RECENT ADVANCEMENT AND FUTURE PERSPECTIVE OF CAR-T CELL FOR MANAGEMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA: A REVIEW

RECENT ADVANCEMENT AND FUTURE PERSPECTIVE OF CAR-T CELL FOR MANAGEMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA: A REVIEW

Shrikrushna Bharat *, Rahul Jain and Neeta Joshi

Formulation and Development Department of Neon Laboratories Limited, MIDC Society, Palghar, Maharashtra, India.

ABSTRACT: Chronic lymphocytic leukaemia (CLL) is a common haematological neoplasm, mainly affecting older individuals, with a higher prevalence in males. Although treatment options have improved, CLL still presents significant challenges, especially in cases that have relapsed or are not responding to therapy. Chimeric Antigen Receptor T-cell The (CAR-T) treatment has arisen as available immunotherapy alternative for the treatment of CLL, harnessing patients T cells which have been designed for combat cancerous cells through genetically engineered receptors. CAR-T therapy, particularly targeting at cluster of differentiation 19 (CD19), has shown significant efficacy in managing CLL, achieving prolonged remission and MRD negativity in certain patients. Nevertheless, obstacles like T-cell exhaustion, cytokine storm, and neural toxicity remain. To address these limitations, new strategies, including armored CAR-T cells and dual-target CARs, are under investigation. Additionally, combination therapies, such as includes combining treatment of CAR-T cells using BTK inhibitors, offer the possibility of increased effectiveness. This investigation assesses the current developments combined with the prospective developments of CAR-T treatment in managing CLL, emphasizing its transformative potential while acknowledging the ongoing difficulties. Emerging trends in the design of CAR-T cells and clinical outcomes may eventually improve patient outcomes, positioning CAR-T therapy crucial therapeutic substitute for CLL in future.

Keywords: CAR-T therapy, CD19, Chronic lymphocytic leukemia, Immunotherapy, T-cell exhaustion, Cytokine release syndrome, Neurotoxicity, Minimal residual disease, Dual-target CARs, BTK inhibitors, Relapsed CLL

INTRODUCTION: The current findings from the database known as Surveillance, Epidemiology, and End Results (SEER) reveal that standardized for age CLL occurrence rates 4.9 cases per 100,000 people annually, making it one of the most commonly diagnosed kinds of leukaemia. The average age at which CLL is diagnosed at 70 years, and only 9.1% of cases occur in individuals under the age of 45 is also more prevalent in men, with a male to female proportion is 1.9:1, a trend observed consistently across all ethnicities ¹.

Around 0.6% of both men and women are predicted to receive a diagnosis of CLL at several stages in their life. The United States was expected to have 21,250 newly diagnosed CLL cases by 2021, as per SEER, accounting for 1.1% of all newly diagnosed cancers. In 2018, approximately 195,129 individuals were estimated to be living with CLL in the U.S. Although the occurrence of CLL has remained constant over the past twenty years, the death rate has been decreasing.

In 2021, CLL is expected to result in 4,320 deaths, comprising 0.7% of overall cancer-related deaths with 1.1 fatalities per 100,000 individuals annually. The five-year relative survival rate for CLL patients was 65.1% in 1975 and has shown a continuous improvement over the years, reaching an estimated 87.2% in 2021 ². CLL is a type of cancer that affects CD5+ B cells, which a type of cancer causes the development of fragile, appearing-looking lymphocytes within blood, and lymphatic tissue. As the illness progresses, it is influenced by signals through surface immunoglobulin an essential component of the B cell receptor along with various genetic alterations. Moreover, CLL cells existence can be attributed to various types of cells, encompassing T cells, stromal cells, and nurse-like within lymph nodes, which contribute to the advancement of the disorder. Innovative treatments such as CAR-T cell treatment have been introduced to medical community, delivering immensely efficient and durable therapeutic outcomes ³.

CAR-T cell therapy become as an innovative strategy for the cure of different varieties of blood cancer, such as CLL ⁴. CAR-T cell treatment serves as immunomodulator treatment; the process of genetic engineering is utilized to alter patients’ antibody receptors on T cells, facilitating them to identify tumor cells. This modification allows T-cells to detect and apoptosis CLL cells, offering a powerful, targeted approach that can address some of the challenges associated with conventional treatments such as chemotherapy and monoclonal antibodies ⁵. For patients with CLL, particularly those experiencing relapsed or refractory illness, CAR-T therapy has shown impressive results, offering hope for remission in cases resistant to other forms of therapy ⁶.

CAR-T cells specifically focus on the protein CD19, frequently located in B cells, and have demonstrated significant efficacy in CLL, showing prolonged survival and remission in some patients. Although promising, CAR-T treatment for CLL presents obstacles, including risks of serious complications including hypercytokinemia and neurological damage, along with issues related to the durability of response in certain cases ⁷.

Currently, FDA-approved second-generation CAR-T medical treatments are utilized to treat those suffering from B-cell lymphomas. One example, Axicabtagene Ciloleucel (axi-cel), employs a single-chain variable fragment (scFv) bind to CD19 and includes both a CD3ζ signaling domain and CD28 co-stimulatory domain. Another recently approved treatment, Brexucabtagene Autoleucel, also uses an scFv domain targeting CD19 and contains the same CD3ζ signaling and CD28 co-stimulatory domains ⁸.

The Mechanism of CAR-T Cells in CLL Treatment: CAR-T-cell treatment has become groundbreaking remedy for multiple blood malignancies, offering patients hope for challenging illnesses ⁹. In the framework of CLL, therapy of CAR-T cell presents a transformative approach that can lead to long-lasting remission, even in individuals who have exhausted all other treatment options. This therapy involves enhancing patients own T cells, enabling more effectively recognize and attack cancerous cells ¹⁰.

