-scale production requires significant investment in biomanufacturing facilities equipped with clean rooms, advanced cell culture systems, and specialized equipment and is, therefore, resource intensive. The manufacturing process involves multiple complex steps, including vector design, cell engineering, and quality control, all of which contribute to the high cost of therapy (often exceeding $300,000 per patient). Achieving consistent product quality across batches is difficult due to variability among patients and the complexity of the manufacturing process. Regulatory standards for ensuring safety and efficacy also add layers of complexity and cost.[9–11]
MANUFACTURING OF CAR T-CELLS
A complex, strictly controlled set of procedures is used for the production of CAR T-cells. These procedures turn a patient's own T-cells into targeted cancer treatments.[11]
T-cell collection (leukapheresis)
Leukapheresis, the first step in CAR T-cell therapy, involves using a machine to draw blood from a patient and process it such that specific parts of the blood can be collected or removed. The machine retains the T-cells and returns the other parts, including red blood cells, plasma, and platelets, to the patient. The process takes a few hours, is performed on an outpatient basis, and is minimally invasive. Leukapheresis lays the foundation for the next stages of CAR T-cell engineering, and it guarantees that an adequate number of T-cells are harvested.[10,11]
T-cell activation
Once they are harvested, T-cells must undergo activation to prepare them for genetic modification. This activation process is critical as it enhances T-cells' ability to proliferate and respond effectively to engineered CARs. Typically, activation is accomplished using substances such as anti-CD3 and anti-CD28 antibodies, which trigger an immune response by interacting with T-cell receptors (TCRs) and costimulatory pathways that imitate natural signals. T-cell proliferation can also be triggered by cytokines such as interleukin-2 (IL-2). This step is essential for ensuring that T-cells are robust and ready for the subsequent genetic engineering process.[12]
Genetic engineering
Once the T-cells are activated, CARs are introduced into their genome through genetic engineering. A viral vector, such as lentivirus or retrovirus, that binds to particular proteins on the surface of white blood cell is usually used to transfer CAR genes into T-cells. Gene transfer can also be achieved without a virus, using methods such as electroporation or clustered regularly interspaced short palindromic repeats (CRISPR) technology. As chimeric molecules, CARs typically consist of a recombinant antigen-binding domain created by scFvs for the specific recognition of target antigens; a flexible hinge region that varies in length between CAR variable domain of heavy chain of heavy chain antibody (VHHs); and a transmembrane portion that anchors to the cell membrane at one end, pointing toward the external environment and allowing scFvs to recognize tumor cell epitopes, and that contains intracellular signaling moieties on the other end, which trigger T-cell activation following target identification. Once CAR genes are successfully introduced, the T-cells that express these genes are identified and chosen for growth; this ensures that only the cells that can successfully target cancer are used in the next phase.[13]
Expansion of CAR T-cells
In a controlled laboratory setting, the chosen CAR T-cells are multiplied to produce an adequate quantity of cells for therapeutic application. The genetically modified T-cells are cultured using growth factors and cytokines, such as IL-2, to promote their survival and proliferation during this expansion phase. The expansion process can take several days to weeks, with the goal of producing millions of CAR T-cells for effective treatment. The health and functionality of the growing T-cell population depends on maintaining ideal culture conditions because any stress or unfavorable circumstances can reduce the cells' therapeutic capacity.[14]
Quality control
Prior to being administered, CAR T-cells are evaluated for their safety, effectiveness, and treatment ability through stringent quality control procedures. The quality control parameters include viability testing to determine the percentage of live T-cells, functional potency tests to confirm the engineered T-cells' capacity to target and eliminate cancer cells, flow cytometry to determine expression levels, specifically by examining a sufficient number (> 3 million) of CAR-positive surfaces that express immune effector power and can directly inhibit tumor growth, and sterility testing to verify that the final products are free of bacteria, fungi, and other harmful organisms. Adherence to regulatory standards is necessary during these checks, which then ensures that the CAR T-cells are safe for infusion.[15]
Cryopreservation
After passing quality control, the CAR T-cells undergo the critical step of cryopreservation, which involves freezing the final products and storing them in liquid nitrogen. This step is necessary to keep the CAR T-cells alive and functioning in an optimal state for infusion. Cryopreservation allows for storing engineered cells for long periods and subsequently administer treatment according to the needs of a patient. In cases where CAR T-cells are manufactured at a central facility, they are transported to treatment centers under strict temperature controls to prevent any degradation or loss of efficacy during transit.[16]
CAR T-cell infusion
Prior to receiving a CAR T-cell infusion, patients typically undergo chemotherapy to reduce the number of lymphocyte cells in their bodies. This procedure provides a more suitable environment for the function of CAR T-cells, leading to increased efficacy and improved outcomes. Similar to a blood transfusion, this infusion is administered via an intravenous line, allowing the CAR T-cells to enter the patient's circulation. The CAR T-cells then travel to the tumor cells that express the specific antigens targeted by the CARs and thereby initiate a directed immune attack on cancer. The manufacturing of CAR T-cells is thus a complex and challenging ordeal. The entire process, from T-cell isolation to infusion, contributes to the optimal delivery of CAR molecules and subsequently results in noteworthy clinical outcomes for some cancers.[17]
NOVEL MOLECULAR TARGETS OF CAR T-cells
As CAR T-cell therapy evolves, researchers are identifying new molecular targets to expand its applicability in addressing solid tumors, improving efficacy, and minimizing adverse effects. Table 1 presents some novel molecular targets of CAR T-cells.
