Cell Chimeric Antigen Receptor Research Articles

Trogocytosis at crossroads: Navigating the duality in tumor-immune cell interactions.

Chimeric antigen receptor cell therapy: A revolutionary approach transforming cancer treatment to autoimmune disease therapy.

TPS7087 Background: Autologous CART options for patients with relapsed or refractory (R/R) T-cell lymphomas (TCL) have faced challenges such as T-cell fratricide during CART manufacture and safety concerns regarding depletion of normal T cells. To overcome these obstacles, we proposed a dual cell population CART product, which contained both autologous 4-1BB costimulated CART cells against CD5 and healthy T-cells, with both populations knocked out for CD5 (CRISPR-Cas9 CD5 short-guide RNA to delete CD5 - Senza5). In vivo experiments using the dual population product of (Senza5 CART5) demonstrated increased CART5 expansion and enhanced antitumor efficacy in TCL xenograft models compared to wild-type (WT) CART5. For clinical use, a novel 5-day manufacturing process was designed to obtain a less differentiated and less exhausted product, with enhanced in vivo expansion and fitness. Methods: A human phase I trial was designed to determine the safety, effectiveness and recommended phase 2 dose (RP2D) of Senza5 CART5 cells in participants with R/R TCL with ≥50% expression of CD5 on malignant cells, and no circulating CD5+ cells. Participants must have a suitable backup stem cell product or donor identified in the unlikely event of T-cell aplasia. Patients with prior allo HCT are currently excluded. Cohorts of patients are treated with escalating doses of Senza5 CART5 cells (3x10 6 to 1.25x10 8 ) using a Bayesian Optimal Interval design following lymphodepletion. The study will enroll and treat participants until a maximum of 9 participants are infused and evaluable for dose limiting toxicity (DLT) assessments at a given dose level, or a maximum of 30 DLT-evaluable participants from all dose levels are infused. The RP2D will be determined based on both safety and biological evidence of efficacy. Study objectives include frequency and severity of treatment-related adverse events, as well as efficacy by assessing overall and complete response rates, duration of response, progression-free and overall survival. Manufacturing feasibility will be determined by the frequency of product release failures and occurrence of dose failures (inability to meet targeted dose). Exploratory objectives will evaluate the persistence and trafficking of Senza5 CART5 cells in blood and tumor by characterizing the kinetics of the infused cells by flow cytometry and qPCR gene expression. We will perform profiling of the tumor microenvironment and measure systemic soluble cytokines before and after treatment. We will also assess the impact of CART5 on normal T cells, and the persistence of CD5KO untransduced T cells that are infused as part of the Senza5 CART5 product by multicolor flow cytometry and qPCR. The trial is sponsored by Vittoria Biotherapeutics and is registered at clinicaltrials.gov as NCT06420089. Enrollment in this trial has begun. Clinical trial information: NCT06420089 .

Malignant gliomas (MGs) are among the most aggressive primary brain tumors, characterized by a high degree of resistance to therapy and poor prognosis. In this work, we develop a mathematical model to investigate the dynamics of MG under the combined effects of chemotherapy and chimeric antigen receptor cell therapy. The proposed model is a five-dimensional dynamical system incorporating impulsive inputs that correspond to the clinical administration of chemotherapy and immunotherapy. We demonstrate the non-negativity of solutions for non-negative initial conditions, ensuring the biological relevance of the model. We show that if we apply both therapies only once, the trajectories are attracted to an invariant surface corresponding to the tumor carrying capacity. Conversely, under constant administration of both treatments, we identify parameter ranges in which tumor eradication is achievable. Furthermore, we numerically study various treatment combinations to determine optimal protocols at the population level. To this end, we generate a cohort of 104 virtual patients with model parameters sampled uniformly within clinically relevant ranges and carry out in silico trials. Our findings indicate that tumor growth rate, chemotherapy efficacy, and tumor-induced immunosuppression are the key determinants of survival outcomes. We believe that our results provide new theoretical insights into treatment optimization and offer a framework for refining the design of clinical trials for MG therapies.