Specifically, a CAR-T cell is genetically modified to generate a receptor capable of targeting antigens like CD19 on CLL cells, marking them for destruction ¹¹. This unique ability to identify cancer cells permits CAR-T cells to efficiently detect and eliminate malignant cells ¹². For CLL patients, therapy with CAR-T cells manifested encouraging outcomes, particularly in cases of recurrent or refractory disease-meaning cancer that has returned after treatment or is unresponsive to standard therapies ¹³.

Some CLL patients have experienced durable subsidence after CAR-T-cell treatment, with the disease remaining controlled and undetectable for extended periods ¹⁴. CAR-T cells are able to destroy malignant cells to the extent of achieving minimal residual disease (MRD) negativity, which is often associated with better long-term outcomes ¹⁴. Although promising, CAR-T cell treatment in CLL presents several challenges. Response rates in CLL have generally been lower than those observed in other blood cancers, such as acute lymphoblastic leukemia (ALL) ¹⁵. This discrepancy is partly due to T-cell exhaustion-a condition common in CLL, where T cells become less effective due to prolonged exposure to cancer cells ¹⁶.

Adverse reaction, likes cytokine release syndrome (CRS) and also neurological toxicity are common. CRS can cause intense flu-like symptoms, while neurotoxicity may result in brain-related complications. These side effects require close monitoring and timely intervention but are generally manageable in clinical settings ¹⁷.

To promote effectiveness of CAR-T-cell therapy in CLL, Investigators are designing new strategies, like dual-target CARs that can detect multiple antigens. This reduces the likelihood of cancer evading treatment. Innovations in CAR design, such as armored CAR-T cells release cytokines to support their own survival, are also being explored. Current clinical studies are investigating the benefits of CAR-T cells with BTK inhibitors, aiming to develop more effective and comprehensive treatment approaches ¹⁸.

Although CAR-T-cell therapy not effective for all patients CLL particularly those with certain comorbidities-it offers a personalized and potentially transformative treatment pathway. The therapy represents a highly individualized approach, as T cells of each patient’s are unique, making CAR-T-cell therapy both powerful and complex option. With ongoing research, CAR-T-cell therapy has the potential to enhance results for patients diagnosed with CLL and may eventually become a widely accessible treatment option ¹⁹.

Optimizing CAR-T-Cell Treatments: Bypassing Significant Histocompatibility Complex (MHC) and Integrating CD28 Co-Stimulatory Signals for Effective Cancer Targeting: CAR-T-cell treatment employs genetically modified T cells that target and eliminate cancerous cells, bypassing the requirement for antigen presentation through MHC pathway. In contrast to natural T-cell receptor (TCR)-mediated recognition, CARs (chimeric antigen receptors) directly bind to Targeted antigens present on cancer cells without requiring MHC-TCR interaction Fig. 1 ²⁰.

FIG. 1: INTERACTION BETWEEN ANTIGEN-PRESENTING CELL AND T CELL

In natural T-cell activation, the T-cell receptor (TCR) identify peptide antigens displayed on the membrane of antigen-presenting cells (APCs) by MHC molecules. However, stimulation through co-stimulatory signaling is also necessary, which is triggered by the interaction between B7-1 (CD80) on the APC and CD28 on the T cell. This dual-signal system ensures proper immune activation and prevents autoimmunity or anergy (a state of non-responsiveness) ²¹. CAR-T-cell designs incorporate molecule like CD28 and 4-1BB acts as co-stimulatory domains that facilitate the proliferation of T cells, persistence, and cytotoxic function. Natural co-stimulatory mechanisms of enhancing the overall effectiveness of the therapy are mimicked by these domains ²².

CAR-T-Cell Development: Optimizing process and functions CAR-T-cell therapy has accomplishes significant progress since its initial development, primarily through advances in design that enhance both its efficacy and safety ²³. Early generations of the CAR-T cells, including those who target CD19 antigen, lacked built-in co-stimulatory domains, which are critical for fully activating T cells and sustaining their antitumor response ²⁴. Without these domains, early generation CAR-T cells unable to elicit robust and durable responses, limiting their effectiveness in treating malignancies ²⁵.

The second generation CD19-targeted CAR-T cells development marked a substantial improvement by incorporating CD28 or 4-1BB (CD137), co-stimulatory domains ²⁶. These domains augment the actuation signal delivered by the chimeric antigen receptor, ensuring that T cells not only recognize the target antigen but also undergo sustained proliferation and exhibit potent cytotoxic activity Fig. 2 ²⁷. Anti-CD19 CAR-T cells have ability of treating blood-related cancers, including non-Hodgkin lymphoma (NHL), as malignant B cells commonly expressed as CD19. This achievement demonstrates CAR-T-cell therapy, a promising approach in the field of cancer treatment ²⁸.

FIG. 2: MECHANISM OF CAR T CELLS IMMUNOTHERAPY FOR CD19-EXPRESSING CANCEROUS B CELLS

Targeted CAR-T cells-Modern CD19 continue to evolve through refined co-stimulatory signaling for optimal therapeutic outcomes. The selection of the co-stimulatory domain significantly impacts the functional behavior of anti-CD19 CAR-T cells, influencing factors such as the risk of toxicities like CRS and immune effectors cell-associated neurotoxicity syndrome (ICANS), as well as their proliferation kinetics and long-term persistence in the body ²⁹.

CD28-based anti-CD19 CAR-T cells tend to proliferate rapidly and demonstrate strong antitumor effects but may be linked to increase the probability of severe toxicities. In contrast, 4-1BB-based CAR-T cells exhibit slower but more sustained activation, which is generally linked to reduced toxicity and longer persistence, making them more suitable for certain patient populations ³⁰.