| Molecular target | Type | Mechanism | Example | Current research | Reference |
| HER2 | Solid tumors (e.g., breast cancer and gastric cancer) | HER2 is overexpressed in certain tumors, and CAR T-cells designed to target HER2 can attack these cancer cells | Various HER2-targeted CAR T-cell products are in development, and some have entered early-phase clinical trials | Ongoing studies are assessing the safety and efficacy of HER2 CAR-T cell therapy in combination with other treatments to improve outcomes of patients with HER2-positive cancers | [17,18] |
| EGFRvIII | Glioblastoma | EGFRvIII is a mutant form of the epidermal growth factor receptor found in a subset of glioblastoma tumors and thus provides a target unique to these cancer cells | Research studies utilizing CAR-T-cells that target EGFRvIII are underway, focusing on glioblastoma patients | Early clinical trials are evaluating the safety and efficacy of EGFRvIII-targeted CAR T-cells in treating glioblastoma, with promising preliminary results | [18] |
| CD19 | Hematologic malignancies (e.g., ALL, NHL) | CD19 is a pan B-cell marker that is consistently expressed on B cells, including malignant B-cell tumors. CAR T-cells engineered to target CD19 can recognize and eliminate these cancerous B cells | Kymriah (tisagenlecleucel) has been approved for pediatric and young adult patients with relapsed/refractory ALL. Yescarta (axicabtagene ciloleucel) has been approved for adult patients with certain types of non-Hodgkin lymphoma |
Ongoing trials are exploring CD19 CAR T-cell therapy for various B cell malignancies and in combination with other treatments to improve efficacy and manage relapse. The ELIANA trial showed an 83% complete remission rate among pediatric and young adult patients with relapsed/refractory ALL |
[19,20] |
| BCMA | MM | BCMA is specifically expressed on malignant plasma cells. CAR T-cells that target BCMA can effectively identify and kill these cells | Abecma (idecabtagene vicleucel) has been approved for adult patients with relapsed/refractory MM | Numerous clinical trials are investigating BCMA-targeted CAR T-cell therapies, focusing on optimizing their efficacy, safety, and durability in treating MM The KarMMa trial demonstrated a 73% overall response rate among patients with relapsed/refractory MM |
[21–23] |
| CD20 | NHL, CLL | CD20 is expressed on B-cells; CAR T-cells targeting this antigen can eliminate malignant B-cell populations | Investigational CD20-targeting CAR T-cell therapies | Early-phase studies are showing promise, with response rates around 60%-80% for certain NHL subtypes | [24,25] |
| MUC1 | Breast cancer, ovarian cancer | MUC1 is overexpressed in various carcinomas. CAR T-cells that target MUC1 can attack tumor cells expressing this protein | Investigational MUC1-targeting CAR T therapies | Early-phase trials are ongoing, with some showing encouraging responses among patients with MUC1-positive tumors | [26,27] |
| Prominin-1 (CD133) | Brain tumors (e.g., glioblastoma), AML | CD133 is a marker for cancer stem cells. CAR T-cells that target CD133 can potentially eliminate tumor-initiating cells | Investigational CD133 CAR T therapies | Ongoing studies are assessing the feasibility and effectiveness of targeting CD133 in glioblastoma and AML | [28–30] |
APPLICATION OF CAR T-CELL THERAPY
Hematological malignancies
In the 2022 and 2023, trials and multi-institutional studies involving CAR-T-cells that could target CD19 have been approved and conducted. In clinical trials such as ELIANA, a complete remission rate of 83% has been observed.[31] Malignant B-cells that expressed CD19 could be identified and eliminated by CD19 CAR T-cells. This global, multicenter phase 2 study evaluated the efficacy of tisagenlecleucel, a CD19-directed CAR T-cell therapy, in pediatric and young adult patients with relapsed or refractory B-cell B-ALL. The trial reported an overall remission rate of 81% within three months of treatment, highlighting the therapy's potential in targeting and eradicating CD19-positive malignant B-cells. Currently, the only approved treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is CD19-targeted CAR T-cell therapy. A 52% overall response rate to this therapy has been found in various research initiatives, such as ZUMA-1, with complete remission seen in 40% of the patients.[32] Thus, CAR T-cells can target the CD19 antigen present in B cells.[33,34] Clinical trials are currently underway to investigate CAR T-cells that target CD19 in patients with chronic lymphocytic leukemia (CLL) who have relapsed following conventional therapies. Initial information is indicative of positive response rates, but further investigation is needed.[35] B-cell maturation antigen (BCMA)-targeted CAR T-cells, such as Abecma (idecabtagene vicleucel), have been approved for relapsed/refractory myeloma and are also used to treat multiple myeloma. In the KarMMa trial, an overall response rate of 73% was seen among patients who had received multiple treatment approaches, including CAR T-cell therapy. CAR T-cells have been shown to bind and kill plasma cells that express BCMA and are critical for myeloma growth.[21]
Solid tumors
Breast cancer
Research is being conducted on treating human epidermal growthfactor receptor 2 (HER2)-positive breast cancer using CAR T-cells that target HER2. Early-phase trials have shown promising results, but challenges related to solid TMEs need to be addressed. HER2-targeted CAR T-cells attack tumor cells that overexpress the HER2 protein. To combat treatment-resistant colorectal cancer, CAR T-cells that target the epidermal growth factor receptor (EGFR) are also being developed. Studies are being conducted to evaluate the safety of this treatment approach and the possible reactions of patients with advanced illness. CAR T-cells that can treat advanced melanoma by targeting New York esophageal squamous cell carcinoma 1 (NY-ESO-1), a cancer/testis antigen, are also being studied, and the results of clinical trials suggest that this could be a good cure for patients whose tumors contain NY-ESO-1. These CAR T-cells are developed especially to identify and eliminate NY-ESO-1-containing melanoma cells.[36] Further, CAR T-cells that target claudin6 (CLDN6) are being studied for the treatment of some germ cell tumors. Early trials have provided encouraging results, and strategies to specifically target these tumors are under investigation. CLDN6 is visible on the surface of some tumor types, so targeted treatment is possible.