Abstract Hairy cell leukemia variant (HCL-v) is a rare B-cell malignancy that is biologically distinct from the classical form (HCL-c) and presents unique treatment challenges. The characteristic genetic or molecular markers of classical HCL include CD11c, CD25, CD103, CD123, the BRAFV600E point mutation, and tartrate resistant acid phosphatase (TRAP) expression. However, HCLv cells have a low immunologic score and don’t carry the BRAFV600E mutation or express TRAP. Treatment with the purine nucleoside analogs (PNAs) is effective in a majority of HCLc patients, who can look forward to a normal lifespan. However, HCLv patients are resistant to this treatment, which likely contributes to the significantly shorter prognosis of 6-9 years, in addition to the relative lack of druggable targets. To address poor clinical outcomes for HCL-v patients, we aimed to test a novel cellular therapy for HCL-v. We recently developed a third generation BAFF-ligand chimeric antigen receptor (CAR-T) cell product. B-cell activating factor (BAFF) is a critical factor that promotes B-cell maturation and survival. BAFF binds to three receptors, including BAFF-Receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B-cell maturation antigen (BCMA). Because of the pro-survival signaling that BAFF enhances upon binding to its receptors, B-cell cancers tend to exploit this signaling, and serum BAFF levels are often elevated. In a panel of HCLv cell lines and patient-derived splenocytes, we found that HCLv cells have high expression levels of all three receptors. In co-culture assays with fluorescently labeled HCLv patient samples and cell lines, CAR-T cells express significantly elevated markers of degranulation (CD107a) and activation (CD69) and secrete elevated levels of pro-inflammatory cytokines and lytic enzymes relative to control T-cells. BAFF CAR-T cells also display significantly increased cancer cell killing relative to control T-cells. This enhanced cancer cell killing was also observed in an autologous model, where CAR-T cells were generated from a de-identified HCLv patient and co-cultured with the patients’ own cancer cells. Similar findings were seen in multiple novel in vivo HCL xenograft models, in which BAFF CAR-T cell treatment (intratumor or intravenous) resulted in decreased tumor burden without significant toxicities.While we have seen success in our in vivo models, we also aim to generate a novel patient-derived xenograft model of HCLv to more accurately model the disease, both for more CAR-T cell translational studies and for more basic investigations into HCLv mechanisms. An additional future direction is to explore whether our BAFF CAR-T cells, which bind three receptors can mitigate antigen escape, the process by which tumor cells downregulate a target to avoid killing. To do so, we will perform single and double receptor knockouts of BAFF-R, TACI, and BCMA and assess if cell killing is intact with in vitro co-culture assays. Citation Format: Claire Elizabeth Fritz, Derek P. Wong, Akshaya Radhakrishnan, Philip Rock, Richard Burack, Reshmi Parameswaran. BAFF ligand CAR-T cells for hairy cell leukemia variant treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6102.

Unlocking the potential of chimeric antigen receptor T cell engineering immunotherapy: Long road to achieve precise targeted therapy for hepatobiliary pancreatic cancers.

Chimeric antigen receptor (CAR) immune cell therapies have revolutionized oncology, particularly in hematological malignancies, yet their efficacy against solid tumors remains limited due to challenges such as dense stromal barriers and immunosuppressive microenvironments. With advancements in nanobiotechnology, researchers have developed various strategies and methods to enhance the CAR cell efficacy in solid tumor treatment. In this Review, we first outline the structure and mechanism of CAR-T (T, T cell), CAR-NK (NK, natural killer), and CAR-M (M, macrophage) cell therapies and deeply analyze the potential of these cells in the treatment of solid tumors and the challenges they face. Next, we explore how biomaterials can optimize these treatments by improving the tumor microenvironment, controlling CAR cell release, promoting cell infiltration, and enhancing efficacy. Finally, we summarize the current challenges and potential solutions, emphasize the effective combination of biomaterials and CAR cell therapy, and look forward to its future clinical application and treatment strategies. This Review provides important theoretical perspectives and practical guidance for the future development of more effective solid tumor treatment strategies.