A critical consideration in designing anti-CD19 CAR-T cells is striking a balance between safety and efficacy. While strong T-cell activation is essential for effective tumor elimination, excessive activation can lead to serious immune-related toxicities ³¹. Therefore, the selection of co-stimulatory domains must be tailored to the specific therapeutic context, considering factors such as cancer type, the patient’s overall medical condition and the associated risk of adverse effects ³². Ongoing research is also exploring next- Development of CAR-T cells anti-CD19 using enhancements such as dual co-stimulatory domains or cytokine-secreting functions, aimed at further improving their therapeutic profile ³³.

In conclusion, the evolution of CAR-T cells anti-CD19 therapy is being driven by innovations in co-stimulatory domain integration, which play essential role in achieving effective T-cell stimulation as well as clinical efficacy. These advancements have not only improved the therapeutic potential of CAR-T-cell immunotherapy but have also expanded its applicability to a broader range of CD19-positive malignancies ³⁴. Future developments will likely focus on fine-tuning these components to reduce side effects and maximize therapeutic outcomes, opening the door towards safer and more effective treatments ³⁵.

Logistics of CAR-T-cell Therapy: Through genetic modification, CAR-T-cell therapy alters a patient's T cells to produce a receptor that recognizes a particular antigen found on tumor cell surfaces. In CLL, the most commonly targeted antigen is CD19, a protein typically present on the surface of B cells, including malignant CLL cells. The purpose of the modified T cells is to recognize and attach to CD19, initiating a cascade of immunological reactions that eradicate CLL cells ³⁶. T cells are extracted from the patient during the apheresis procedure, and the collected T cells are subsequently then genetically engineered in a laboratory to express CARs ³⁷. T cells are then genetically engineered in the laboratory to express chimeric antigen receptors (CARs). A CAR is typically composed of three main structural elements: an intracellular signaling domain that triggers T-cell activation, a trans-membrane domain which triggers T-cell activation and , and an antigen-binding domain-often derived from monoclonal antibodies-which enables antigen recognition and triggers effect or functions Fig. 3.

FIG. 3: STEPS INVOLVED IN CAR T-CELL THERAPY FOR CLL

After being reinfused, the modified T cells travel through the patient's bloodstream, actively seeking out and binding to CLL cells that express CD19 on their surface ³⁸. CAR-T-cell activation begins when CD19 is bound. The CAR’s antigen-binding domain recognizes and binds to the CD19 antigen on the CLL cell, causing a conformational change in the receptor ³⁹. This triggers domain of the intracellular signaling, which includes chain of the CD3ζ. T-cell activation, cytokine release, and The creation of an immunological synapse connecting the CAR-T cell to the target CLL cell are all initiated by the signaling cascade triggered by CD3ζ. As a result, cytotoxic proteins such as granzymes and perforin are released, the initiation of apoptosis within the target CLL cell ⁴⁰. Activated CAR-T cells not only eliminate CLL cells directly but also produce cytokines namely TNF-α and IFN-γ that enhance immune response ⁴¹. These cytokines help draw more immune cells to the tumor location, strengthening the overall anti-cancer response. Co-stimulatory molecules, such as CD28 or 4-1BB, incorporated into the CAR design, are essential for activation, proliferation, and persistence of T-cell. The long-term survival and function of CAR-T cells in the body are supported by these mechanisms, ensuring continued defense against residual CLL cells ⁴².

Activity of CAR-T-cell is highly efficient because of its ability to selectively target CD19-expressing CLL cells while sparing normal, non-malignant cells ⁴³. However, challenges remain, such as relapse caused by antigen escape (e.g., down regulation of CD19) or the immunosuppressive tumor microenvironment. Despite these obstacles, mechanism in which CAR-T cells involve detection and elimination of CLL cells represents a highly promising and evolving approach for relapsed or refractory CLL treatment ³³.

Difficulties and Restrictions of CAR-T-cell Immunotherapy in CLL: CAR-T-cell treatment for CLL is challenging due to the disease’s unique biology and immunology. The tumor microenvironment (TME) is characterized by a high concentration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and immunosuppressive cytokines such as IL-10 and TGF-β, posing a significant challenge. These components inhibit the immune system, making antitumor immune responses less effective ⁴⁴. This environment suppresses CAR-T-cell activation and proliferation while promoting T-cell exhaustion, so that therapeutic efficacy may be reduced. Furthermore, the chronic nature of CLL leads to widespread immune dysfunction, including hypogammaglobulinemia and impaired T-cell cytotoxicity, which further limits CAR-T-cell effectiveness ^{45, 46}.

The Tumor Microenvironment (TME): Antigen escape is another critical challenge, wherein malignant CLL cells lose expression of CD19, the primary target of the vast majority of CAR-T-cell therapies ⁴⁷. This results in tumor evasion and disease relapse. Emerging strategies, such as CAR-T cells dual-targeting and those genetically modified to target various tumor-associated antigens, are being investigated to address this issue but remain primarily experimental ⁴⁸.

Additionally, the slow progression of CLL and its associated immune dysregulation make it more difficult to maintain the robust antitumor responses observed in other hematologic malignancies ⁴⁹. Toxicity concerns also hinder the broader application of CAR-T-cell therapy in CLL. CRS and immune effect or cell-associated neurotoxicity syndrome (ICANS) are frequent complications, particularly in elderly individuals or those with comorbidities ⁵⁰. These toxicities are exacerbated by the need for higher CAR-T-cell doses to overcome the suppressive microenvironment, increasing the severe adverse effects risk. Efforts to mitigate these toxicities include the CAR-T cells development with safety mechanisms, like inducible safety switches, or the incorporation of co-stimulatory domains like 4-1BB, which promote controlled activation and proliferation ⁵¹.