Brain tumors
Glioblastoma and other central nervous system (CNS) tumors are currently being studied using CAR T-cells that target CD133 and other antigens. It is extremely difficult to determine the safety and efficacy of CAR T-cell therapy in brain TMEs, which is a current focus of research. The goal of these CAR T-cells is to specifically destroy stem-like cancer cells that are typically resistant to conventional therapy.[37]
Clinical trials involving HER2-targeted and EGFR-targeted CARs
HER2-targeted CAR T-cell therapy
A Phase I study has been conducted to evaluate HER2-specific CAR T-cell therapy for patients with advanced sarcoma. In this study, 13 patients received multiple CAR T-cell infusions following lymphodepletion. HER2-CAR T-cell expansion occurred after 19 of 21 infusions, with 50% of patients experiencing clinical benefits. Notably, one patient with metastatic rhabdomyosarcoma exhibited an exceptional response and remained cancer-free for over five years. In this investigation, systemically administered HER2-CAR Cytomegalovirus (CMV) bispecific T-cells were found to be safe, with approximately 38% of patients experiencing durable clinical benefits.[38]
EGFR-targeted CAR T-cell therapy
Third-generation CAR T-cell therapy (CARv3-TEAM-E) T-cells engineered to target both EGFR variant III and wild-type EGFR in patients with recurrent glioblastoma were assessed in a Phase I trial. A total of six patients were treated with intrathecally delivered CARv3-TEAM-E T-cells engineered to target both EGFR variant III (IL13Rα2) and wild-type EGFR in patients with recurrent glioblastoma were assessed in a Phase I trial. The CAR T-cells were intrathecally delivered to a total of six patients magnetic resonance imaging (MRI) scans taken 24-48 h post treatment showed reduced tumor sizes in all patients, with sustained reductions in some cases. Three patients exhibited dramatic tumor regression within days (Day 1, 2 and 5, respectively) of treatment.
The findings of the two Phase I trials described above demonstrate the potential of using HER2- and EGFR-targeted CAR T-cell therapies to treat solid tumors. However, challenges such as tumor heterogeneity, antigen escape, and immunosuppressive TMEs remain. Research into enhancing the efficacy and safety of these therapies is ongoing.[39,40]
Combination therapies
The interplay between CAR T-cell therapy and other therapeutic approaches, such as checkpoint inhibitors and monoclonal antibodies, is currently a growing area of research attention. The aim is to strengthen antitumor responses to the mechanisms of resistance that may result in CAR T-cell therapies being ineffective. A combination of different therapies may enable the activation of multiple immune pathways and thus lead to a more powerful immune response to tumors. Initial studies in this area have provided promising results that indicate that, compared to CAR T-cell therapy alone, a multifaceted strategy could be beneficial for patients with various types of cancer by increasing the durability of the immune responses and decreasing the tumor burden.[41]
Personalized medicine
Personalized CAR T-cell therapy entails adjusting the course of treatment according to the unique features of each patient's tumor. By selecting target antigens that are either overexpressed or uniquely expressed in a patient's cancer, clinicians can improve the precision and effectiveness of CAR T-cell therapies and thereby enhance the likelihood of successful tumor targeting, leading to better patient outcomes. Ongoing research is focused on determining various methodologies for profiling tumors at the molecular level and on identifying optimal targets for CAR T-cell therapies to address the heterogeneity often seen in cancers.[40,41]
Targeting cancer stem cells (CSC)
Targeting CSCs with CAR T-cell therapy is an emerging area of research aimed at combating tumor recurrence and improving long-term survival rates. CSC variations are often resistant to conventional therapies and may play a key role in cancer relapse due to their ability to regenerate tumors. By designing CAR T-cells that specifically recognize antigens associated with these resilient cell populations, researchers hope to effectively eliminate CSCs and reduce the risk of relapse. Early preclinical studies have provided encouraging results, suggesting that targeting these markers could lead to more durable therapeutic responses and potentially enhance overall patient survival.[42,43]
Autoimmune diseases
CAR T-cell therapy shows a lot of promise for the treatment of autoimmune diseases—a brand-new application for this therapeutic method. Scientists have developed CAR T-cells that can target immune cells that mistakenly attack a patient's body and cause autoimmune diseases. Early studies using animal models have shown that CAR T-cells can selectively deprive certain mice of the autoreactive population and thus significantly reduce the number of autoimmune diagnoses. Ongoing investigations will involve enrolling adult patients in clinical trials to evaluate the safety and effectiveness of CAR T-cell therapies in treating immune-mediated diseases. The ultimate objective is to provide patients who have limited treatment options with a targeted and efficient therapy alternative. Autoimmune diseases involve dysregulated immune responses, causing the immune system to attack the body's own tissues. CAR T-cell therapy can be harnessed to reprogram the immune system and restore tolerance. Tregs play a central role in maintaining immune homeostasis. Engineering CAR Tregs to target specific autoantigens can enable precise immunosuppression at sites of inflammation. In preclinical studies, CAR Tregs that targeted the myelin oligodendrocyte glycoprotein (MOG) showed efficacy in models of multiple sclerosis (MS) by reducing neuroinflammation. Further, CAR Tregs that targeted pancreatic islet antigens demonstrated the ability to preserve beta-cell function in Type 1 diabetes cases. Autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis involve overactive or autoreactive B cells. CD19-targeted CAR T-cells have been used in experimental settings to deplete these B cells, leading to disease remission in refractory SLE cases. In a study conducted in 2021, complete remission was seen in five patients with severe refractory SLE who were treated with CD19 CAR T-cells. Disease activity remained low for up to 17 months post treatment.[44,45]
Cardiovascular disorders