Abstract: The world's one of the major causes of death are cancer. Cancer is still a complex disease over the years that needs to be cured. Traditional cytotoxic approaches, although they have been implemented for years for treating neoplastic diseases, yet are limited due to the intricacy and low efficiency of cancer cells. Researchers are thus compelled to seek more potent therapeutic strategies. Chimeric antigen receptor (CAR-T) cell therapy is one such innovative insight where T lymphocytes are altered genetically to target cancer cells. Despite the outstanding accomplishment in patients with haematological malignancies, CAR-T cell treatment has demonstrated minimal impact on solid tumours due to a number of obstacles, including proliferation, stability, trafficking, and fate within tumors. Furthermore, interactions between the host and tumour microenvironment with CAR-T cells significantly alter CAR-T cell activities. Designing and implementing these treatments additionally also requires a complex workforce. Overcoming these significant challenges, there is a requirement for innovative strategies for developing CAR-T cells with greater anti-tumour efficacy and reduced toxicity. In this chapter, the current advancement in CAR-T cell technology in order to increase clinical efficacy in both solid tumors and haematological, as well as possibilities to conquer the limits of CAR-T cell therapy in both solid and haematological tumours has been discussed.

Chimeric antigen receptor (CAR) T cells are revolutionizing cancer therapy, particularly for haematological malignancies, conferring durable and sometimes curative responses in patients with advanced-stage disease. The CAR T cell products currently approved for clinical use are all autologous and are often effective; however, in patients who are lymphopenic and/or heavily pretreated with chemotherapy, autologous T cells can be difficult to harvest in sufficient numbers or have functional impairments that might ultimately render them less efficacious. Moreover, autologous products take several weeks to produce, and each product can be used in only one patient. By contrast, allogeneic CAR T cells can be produced for many patients using T cells from a single healthy donor, can be optimized for safety and efficacy, can be instantly available for 'off-the-shelf' use and, therefore, might also be more cost-effective. Despite these potential advantages, the development of allogeneic CAR T cells has lagged behind that of autologous products, owing to the additional challenges such as avoiding graft-versus-host disease and host-mediated graft rejection. Over the past few years, the development of advanced genome-editing techniques has facilitated the generation of novel allogeneic CAR T cell products. Furthermore, CAR cell products derived from other cell types such as induced pluripotent stem cells and natural killer cells are being investigated for clinical use. In this Review, we discuss the potential of allogeneic CAR cell products to expand life-saving immunotherapy to a much broader population of patients in the coming years, the progress made to date and strategies to overcome remaining hurdles.

A Phase 2 Clinical Trial of Anti-CD19 CAR-T (pCAR-19B) in Chinese Pediatric and Young Adult with Relapsed/Refractory (R/R) CD19+ B-ALL: The First Pivotal Study in an Asian Population

CD5-Deleted Chimeric Antigen Receptor Cells (Senza5™ CART5) to Enhance Immunotherapy Against T-Cell Non-Hodgkin Lymphoma: A First-in-Human Phase I Clinical Trial

As a result of advances in screening, diagnosis and treatment methods in modern oncology, survival rates of patients with malignant neoplasms have considerably improved. Among the most promising therapeutic trends, emphasis is on the new immunotherapy method with T-cells expressing chimeric antigen receptors (CAR-T). CAR-T cell therapy is most commonly used in oncohematology. However, despite the efficacy of new therapeutic methods, also CAR-T cell therapy, more and more evidence on side effects becomes available. One of the most common complications (in about 1/3 of all cases) is cardiovascular toxicity (CVT) with high mortality. This accounts for an actively developing new interdisciplinary field of research called cardio-oncology that studies cardiovascular complications of chemotherapy and the methods of their monitoring and prevention. This review covers currently known pathophysiologic mechanisms of CVT on CAR-T cell therapy. Additionally, it discusses clinical manifestations, prevention strategy, and programs for monitoring cardiovascular adverse events reported by hematologists.

The incorporation of novel therapeutic agents such as antibody-drug conjugates, radio-conjugates, T-cell engagers, and chimeric antigen receptor cell therapies represents a paradigm shift in oncology. Cell-surface target quantification, quantitative assessment of receptor internalization, and changes in the tumor microenvironment (TME) are essential variables in the development of biomarkers for patient selection and therapeutic response. Assessing these parameters requires capabilities that transcend those of traditional biomarker approaches based on immunohistochemistry, in situ hybridization and/or sequencing assays. Computational pathology is emerging as a transformative solution in this new therapeutic landscape, enabling detailed assessment of not only target presence, expression levels, and intra-tumor distribution but also of additional phenotypic features of tumor cells and their surrounding TME. Here, we delineate the pivotal role of computational pathology in enhancing the efficacy and specificity of these advanced therapeutics, underscoring the integration of novel artificial intelligence models that promise to revolutionize biomarker discovery and drug development.