CLL patients, another major challenge lies in manufacturing process of CAR-T cells. The T cells extracted from CLL patients are often dysfunctional, exhibiting markers of exhaustion and poor proliferative capacity. This diminishes CAR-T cell’s therapeutic potential of once engineered as well as reinfused. Enhancing T-cell quality through cytokine supplementation (e.g., IL-7 and IL-15) or optimizing preconditioning regimens during manufacturing are strategies currently under investigation. Moreover, the production process itself is time-consuming and expensive, creating logistical barriers to widespread clinical application ⁵².

Finally, achieving durable responses in CLL patients remains a significant hurdle. Compared to diseases like acute lymphoblastic leukemia (ALL), where therapy of CAR-T-cell has yielded high expansion and remission rates, outcomes in CLL are less consistent. Factors such as reduced proliferation of CAR-T cells and limited persistence in the patient contribute to this variability. This necessitates further research to optimize both CAR design and therapeutic protocols. This section highlights the core challenges without concluding remarks, maintaining focus solely on the limitations of CAR-T-cell therapy in CLL.

Current Research and Advances in CAR-T-Cell Therapy for CLL:

Combination Strategies for Enhanced Efficacy: Recent studies have demonstrated that combining CAR-T-cell therapy with other treatments, such as tyrosine kinase inhibitors (TKIs) like ibrutinib, can significantly improve outcomes in CLL. This approach restores T-cell functionality, enhances CAR-T-cell persistence, and reduces severe toxicities such as CRS. Preclinical and clinical trials have shown that concurrent administration of ibrutinib with CAR-T-cell therapy increases complete response rates while lowering toxicity profiles ⁵³.

Next-Generation CAR Designs: The immunosuppressive microenvironment in CLL presents a significant challenge for CAR-T-cell efficacy. Researchers are exploring methods to counteract this, including modifying CAR-T cells to secrete pro-inflammatory cytokines or resist inhibitory signals, thereby maintaining their functionality in hostile tumor environments ​ ⁵⁴.

Addressing Immunosuppressive Micro-environments: The immunosuppressive microenvironment in CLL presents a significant challenge for CAR-T-cell efficacy. Researchers are exploring methods to counteract this, including modifying CAR-T cells to secrete pro-inflammatory cytokines or resist inhibitory signals, thereby maintaining their functionality in hostile tumor environments ^{44, 55}.

Preconditioning Regimens for Better Outcomes: Optimized lymphodepletion strategies prior to CAR-T-cell infusion are investigated to increase CAR-T-cell engraftment and expansion. Conditioning regimens using agents like Fludarabine and cyclophosphamide have shown promise in developing a more advantageous for CAR-T-cell activation as well as multiplication in CLL patients ⁵⁶.

Minimal Residual Diseases (MRD) function in Monitoring: Achieving undetectable minimal residual disease (uMRD) has been identified as a strong predictor of long-term progression-free survival (PFS) and overall survival (OS) in CLL patients treated with CAR-T cells. Recent trials have focused on using MRD status as a marker to refine patient selection and optimize therapy protocols ⁵⁷.

Dual-Targeting CAR-T-Cell Therapies: Emerging dual-targeting CAR-T cells, designed to recognize multiple antigens on CLL cells, are being tested to address antigen escape is a prevalent resistance mechanism. These constructs aim to provide broader tumor coverage and prevent relapse due to the loss of a single target antigen ⁵⁸.

CAR-T-Cell Therapy in Richter Transformation (RT): In patients with Richter transformation (RT), where CLL evolves into an aggressive lymphoma, CAR-T-cell therapy has shown promise. There have been reports of high response rates in clinical trials employing CD19-targeted CAR-T cells, although the durability of responses remains an area of ongoing investigation​ ⁵⁹.

Overcoming Resistance Mechanisms: Research is focusing on overcoming resistance mechanisms in CLL, such as defective T-cell activation and antigen down regulation. Among the strategies are engineering CAR-T cells with enhanced signalling capabilities and integrating genetic modifications to counteract resistance ⁶⁰.

Safety Innovations: To lessen the possibility of serious toxicities like CRS and immune effect or cell-associated neurotoxicity syndrome (ICANS), novel CAR-T-cell constructs incorporate safety switches and is designed for controlled activation. This ensures a more predictable and safer therapeutic response​ ⁶¹.

Clinical Trials and Future Directions: Ongoing clinical trials are testing CAR-T cells targeting alternative antigens beyond CD19, such as CD20 and ROR1, for relapsed or refractory CLL. These trials aim to increase the applicability of therapy of CAR-T-cell and improve outcomes for those who don't react to the present CD19-targeted approaches ⁶².

Bristol Myers Squibb® is a Pioneering Treatment for Recurring or Untreated Small Lymphocytic Lymphoma and CLL using CAR-T Cells: Bristol Myers Squibb's Breyanzi^® the FDA has accelerated clearance for (lisocabtagene maraleucel; liso-cel) as one and only CAR-T cell treatment for people with refractory or relapsed CLL or small lymphocytic lymphoma (SLL). After minimum of two previous lines of treatment, including B-cell lymphoma 2 (BCL-2) and bruton tyrosine kinase (BTK), This approval marks a notable advancement in treatment CLL and SLL, as there has historically been a lack of established standard therapies for patients who have become refractory or relapsed after these targeted treatments. Breyanzi offers a personalized, one-time infusion with the potential for durable and deep responses, addressing the critical unmet need for patients in this setting.

The crucial TRANSCEND CLL 004 trial is the first extensive investigation to assess CAR-T-cell treatment for people with refractory or relapsed CLL or small lymphocytic lymphoma (SLL). In this trial, 20% of patients had a complete response (CR); however, the median CR duration has yet to be determined. The total response rate was 45%, with a median duration of response (DOR) of 35.3 months. Importantly, Patients having a CR had elevated levels of negative MRD, suggesting that Breyanzi can provide not only a response but potentially long-term remission for those with these challenging malignancies. Breyanzi is now approved for CLL and SLL, in addition to its earlier clearance for relapsed or refractory large B-cell lymphoma (LBCL), broadening its treatment options for B-cell malignancies. The treatment entails collecting the patient's T cells by leukapheresis, genetically modifying them for production of CAR-T cells, and administering them again. The TRANSCEND CLL 004 study found that this one-time infusion had tolerable safety issues, such as CRS and low-grade neurological episodes (NEs). These findings highlight CAR-T cell treatments as a promising therapy for relapsed or refractory blood malignancies, providing hope to patients with limited alternatives.