Although still in its infancy, CAR T-cell therapy is being explored for treating cardiovascular diseases, particularly those with immune or inflammatory components. Atherosclerosis is driven by chronic inflammation and immune cell infiltration in arterial plaques. CAR T-cells that target antigens expressed by inflammatory macrophages or smooth muscle cells can selectively eliminate proinflammatory cells and thereby stabilize plaques. CAR T-cells that targeting lectin-type oxidized LDL receptor (LOX-1), a receptor expressed on foam cells (lipid-laden macrophages), have been shown to reduce plaque burden and inflammation in preclinical models. In conditions such as heart failure, cardiac fibrosis contributes to disease progression. CAR T-cells that target fibroblast activation protein (FAP) have been studied in preclinical models for their ability to reduce fibrosis and improve cardiac function. A study in 2021 demonstrated that FAP-specific CAR T-cells could reduce cardiac fibrosis in mice with pressure overload-induced heart failure, improving ejection fraction. Further, one-time therapy can provide long-term benefits compared to chronic pharmacological treatments.[45,46]
Other emerging applications
CAR T-cells are being engineered to target chronic viral infections, such as human immunodeficiency virus (HIV) or hepatitis B, by recognizing viral antigens on infected cells. In preclinical studies, dual-specific CAR T-cells that target HIV envelope proteins have exhibited the potential to eliminate latent viral reservoirs.[47] Conditions such as liver cirrhosis and idiopathic pulmonary fibrosis (IPF) could benefit from CAR T-cells that target FAP-expressing fibroblasts. CAR Tregs can promote graft tolerance by targeting donor-specific antigens, reducing the need for lifelong immunosuppressive therapy.[48,49]
ADVANTAGES OF CAR T-CELL THERAPY
Targeted therapy
CAR T-cell therapy has become a revolutionary cancer treatment approach, as it can be used to target distinct antigens found on the surfaces of tumor cells. Genetically modified T-cells can hone in on and attach to tell-tale proteins better than ordinary immune system components such as antibodies or naked killer lymphocytes used for other immunotherapies. This method only targets the bad actors, which is in sharp contrast to conventional therapies such as chemotherapy and radiation that frequently kill healthy cells along with cancer cells and cause negative side effects, including nausea, hair loss, and immune suppression. CAR T-cell therapy is so precise that its increased treatment effectiveness is associated with improved quality of life for patients, as they encounter fewer severe side effects and are healthier overall during their journey to restored health.[50]
High efficacy
The effectiveness of CAR T-cell therapy has been demonstrated by a high rate of total remission among patients with relapsed or refractory cancers. CAR T-cell therapies have demonstrated remarkable success in bringing significant percentages of patients with diseases such as DLBCL and ALL into complete remission, whereas other treatment approaches have failed. This notable achievement is all the more important for aggressive malignancies that fail to be addressed by traditional therapies. In addition to giving patients with bleak prognoses hope, the high effectiveness of CAR T-cell therapy represents a paradigm shift in the way that different hematological cancers are treated.[51,52]
Durable responses
One of the most remarkable effects of CAR T-cell therapy is its capacity to produce stable responses in patients, allowing them to live cancer-free lives for years after treatment in certain situations. This effect of CAR T-cells is sustainable because they exist in the body as memory T-cells that continue to obstruct cancer. By establishing a foundation of these memory cells, CAR T-cell therapy gives the immune system the chance to recognize and promptly combat cancer cells should they reappear. The ability to monitor cancer for a long period drastically improves overall disease management and allows for getting rid of the disease with minimal subsequent interventions or additional therapies.[53,54]
Personalized medicine
The principles of personalized medicine, which involves tailoring treatments to the particulars of each patient's tumor, are exemplified by CAR T-cell therapy. Clinicians can create T-cells that precisely target certain features by analyzing the antigens present on a patient's cancer cells. This personalization not only increases the probability of a successful therapeutic outcome but also provides clinicians with the ability to offer treatments that are more in line with a patient's particular disease profile. By increasing the likelihood of positive responses and reducing needless toxicity, tailored CAR T-cell therapies can ensure that a patient receives treatment that is primarily based on their cancer biology.[55]
Immune memory
In addition to destroying cancer cells directly, CAR T-cell therapy contributes to long-term cancer care by fostering immune memory. Following initial treatment, CAR T-cells have the ability to develop into memory T-cells that stay in the body and launch an attack as soon as a tumor recurs. The best thing about this discovery is that the ongoing surveillance associated with memory T-cells can stop cancer from coming back. The availability of memory T-cells means that patients have a strong immune response that can prevent further tumor growth. This component of CAR T-cell therapy is revolutionary because it focuses not only on the immediate removal of a tumor but also on promoting effective immune protection against recurrence, allowing patients to remain in remission for a long period of time.[55,56]
Combination potential
The adaptability of CAR T-cell therapy has been demonstrated by its use in a number of different therapeutic modalities, including immune checkpoint inhibitors, chemotherapy, and targeted therapies. This method can be used in cases where single-agent treatments don't work or where the cancer is very aggressive and starts fighting the treatment. By synergizing these therapies, the main goal is to amplify the strength of the treatment and thus the patients' responses.[57]
APPLICATION OF CAR T-CELLS BEYOND ONCOLOGY
CAR T-cell therapy is primarily known for its applications in oncology, but researchers are increasingly exploring its potential in other medical fields (Figure 1).
Figure 1. Application of CAR T-cells beyond oncology. CAR, chimeric antigen receptor.