Breyanzis approval is a significant advancement in treatment of CLL and SLL, Changing the framework for of treatment from ongoing therapy with successive regimens to a customized, T-cell-based strategy that is administered once. This innovative therapy approach could significantly benefit patients, lasting remission, offering a promising alternative for those who have exhausted other treatment options. Furthermore, Bristol Myers Squibb continues to support patients and healthcare providers through digital platforms and resources aimed at improving access to treatment and enhancing the overall care experience ⁶³.

Aurigene Oncology's Ribrecabtagene Autoleucel Gains DCGI Approval for Phase-2 Trials in Myeloma: The Drugs Controller General of India (DCGI) has authorized Aurigene Oncology Limited, a division of Dr. Reddy's Laboratories, to start phase-2 clinical trials for Ribrecabtagene autoleucel, a pioneering treatment using autologous BCMA-directed CAR-T cells in India. This study expands on the successful phase 1 trial for multiple myeloma patients who have relapsed or are resistant, where all eight patients showed clinical responses, and five achieved stringent complete responses. No high-grade safety concerns were noted. Aurigene's CAR-T GMP facility in Bengaluru manufactures the treatment, which includes a humanized single-domain antibody for antigen binding and a lentivirus vector for gene transfer. This medication provides hope for individuals with advanced multiple myeloma, particularly those who have failed earlier regimens ⁶⁴.

Future of CAR-T-Cell Therapy for CLL: To enhance therapy of CAR-T-cell for treatment of CLL, there is a focus on improving the accessibility and scalability of this innovative treatment. The innovation of allogeneic "off-the-shelf" products of CAR-T-cell is a transformative advancement that reduces production time and costs. These ready-made treatments aim to overcome the hindrance  of individualized autologous CAR-T-cell therapies, which are time-consuming and resource-intensive. Reducing graft-versus-host disease (GvHD) and immunological rejection in allogeneic treatments is critical for their widespread use. Automation and optimized manufacturing processes are being investigated to standardize CAR-T-cell production, ensuring uniform quality and scalability, which will increase patient access.

To address resistance and recurrence, researchers are studying immune evasion mechanisms in CLL cells and developing novel CAR-T-cell designs. Strategies include preventing T-cell depletion and targeting resistant CLL cells that result from genetic or phenotypic alterations. Combination therapies such as immune checkpoint inhibitors, CAR-T cells, monoclonal antibodies, as well as tyrosine kinase inhibitors such as ibrutinib, show potential. These combinations aim to enhance treatment outcomes, increase CAR-T-cell activity, and reduce side effects, including CRS.

The immunosuppressive tumor microenvironment in CLL presents a considerable challenge for CAR-T-cell effectiveness. The microenvironment, which involve inhibitory cytokines, myeloid-derived suppressor cells, and regulatory T cells, which hinder treatment efficiency. To overcome these limitations, innovations such as inhibition of immune checkpoint, cytokine manipulation, and the creation of CAR-T cells with immune stimulatory capabilities are being explored. Researchers aim to improve treatment outcomes by enhancing CAR-T cells' ability to function in unfavourable conditions.

CRISPR-Cas9 technology is revolutionizing therapy of CAR-T-cell which empowers more precise and complex constructs. Modifications made through this technology can improve CAR-T-cell selectivity, minimize off-target effects, and increase resistance to immune evasion. Advancements in gene editing are facilitating the development of universally available CAR-T-cell products, which could further streamline therapy production and reduce costs. Additionally, the integration of machine learning and predictive analytics is helping identify biomarkers that guide patient selection and optimize treatment regimens. These tools also improve the precision of monitoring residual disease, ensuring timely adjustments to therapeutic strategies.

Exploring epigenetic modification as a supplement to therapy of CAR-T-cell is a encouraging avenue. Epigenetic regulators can make tumor cells extra liable to CAR-T-cell-mediated death or boost the immune response to CLL. Long-term surveillance of CAR-T cells treated patients is crucial for identifying variables that impact long-term remissions and relapses. Continuous evaluation is essential for refining therapy regimens and maintaining treatment success. Collaboration across disciplines, such as oncology, immunology, bioengineering, and data analytics, is vital to achieve the optimal impact of therapy CAR-T-cell. These partnerships drive innovation by addressing complex issues such as antigen targeting, toxicity control, and therapeutic customization. set to play a pivotal role in the management of CLL, making it more manageable and improving patient outcomes.

CONCLUSION: CLL remains a significant challenge in clinical oncology, particularly for individuals with recurrent or treatment-resistant disease. CAR-T-cell therapy has yielded hopeful results in treating CLL, offering a targeted as well as personalized approach to immunotherapy. CD19 targeted by CAR-T cells have showed substantial therapeutic benefits, including long-term remission and the achievement of minimal residual disease (MRD) negativity in certain individuals. Nevertheless, the therapy presents several challenges, such as T-cell exhaustion, significant adverse effects associated with CAR-T-cell therapy like CRS, and neurotoxicity,   necessitating vigilant monitoring and clinical oversight.

To address these limitations, current research is Concentrated on strengthening CAR-T-cell development, enhancing efficacy through dual-targeting strategies and armored CAR constructs, and exploring combination therapies-incorporating CAR-T cells therapy  in combination with BTK inhibitors.