Autoimmune diseases
CAR T-cell therapy, which targets autoreactive T-cells that contribute to disease pathology, is gaining traction in the treatment of autoimmune diseases such as MS and rheumatoid arthritis. Engineered CAR T-cells have the potential to alleviate symptoms and enhance joint function in rheumatoid arthritis by reducing the number of T-cells that cause inflammation and joint damage.[58] Similarly, in MS, targeting myelin-reactive T-cells can decrease the demyelination of neurons, thereby enhancing neurological recovery and slowing disease progression. According to preliminary research, CAR T-cell therapy may offer a fresh approach to reestablishing immunological balance and enhancing the outcomes of patients with autoimmune diseases.
Infectious diseases
The application of CAR T-cell therapy to combat infectious diseases is focused on chronic viral infections such as HIV and hepatitis B. Researchers are engineering CARs that recognize HIV-specific antigens and can thus enable the elimination of HIV-infected cells from the human body. The aim of this approach is to achieve sustained viral suppression without the need for continuous antiretroviral therapy, potentially transforming the management of HIV. In hepatitis B cases, CAR T-cells can target infected liver cells and offer a path to a functional cure by clearing the virus and restoring liver health. These innovative strategies can significantly change treatment paradigms for chronic viral infections, shifting the focus from lifelong management to potential eradication of the virus.[59]
Transplant rejection
CAR T-cells are also being investigated in the context of transplantation in order to avoid graft-versus-host disease (GVHD), a potentially fatal side effect in which recipients' tissues are attacked by transplanted immune cells. Researchers are looking to genetically modify triggered CAR T-cells to deplete those specific T-cells that do harm; this is aimed at boosting transplant success rates and decreasing the need for immunosuppressive therapies, which often cause harmful side effects and increase the risk of infection. The development of CAR T-cells may be a major step toward bettering transplant outcomes, which is especially pertinent in hematopoietic stem cell transplantation, where GVHD is a frequent and dangerous complication.[60]
Infectious pathogens
CAR T-cells have the potential to combat bacterial infections, particularly those caused by antibiotic-resistant pathogens such as Mycobacterium tuberculosis, and thus constitute an exciting area of research. By engineering CAR T-cells that recognize specific bacterial antigens, the immune response against tuberculosis can be significantly enhanced. This innovative approach can overcome the limitations of traditional antibiotic treatments, especially in cases of drug-resistant tuberculosis. By harnessing the specificity and adaptability of CAR T-cells, researchers hope to develop new therapeutic options that can effectively address chronic bacterial infections and improve patient outcomes.[61]
Chronic inflammatory conditions
In chronic inflammatory diseases such as SLE, CAR T-cell therapy may be used to target and deplete the autoreactive B cells responsible for producing harmful autoantibodies. By selectively targeting these B cells, researchers aim to improve disease control and reduce the frequency and severity of flares. This method might provide a more successful course of treatment for lupus patients, enhancing their quality of life and lessening the burden of the disease. There is considerable potential for treating a number of chronic inflammatory diseases due to CAR T-cells' capacity to selectively eradicate troublesome immune cell populations.[62]
Cardiovascular diseases
The goal of CAR T-cell research for cardiovascular disorders is to alter the immune responses that contribute to the development of atherosclerosis. Plaques that form in arteries due to inflammatory processes are hallmarks of atherosclerosis. By targeting inflammatory pathways, CAR T-cells can help reduce plaque formation and stabilize existing atherosclerotic lesions, ultimately lowering the risk of cardiovascular events such as heart attacks and strokes. Thus, by targeting the underlying immune mechanisms that contribute to cardiovascular diseases, CAR T-cell therapy may result in new approaches to disease management.[63]
Gene therapy applications
CAR T-cells are being explored as delivery vehicles for gene therapies aimed at correcting genetic disorders such as hemophilia and beta thalassemia. CAR T-cells engineered to transport functional genes directly to hematopoietic stem cells can provide long-term corrective therapies for patients with genetic disorders. The use of CAR T-cells as a means of delivering therapeutic genes allows for targeted and efficient gene transfer, which can potentially overcome some of the limitations associated with traditional gene therapy methods. This innovative strategy holds great promise for improving the lives of patients with inherited conditions.[64]
Vaccine development
In the area of vaccine development, CAR T-cells are being investigated as adjuvants that can enhance the immune system’s recognition of and response to vaccine antigens and thereby improve the efficacy of vaccines that target infectious diseases, in turn, leading to stronger, more durable immune responses. This is particularly relevant for emerging infectious diseases, as rapid and effective immune responses are crucial for controlling outbreaks. The use of CAR T-cells as powerful immune modulators, in conjunction with vaccination, may significantly enhance the effectiveness of preventive strategies and contribute to improved public health outcomes.[65]Table 2 represents the omparison of CAR T-Cell therapy and checkpoint inhibitors.