Although therapy CAR-T-cell offers personalized along with potentially transformative outcomes, further studies are necessary to improve its accessibility and broaden its applicability to a wider population of CLL patients. With continued advancements, CAR-T-cell therapy has the ability to significantly upgrade both survival rates and personal well-being of individuals with CLL.

ACKNOWLEDGEMENTS: The authors would like to thank Formulation and Development Department, for their kind support.

Author Contributions: All authors contributed significantly to the development of this manuscript. Conducted the primary literature review and drafted the initial version of the manuscript, focusing on the epidemiology, clinical challenges, and current treatment landscape of chronic lymphocytic leukaemia (CLL). Provided critical analysis and interpretation of recent advancements in CAR-T cell therapy, including mechanisms, therapeutic targets such as CD19, and associated toxicities. Also contributed to the discussion on emerging strategies, such as armored and dual-target CAR-T cells, as well as the role of combination therapies with BTK inhibitors. All authors reviewed and edited the manuscript for intellectual content and approved the final version for submission.

CONFLICTS OF INTERESTS: The authors declare that they have no competing interests.

REFERENCES:

1. Hallek M and Al-Sawaf O: Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. Am J Hematol [Internet]. 2021 Dec 1 [cited 2024 Nov 5]; 96(12):1679–705. Available from: https://pubmed.ncbi.nlm.nih.gov/34625994/
2. Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G and Wierda WG: Chronic lymphocytic leukaemia. Nat Rev Dis Primers [Internet]. 2017 Jan 19 [cited 2024 Nov 9]; 3. Available from: https://pubmed.ncbi.nlm.nih.gov/28102226/
3. June CH, O’Connor RS, Kawalekar OU, Ghassemi S and Milone MC: CAR T cell immunotherapy for human cancer. Science [Internet]. 2018 Mar 23 [cited 2024 Nov 9]; 359(6382):1361–5. Available from: https://pubmed.ncbi.nlm.nih.gov/29567707/
4. Borogovac A and Siddiqi T: Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them. Cancer Drug Resistance [Internet]. 2024 [cited 2024 Nov 9]; 7: 18. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11149098/
5. Jogalekar MP, Rajendran RL, Khan F, Dmello C, Gangadaran P and Ahn BC: CAR T-Cell-Based gene therapy for cancers: new perspectives, challenges, and clinical developments. Front Immunol [Internet]. 2022 Jul 22 [cited 2024 Nov 9]; 13: 925985. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9355792/
6. Borogovac A and Siddiqi T: Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them. Cancer Drug Resistance [Internet]. 2024 [cited 2024 Nov 9]; 7: 18. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11149098/
7. Cappell KM and Kochenderfer JN: Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol [Internet]. 2023 Jun 1 [cited 2024 Nov 9]; 20(6): 359. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10100620/
8. Heyman BM, Tzachanis D and Kipps TJ: Recent Advances in CAR T-Cell Therapy for Patients with Chronic Lymphocytic Leukemia. Cancers (Basel) [Internet]. 2022 Apr 1 [cited 2024 Nov 9]; 14(7): 1715. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8996890/
9. Zhu S: CAR-T in cancer therapeutics and updates. Journal of the National Cancer Center 2024; 4(3): 189–94.
10. Mitra A, Barua A, Huang L, Ganguly S, Feng Q and He B: From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol [Internet]. 2023 [cited 2024 Nov 9]; 14: 1188049. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10225594/
11. Salter AI, Pont MJ and Riddell SR: Chimeric antigen receptor–modified T cells: CD19 and the road beyond. Blood [Internet]. 2018 Jun 14 [cited 2024 Nov 18]; 131(24):2621. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6032892/
12. Uscanga-Palomeque AC, Chávez-Escamilla AK, Alvizo-Báez CA, Saavedra-Alonso S, Terrazas-Armendáriz LD and Tamez-Guerra RS: CAR-T Cell Therapy: From the Shop to Cancer Therapy. Int J Mol Sci [Internet]. 2023 Nov 1 [cited 2024 Nov 18]; 24(21):15688. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10649325/
13. Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N and Djurdjevic P: CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings. Current Oncology [Internet]. 2022 May 1 [cited 2024 Nov 18]; 29(5): 3647. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9139644/
14. Cappell KM and Kochenderfer JN: Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol [Internet]. 2023 Jun 1 [cited 2024 Nov 18]; 20(6):359. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10100620/
15. Can I, Cox MJ, Siegler EL, Sakemura R and Kenderian SS: Challenges of chimeric antigen receptor T-cell therapy in chronic lymphocytic leukemia: lessons learned. Exp Hematol 2022; 108: 1–7.
16. Peters FS, Strefford JC, Eldering E and Kater AP: T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective. Haematologica [Internet]. 2021 May 1 [cited 2024 Nov 25]; 106(5): 1234. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8586819/
17. Spring J and Munshi L: Oncologic Emergencies: Traditional and Contemporary. Crit Care Clin 2021; 37(1): 85–103.
18. Jin X, Xie D, Sun R, Lu W, Xiao X and Yu Y: CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells. Oncoimmunology [Internet]. 2023 [cited 2024 Nov 25]; 12(1): 2248826. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10461507/
19. Dagar G, Gupta A, Masoodi T, Nisar S, Merhi M and Hashem S: Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments. Journal of Translational Medicine 2023 21: 1 [Internet]. 2023 Jul 7 [cited 2024 Nov 25]; 21(1):1–36. Available from: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04292-3