| Aspects | CAR T-cell therapy | Checkpoint inhibitors |
| Mechanism of action | Engineered T-cells target tumor-specific antigens directly. | Antibodies block immune checkpoints (e.g., PD-1 and CTLA-4) to restore T-cell activity |
| Efficacy | High response rates in hematologic malignancies (e.g., 90% CR in B-cell ALL) Variable efficacy in solid tumors due to tumor microenvironment challenges | Effective with a broad range of cancers, especially solid tumors such as melanoma and non-small cell lung cancer varied response rates (about 20%-40%), with some durable responses |
| Durability of response | Long-lasting remissions in many cases, particularly in hematologic cancers, with some patients remaining disease-free for years | Durable responses in a subset of patients, with ongoing research to identify predictors of long-term remission |
| Target specificity | Highly specific to tumor-associated antigens (e.g., CD19 and BCMA) | Targets immune checkpoints broadly, enhancing overall T-cell response, but not tumor-specific |
| Side effects | CRS, neurotoxicity, and risk of on-target, off-tumor effects. Requires hospitalization and close monitoring |
Autoimmune-like toxicities, such as colitis, dermatitis, and pneumonitis Generally manageable in outpatient settings |
| Cost | High upfront costs ($300,000-$500,000 per treatment) Additional costs for managing severe side effects |
Relatively low per-patient costs (about $100,000-$150,000 annually) Often requires chronic treatment |
| Accessibility | Limited by the complexity of manufacturing and logistics Requires personalized production for each patient (autologous therapy) |
Widely available as off-the-shelf drugs No personalization needed, making them easier to distribute |
| Applications | Approved mainly for hematologic malignancies (e.g., ALL, DLBCL, and MM) Early-phase trials for solid tumors |
Approved for a variety of cancers, including melanoma, NSCLC renal cell carcinoma |
| Combination potential | Combination with other therapies (e.g., checkpoint inhibitors and oncolytic viruses) is under investigation to improve efficacy in solid tumors | Often used in combination with chemotherapy, radiotherapy, or other immunotherapies to enhance outcomes |
CHALLENGES OF CAR T-CELL THERAPY
Although CAR T-cell therapy has demonstrated great promise in treating a variety of hematologic malignancies, a number of issues need to be resolved to increase its efficacy and expand its range of applications.
Cytokine release syndrome (CRS)
CRS is one of the most significant and common toxicities that arise following CAR T-cell infusion. This is because CD19-CAR secrete a cytokine storm that is caused by the explosive activation and proliferation of CAR T-cells. The symptoms of CRS range from mild, flu-like manifestations (e.g., fever and fatigue) to severe reactions such as hypotension, respiratory distress, and multiple organ failure. While mild cases may be managed with supportive care, severe instances often require pharmacological intervention, such as the administration of tocilizumab, which targets IL-6, or corticosteroids to reduce inflammation. To manage CRS and avoid major complications, early intervention and effective monitoring are essential.[66] CRS is a significant adverse effect associated with CAR T-cell therapy and is characterized by an excessive immune response leading to elevated levels of proinflammatory cytokines. Recent advancements have given rise to several strategies to mitigate CRS effectively. For instance, Tocilizumab, an IL-6 receptor antagonist, is commonly used to manage CRS symptoms, and its prophylactic administration has been explored to prevent CRS onset without compromising the antileukemic efficacy of CAR T-cells.[67]
Anakinra, an IL-1 receptor antagonist, has exhibited potential in preventing both CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) when used prophylactically, simultaneously maintaining the therapeutic activity of CAR T-cells. Agents such as dasatinib can act as pharmacologic “on/off” switches for CAR T-cells, temporarily suppressing their activity to control severe CRS episodes. Incorporating inducible caspase-9 suicide genes into the treatment approach enables the selective elimination of CAR T-cells in the event of severe CRS, thereby controlling the immune response. Designing CAR T-cells capable of autonomously neutralizing key cytokines involved in CRS can help modulate the immune response and reduce toxicity. Further, administering corticosteroids can suppress the hyperactive immune response that is characteristic of CRS. However, careful dosing is essential to avoid impairing the efficacy of CAR T-cell therapy.[67,68]
Neurotoxicity
Neurotoxicity is a severe side effect linked to CAR T-cell therapy, leading to neurological symptoms such as disorientation, seizures, agitation, and cognitive impairments. The precise mechanisms underlying CAR T-cell-related neurotoxicity are poorly understood, but it is believed to be associated with the inflammatory processes that occur during T-cell activation. Management of neurotoxicity typically involves symptomatic treatment, close monitoring, and, in severe cases, the use of corticosteroids or other medications to alleviate symptoms. Understanding the triggers and mechanisms of neurotoxicity is essential for improving patient safety. Neurotoxicity, particularly ICANS, is a notable adverse effect of CAR T-cell therapy. Recent advancements have given rise to several strategies to mitigate this condition. For instance, the efficacy of anakinra, an IL-1 receptor antagonist, in preventing neurotoxicity has been demonstrated using preclinical models, and it is currently under clinical evaluation for this purpose. Dasatinib, a tyrosine kinase inhibitor, can transiently suppress CAR T-cell activity, serving as a pharmacological “off switch” to control severe neurotoxic events. The prophylactic administration of antiepileptic medications can reduce the risk of seizures associated with neurotoxicity. Regular neurological assessments enable the early detection and management of neurotoxic symptoms, potentially preventing their progression to severe stages. Incorporating inducible suicide genes into CAR T-cells allows for their selective elimination in response to severe neurotoxicity and, in turn, for controlling their adverse effects. Engineering CAR T-cells to modulate cytokine release can mitigate the inflammatory responses contributing to neurotoxicity.[68,69]Table 3 presents the current status of various CAR T-cell therapies for different cancers.