20. Shah K, Al-Haidari A, Sun J and Kazi JU: T cell receptor (TCR) signaling in health and disease. Signal Transduction and Targeted Therapy 2021 6:1 [Internet]. 2021 Dec 13 [cited 2024 Nov 25]; 6(1):1–26. Available from: https://www.nature.com/articles/s41392-021-00823-w
21. Zhang YQ, Van Neerven RJJ, Van Gool SW, Coorevits L, De Boer M and Ceuppens JL: B7-CD28 interaction is a late acting co-stimulatory signal for human T cell responses. Int Immunol [Internet]. 1997 [cited 2024 Nov 25]; 9(8): 1095–102. Available from: https://pubmed.ncbi.nlm.nih.gov/9263006/
22. Sterner RC and Sterner RM: CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal 2021 11:4 [Internet]. 2021 Apr 6 [cited 2024 Nov 25]; 11(4):1–11. Available from: https://www.nature.com/articles/s41408-021-00459-7
23. Bui TA, Mei H, Sang R, Ortega DG and Deng W: Advancements and challenges in developing in-vivo CAR T cell therapies for cancer treatment. EBioMedicine 2024; 106: 105266.
24. Han X, Wang Y, Wei J and Han W: Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy. J Hematol Oncol [Internet]. 2019 Nov 29 [cited 2024 Dec 6]; 12(1):1–10. Available from: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0813-7
25. Sadelain M, Brentjens R and Rivière I: The basic principles of chimeric antigen receptor design. Cancer Discov [Internet]. 2013 Apr 1 [cited 2024 Dec 6]; 3(4): 388–98. Available from: /cancerdiscovery/article/3/4/388/3902/The-Basic-Principles-of-Chimeric-Antigen-Receptor
26. Lesch S, Benmebarek MR, Cadilha BL, Stoiber S, Subklewe M and Endres S: Determinants of response and resistance to CAR T cell therapy. Semin Cancer Biol 2020; 65: 80–90.
27. Finney HM, Akbar AN and Lawson ADG: Activation of Resting Human Primary T Cells with Chimeric Receptors: Costimulation from CD28, Inducible Costimulator, CD134, and CD137 in Series with Signals from the TCRζ Chain. The Journal of Immunology [Internet]. 2004 Jan 1 [cited 2024 Dec 6]; 172(1): 104–13. Available from: https://dx.doi.org/10.4049/jimmunol.172.1.104
28. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB and Jacobson CA: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med [Internet]. 2017 Dec 28 [cited 2024 Dec 6]; 377(26): 2531–44. Available from: https://pubmed.ncbi.nlm.nih.gov/29226797/
29. Dagar G, Gupta A, Masoodi T, Nisar S, Merhi M and Hashem S: Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments. Journal of Translational Medicine 2023 21:1 [Internet]. 2023 Jul 7 [cited 2024 Dec 6]; 21(1): 1–36. Available from: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04292-3
30. Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC and Gunset G: Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells. Cancer Cell [Internet]. 2015 Oct 12 [cited 2024 Dec 6]; 28(4): 415–28. Available from: https://pubmed.ncbi.nlm.nih.gov/26461090/
31. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C and Locke FL: Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nature Reviews Clinical Oncology 2017 15:1 [Internet]. 2017 Sep 19 [cited 2024 Dec 6]; 15(1):47–62. Available from: https://www.nature.com/articles/nrclinonc.2017.148
32. June CH, O’Connor RS, Kawalekar OU, Ghassemi S and Milone MC: CAR T cell immunotherapy for human cancer. Science [Internet]. 2018 Mar 23 [cited 2024 Dec 6]; 359(6382): 1361–5. Available from: https://pubmed.ncbi.nlm.nih.gov/29567707/
33. Tomasik J, Jasiński M and Basak GW: Next generations of CAR-T cells - new therapeutic opportunities in hematology? Front Immunol [Internet]. 2022 Oct 28 [cited 2024 Dec 6]; 13: 1034707. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9650233/
34. Sadelain M, Brentjens R and Rivière I: The basic principles of chimeric antigen receptor design. Cancer Discov [Internet]. 2013 Apr 1 [cited 2024 Dec 6]; 3(4): 388–98. Available from: /cancerdiscovery/article/3/4/388/3902/The-Basic-Principles-of-Chimeric-Antigen-Receptor
35. Zheng Z, Li S, Liu M, Chen C, Zhang L and Zhou D: Fine-Tuning through Generations: Advances in Structure and Production of CAR-T Therapy. Cancers (Basel) [Internet]. 2023 Jul 1 [cited 2024 Dec 6]; 15(13): 3476. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10340266/
36. Sterner RC and Sterner RM: CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal 2021l 11: 4.
37. DeSimone RA, Racine-Brzostek SEWA and Pham HP: Therapeutic Apheresis. Immunologic Concepts in Transfusion Medicine 2020; 239–49.
38. Wang C, Wang J, Che S and Zhao H: CAR-T cell therapy for hematological malignancies: History, status and promise. Heliyon 2023; 9(11): 21776.
39. Onea AS and Jazirehi AR: CD19 chimeric antigen receptor (CD19 CAR)-redirected adoptive T-cell immunotherapy for the treatment of relapsed or refractory B-cell Non-Hodgkin’s Lymphomas. Am J Cancer Res [Internet]. 2016 [cited 2024 Dec 8]; 6(2): 403. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC4859669/
40. Wu W, Zhou Q, Masubuchi T, Shi X, Li H and Xu X: Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy. Cell [Internet]. 2020 Aug 20 [cited 2024 Dec 8]; 182(4): 855-871.e23. Available from: http://www.cell.com/article/S0092867420308837/fulltext
41. Korell F, Berger TR and Maus MV: Understanding CAR T cell-tumor interactions: Paving the way for successful clinical outcomes. Med 2022; 3(8): 538–64.
42. Tang L, Pan S, Wei X, Xu X and Wei Q: Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development. Molecular Therapy 2023; 31(11): 3146–62.
43. Srivastava S and Riddell SR: CAR T Cell Therapy: Challenges to Bench-to-Bedside Efficacy. J Immunol [Internet]. 2018 Jan 15 [cited 2024 Dec 8]; 200(2): 459. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5957501/