| CAR T-cell therapy | Target antigen | Indication | Status | Key details |
| Tisagenlecleucel (Kymriah) | CD19 | ALL, DLBCL | Approved (FDA, EMA) | First FDA-approved CAR T-cell therapy for ALL (2017). |
| Axicabtagene ciloleucel (Yescarta) | CD19 | DLBCL, PMBCL, Follicular Lymphoma | Approved (FDA, EMA) | Approved for DLBCL and other NHLs. |
| Brexucabtagene autoleucel (Tecartus) | CD19 | MCL | Approved (FDA) | First CAR T-cell therapy approved for MCL. |
| Lisocabtagene maraleucel (Breyanzi) | CD19 | DLBCL, High-grade B-cell lymphoma | Approved (FDA) | Approved for relapsed/refractory large B-cell lymphomas. |
| Idecabtagene vicleucel (Abecma) | BCMA | MM | Approved (FDA) | First FDA-approved BCMA-targeted CAR T therapy for MM. |
| Ciltacabtagene autoleucel (Carvykti) | BCMA | MM | Approved (FDA) | Known for high response rates in MM clinical trials. |
| HER2-CAR T | HER2 | Sarcoma, breast cancer, gastric cancer | Phase I/II trials | Ongoing trials for HER2-positive solid tumors. |
| EGFR-CAR T | EGFR | Glioblastoma, head and neck cancers | Phase I/II trials | Investigational use in refractory solid tumors. |
| Mesothelin-CAR T | Mesothelin | Mesothelioma, pancreatic, ovarian cancers | Phase I trials | Early-phase trials targeting mesothelin-expressing tumors. |
| GPC3-CAR T | GPC3 | HCC | Phase I Trials | Preclinical studies show promise for GPC3-positive tumors. |
Antigen escape
Antigen escape is a phenomenon that occurs when cancer cells suppress or cease to express their targeted antigens, such as CD19 in some B-cell malignancies, to avoid being recognized and eliminated by CAR T-cells. This escape mechanism can lead to treatment failure and disease relapse, which emphasizes the need for more robust targeting strategies. Researchers are investigating combination therapies that include CAR T-cells and other treatment modalities to improve overall efficacy and lower the risk of antigen escape, as well as dual-targeting CARs that can recognize multiple antigens at once.[70]
Limited efficacy in solid tumors
CAR T-cell therapy has proven to be successful for treating blood cancers but has failed to reach a similar leading position in treating solid tumors. The T-cell tumor microenvironment is a key factor in this regard, as it makes solid tumors immune makes solid tumors immune to attacks on cancer cells. Solid tumors are often surrounded by a lot of stromal material, which makes T-cells unable to stop having activated immune responses. They also tend to be unable to reach neoplastic materials due to the continuous supply of connective tissues.[71] However, the focus of ongoing clinical trials is on the modification of CAR T-cell structures, combinatorial therapy, and the application of technologies that can control TME conditions so that it may be easier for T-cells to be activated and maintain their antitumor activity against solid tumors.
Manufacturing complexities
CAR T-cell engineering and improvements in this area are challenging, resource-intensive tasks that take weeks to complete, as they involve removing a patient's T-cells and genetically modifying them to express CARs. The cells are then further expanded in a laboratory. Maintaining the consistency and quality of CAR T-cell products is challenging because variability in manufacturing can result in differing therapeutic outcomes. Simplifying the production processes and coming up with standardized protocols are the main issues that need to be tackled to enhance the scalability and reliability of CAR T-cell therapies.[72]
Cost and accessibility
CAR T-cell therapy is associated with a substantial cost burden, with treatment costs often exceeding $373,000 per patient. This can limit access to therapy, particularly for patients in regions with limited healthcare resources or differing insurance coverage policies, and disparities in access can lead to inequalities in treatment outcomes. This highlights the need for strategies that can reduce costs and improve availability. Efforts to negotiate pricing, enhance insurance coverage, and develop more affordable CAR T-cell options are crucial for addressing these challenges.[73]
T-cell exhaustion
T-cell exhaustion is characterized by decreased effector function, restricted proliferation, and reduced persistence, and it can be exacerbated by the ongoing activation of CAR T-cells in the presence of persistent tumor antigens. Upregulated inhibitory receptors (e.g., PD-1) and metabolic dysregulation are two factors that contribute to this phenomenon. Research into approaches for reinvigorating exhausted CAR T-cells is ongoing; these approaches include using checkpoint inhibitors, modifying CAR designs to enhance resilience, and utilizing metabolic interventions to restore T-cell functionality.[74]
MECHANISMS RESPONSIBLE FOR CAR T-CELL RESISTANCE
Various resistance strategies limit the ability of CAR T-cell therapy to effectively treat tumors, posing a common problem (Figure 2). The loss or complete downregulation of target antigens, such as CD19 in B-cell malignancies, leads to immune escape, reducing the effectiveness of therapies like CD19-CAR-T cells. To overcome this challenge, strategies such as dual-targeting CAR-T cells, alternative antigen selection, and combination therapies are being explored. Total loss of the target antigen in immune escape is caused by the loss or complete downregulation of the goal antigen for the tumors called CD19 in B-cell malignancies, which is the most important remedy. CAR T-cell resistance is made worse by immunosuppressive TMEs, including myeloid-derived suppressor cells (MDSCs) and Tregs that prevent T-cell activation. Tumors cause changes in chemokine gradients, and these make it difficult for CAR T-cells to access tumor sites and survive, leading to reduced immune responses with time. T-cell exhaustion also results from the consumption of tryptophan by indoleamine 2,3-dioxygenase (IDO). All of these elements add to the difficulties surrounding CAR T-cell therapy, necessitating the development of novel techniques that can improve T-cell trafficking and persistence and metabolic support and thereby increase the likelihood of successful cancer treatment, with long-lasting effects.[74,75]Figure 2 shows the various mechanisms responsible for CAR T-cell resistance.
Figure 2. The various mechanisms responsible for CAR T-Cell resistance. CAR, chimeric antigen receptor.