44. Kankeu Fonkoua LA, Sirpilla O, Sakemura R, Siegler EL and Kenderian SS: CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities. Mol Ther Oncolytics [Internet]. 2022 Jun 16 [cited 2024 Dec 8]; 25: 69. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8980704/
45. Zenz T: Exhausting T cells in CLL. Blood [Internet]. 2013 Feb 28 [cited 2024 Dec 8]; 121(9): 1485–6. Available from: https://dx.doi.org/10.1182/blood-2013-01-475939
46. Collins MA, Jung IY, Zhao Z, Apodaca K, Kong W and Lundh S: Enhanced Costimulatory Signaling Improves CAR T-cell Effector Responses in CLL. Cancer Research Communications [Internet]. 2022 Sep 2 [cited 2024 Dec 8]; 2(9): 1089–103. Available from: /cancerrescommun/article/2/9/1089/709530/Enhanced-Costimulatory-Signaling-Improves-CAR-T
47. Xu X, Sun Q, Liang X, Chen Z, Zhang X and Zhou X: Mechanisms of Relapse After CD19 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia and Its Prevention and Treatment Strategies. Front Immunol 2019; 10: 495638.
48. van der Schans JJ, van de Donk NWCJ and Mutis T: Dual Targeting to Overcome Current Challenges in Multiple Myeloma CAR T-Cell Treatment. Front Oncol 2020; 10: 534747.
49. Langerbeins P and Eichhorst B: Immune Dysfunction in Patients with Chronic Lymphocytic Leukemia and Challenges during COVID-19 Pandemic. Acta Haematol [Internet]. 2021 Sep 1 [cited 2024 Dec 8]; 144(5): 1. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8018219/
50. Rees JH: Management of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). The EBMT/EHA CAR-T Cell Handbook [Internet]. 2022 Feb 7 [cited 2024 Dec 8]; 141–5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK584157/
51. Foster MC, Savoldo B, Lau W, Rubinos C, Grover N and Armistead P: Utility of a safety switch to abrogate CD19.CAR T-cell–associated neurotoxicity. Blood [Internet]. 2021 Jun 10 [cited 2024 Dec 8]; 137(23): 3306–9. Available from: https://dx.doi.org/10.1182/blood.2021010784
52. Huang Z, Dewanjee S, Chakraborty P, Jha NK, Dey A and Gangopadhyay M: CAR T cells: engineered immune cells to treat brain cancers and beyond. Molecular Cancer 2023 22:1 [Internet]. 2023 Jan 31 [cited 2024 Dec 8]; 22(1):1–27. Available from: https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01712-8
53. Xiao X, Wang Y, Zou Z, Yang Y, Wang X and Xin X: Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies. Front Immunol 2022; 13: 954235.
54. Hong M, Clubb JD and Chen YY: Engineering CAR-T Cells for Next-Generation Cancer Therapy. Cancer Cell 2020; 38(4): 473–88.
55. Kankeu Fonkoua LA, Sirpilla O, Sakemura R, Siegler EL and Kenderian SS: CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities. Mol Ther Oncolytics [Internet]. 2022 Jun 16 [cited 2024 Dec 22]; 25: 69. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8980704/
56. Fabrizio VA, Boelens JJ, Mauguen A, Baggott C, Prabhu S and Egeler E: Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv [Internet]. 2022 Apr 12 [cited 2024 Dec 22]; 6(7): 1961. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9006295/
57. Gill S, Vides V, Frey NV., Hexner EO, Metzger S and O’Brien M: Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv [Internet]. 2022 Nov 8 [cited 2024 Dec 22]; 6(21): 5774–85. Available from: https://dx.doi.org/10.1182/bloodadvances.2022007317
58. Simon S and Riddell SR: Dual Targeting with CAR T Cells to Limit Antigen Escape in Multiple Myeloma. Blood Cancer Discov [Internet]. 2020 Sep 1 [cited 2024 Dec 22]; 1(2): 130. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8447280/
59. Benjamini O, Fried S, Shouval R, Flynn JR, Beyar-Katz O and Leslie LA: Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma. Haematologica [Internet]. 2024 Jun 20 [cited 2024 Dec 22]; 109(11): 3566. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11532690/
60. Ruella M, Korell F, Porazzi P and Maus MV: Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies. Nat Rev Drug Discov [Internet]. 2023 Dec 1 [cited 2024 Dec 22]; 22(12): 976. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10965011/
61. Sterner RC and Sterner RM: Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. Front Immunol [Internet]. 2022 Aug 23 [cited 2024 Dec 22]; 13: 879608. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9445841/
62. Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N and Djurdjevic P: CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings. Current Oncology [Internet]. 2022 May 1 [cited 2024 Dec 22]; 29(5): 3647. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9139644/
63. Bristol Myers Squibb - U.S. FDA Approves Bristol Myers Squibb’s Breyanzi ® as the First and Only CAR T Cell Therapy for Adults with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) [Internet]. [cited 2024 Dec 22]. Available from: https://news.bms.com/news/details/2024/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Breyanzi--as-the-First-and-Only-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx
64. Dr Reddy’s co gets nod for cell therapy phase-2 trials - Times of India [Internet]. [cited 2024 Dec 22]. Available from: https://timesofindia.indiatimes.com/city/hyderabad/dr-reddys-laboratories-secures-phase-2-trial-approval-for-groundbreaking-car-t-cell-therapy/articleshowprint/114057713.cms
    

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    Bharat S, Jain R and Joshi N: Recent advancement and future perspective of car-t cell for management of chronic lymphocytic leukemia: a review. Int J Pharm Sci & Res 2026; 17(1): 145-56. doi: 10.13040/IJPSR.0975-8232.17(1).145-56.

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