Techniques to improve the effectiveness of CAR T-cells
Combination therapies and dual- and multitarget CARs can increase the efficacy of CAR T-cell therapy.[76] Dual- and multitarget CARs help T-cells simultaneously target multiple antigens on tumor cells and reduce the risk of antigen escape, leading to derailed targeting and coverage for heterogeneous tumors. There are certain benefits to these methods when there is tangible intratumoral heterogeneity in the expression of antigens commonly found in cancers. Combination therapeutic approaches are based on solid scientific evidence supporting the synergistic effectiveness of CAR T-cell therapy in conjunction with at least one other technique to increase tumor immunity and lessen hostile immune suppression (e.g., anti-PD-1 or anti-CTLA-4 inhibitors) or with nonimmune therapies such as conventional chemotherapy. This method increases T-cell activation, proliferation, and persistence, mainly in the context of solid tumors associated with a strong suppression of local immune system responses, which ultimately results in reduced cure rates and long-term patient survival rates.[76,77] Gene editing techniques, such as CRISPR/CRISPR-associated protein 9 (Cas9) are other new tools that can improve the efficiency of CAR-T-cells by enhancing key features for their function and survival. With gene editing, scientists can adjust T-cells to some degree, express new CARs, increase the cells' resilience to TMEs, or even remove inhibitory receptors that cause T-cell-exhaustion. By using this strategy, CAR T-cells can be designed to survive and expand in response to recurrent tumor antigens. Moreover, gene editing can be used to simultaneously knock down multiple genes that may block T-cell activity and thereby enhance the therapeutic potential of such agents. These developments can markedly increase response rates and the durability of CAR T-cell therapy for a broad variety of malignancies.[78,79]
FUTURE DIRECTIONS FOR CAR T-CELL THERAPY
The future of CAR T-cell therapy is expected to involve creative strategies that can overcome current constraints and increase the range of possible treatment applications. Next-generation CARs that can recognize multiple antigens simultaneously will be the main focus of future advancements in this area. This is especially crucial for dealing with the problem of antigen escape, which means that tumors suppress or lose the antigens targeted by CAR T-cells, resulting in resistance to treatment. CAR T-cells engineered to detect multiple tumor antigens would increase the possibility of successful targeting, particularly in tumors that are heterogeneous and express distinct markers. Next-generation CARs may also include modifications that allow them to secrete cytokines or express additional costimulatory signals.[80,81] These enhancements can boost T-cell activity, proliferation, and persistence within challenging TMEs. Another significant focus for future research is to improve the persistence and functionality of CAR T-cell therapy. For instance, researchers are investigating ways to create CAR T-cells with long-term memory to enhance their durability and response rates in patients. Scientists are also exploring various strategies to combat T-cell exhaustion—an issue that arises from chronic antigen exposure—such as by incorporating checkpoint inhibitors or metabolic reprogramming techniques.[82] Solid tumors present unique challenges in the application of CAR T-cell immunotherapy because of their locally immunosuppressive microenvironments. Determining a series of actions that can be taken to get around existing barriers is another target of future research. These actions may include modifications to CAR T-cells or establishing delivery systems that would improve the capacity of these cells to penetrate solid tumors. It is also crucial to identify and focus on novel tumor antigens that are less likely to be downregulated because of the possibility that better results may be achieved by CAR T-cells against solid tumors that are traditionally recalcitrant to treatment when compared to hematologic malignancies.[83]
The incorporation of gene editing technologies, particularly CRISPR, into CAR T-cell design offers significant potential for enhancing therapy. CRISPR allows for precise modifications that can improve T-cell functionality, such as enhancing their ability to proliferate and survive in hostile tumor environments. Furthermore, gene editing can lessen off-target effects, increasing the safety and efficacy of T-cell therapy. It offers a way to further customize CAR T-cell therapies based on the unique requirements of individual patients or tumor features and thus improve therapeutic effectiveness.[84] The future is being defined by CAR T-cell therapy and the aim of increasing its efficacy, robustness, and applicability across more diseases. Researchers are focusing on next-generation designs, improved targeting mechanisms, combination therapies, innovative delivery methods, and advanced gene editing technologies to overcome the existing limitations of CAR T-cell therapy and unlock its full potential. The treatment of different malignancies and the possibility of the therapy addressing other difficult medical conditions are two clear ways in which this dynamic area of research can change the medical field.[83,84]
CONCLUSION
CAR T-cell therapy is an innovative approach to cancer treatment and a new milestone in healthcare but not the end of journey for durable responses and personalized medicine. Despite the advancements made in this area, CAR T-cell treatment is not easy due to resistance mechanisms, including antigen loss in some treated tumors, tumor microenvironment suppression, and T-cell trafficking or persistence. The focus of current research is on next-generation CAR designs, T-cell metabolism regulation, and addressing TMEs to solve the aforementioned shortcomings. A better understanding of these mechanisms can lead to enhanced outcomes with hematologic malignancies and allow for expanding the application of CAR T-cell therapy to solid tumors and noncancerous situations, thereby altering immunotherapy. With the rapid rise of CAR T-cell therapy, it is necessary to first ensure its safety and efficacy in clinical settings. Next-generation CAR T-cells will likely have enhanced durability or resistance in unfavorable environments and improve response rates by expanding the dual-specificity targeting of cancer cells. To maximize its antitumor effects, CAR T-cell treatment should be used in combination with immune checkpoint inhibitors or oncolytic viruses. Clinical trials and technical advancements can lead to novel medicines for treating late-stage patients using CAR T-cell therapy.
DECLARATIONS
Acknowledgement
We thank the Divine College of Pharmacy, Satana, and METs, Institute of Pharmacy, Adgaon, Nashik, Maharashtra, India for their constant support and providing all facilities to complete this work.
Author contributions
Kasar GN, Rasal PB, Jagtap MN, Ahire ED: Writing—Original draft. Ahire ED, Surana KR, Sonawane DD and Mahajan SK: Writing—Review and Editing. All authors have read and approved the final version of the manuscript.
Source of funding
This review received no external funding.
Ethical approval
Not applicable.
Conflict of interest
Eknath D. Ahire and Khemchand R. Suarana are members of the Editorial Board of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of the editor and their research groups.
Use of large language models, AI and machine learning tools
None declared.
Data availability statement
No additional data.
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