Although our previous data indicated that claudin 18 isoform 2 (CLDN18.2)-targeted chimeric antigen receptor(CAR)T cells displayed remarkable clinical efficacy in CLDN18.2-positive gastric cancer, their efficacy is limited in pancreatic ductal adenocarcinoma (PDAC). The tumour microenvironment (TME) is one of the main obstacles to the efficacy of CAR-T and remodelling the TME may be a possible way to overcome this obstacle. The TME of PDAC is characterized by abundant cancer-related fibroblasts (CAFs), which hinder the infiltration and function of CLDN18.2-targeted CAR-T cells. The expression of fibroblast activation protein alpha (FAP) is an important feature of active CAFs, providing potential targets for eliminating CAFs. In this study, we generated 10 FAP/CLDN 18.2 dual-targeted CAR-T cells and evaluated their anti-tumour ability in vitro and in vivo. Compared with conventional CAR-T cells, some dual-targeted CAR-T cells showed improved therapeutic effects in mouse pancreatic cancers. Further, dual-targeted CAR-T cells with better anti-tumour effect could suppress the recruitment of myeloid-derived suppressor cells (MDSCs) to improve the immunosuppressive TME, which contributes to the survival of CD8+ T cells. Moreover, dual-targeted CAR-T cells reduced the exhaustion of T cells in transforming TGF-β dependent manner. The dual-targeted CAR-T cells obtained enhancement of T effector function, inhibition of T cell exhaustion, and improvement of tumour microenvironment. Our findings provide a theoretical rationale for dual-targeted FAP/CLDN 18.2 CAR-T cells therapy in PDAC.

BackgroundAdoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy...

Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice. New molecular technologies have allowed the detection of MRD to levels as low as 10- 6. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.

e19006 Background: Chimeric antigen receptor (CAR-T) Chimeric antigen receptor (CAR) T-cell therapy presents a promising avenue in the treatment of hematological malignancies. However, the application of CAR-T cell therapy comes with a range of adverse effects, some of which are not fully understood yet. While previous research has primarily focused on immune effector cell-associated neurotoxicity (ICANs) and cytokine release syndrome (CRS), the cardiovascular safety profile of CAR-T cell therapy remains less defined. This meta-analysis assesses the incidence of cardiovascular (CV) events associated with CAR-T therapy, thereby providing critical insights into these events and guiding clinical decision-making. Methods: We conducted a Pubmed search of clinical trials evaluating the effect of CAR-T cell therapy in cancer patients with cardiovascular adverse events. For phase III trials, a quantitative assessment of Grade 3 or higher CV events was performed using the Review Manager (Rev-Man) Version 5.4 (The Cochrane Collaboration, 2020) and the results were reported as Odd Ratio (OR) with 95% Confidence Interval (CI). A fixed effect model was used. For phase I/II trials, the event rates were calculated for all-grade as well as grade 3 and higher CV adverse events. Results: A total of four Phase III clinical trials with 1345 patients were included for the comparison analysis. Among those trials, two involved multiple myeloma patients, and two involved large B cell lymphoma patients. The age range across trials was 20-83 years with a male-to-female ratio of 1.5:1. The analysis revealed that there was no statistically significant difference in Grade 3 or higher CV events between the CAR-T cell therapy and control (standard of care) groups: OR with 95% CI was 1.44 (0.73,2.82) (p=0.29). Grade 3 and above CV adverse event rates were 3.4% for the CAR-T and 2.1% for the control groups. Notably, there were two CV deaths in the CAR-T group and one CV death in the control group. Additionally, a total of 41 single-arm, Phase I/II clinical trials with 1479 participants were analyzed. Seven studies included solid cancers such as metastatic pancreatic cancer, biliary tract cancer and melanoma. The age range was 17-86 yr and male/female ratio was 1.5:1. Total all-grade CV adverse event rate was 21.83% and total grade 3 and above CV adverse event rate was 8.82%. There were eight CV deaths. Conclusions: There were significantly more CV adverse events reported in Phase I/II trials when compared to those reported in Phase III trials. This indicates that CV adverse events are important consequences of CAR-T cell therapy but are likely underreported in the Phase III clinical trials. Increased awareness and more standardized evaluation of CV adverse events of CAR-T is needed in the future clinical trials.

7035 Background: All the FDA-approved CD19 CAR-T products are based on FMC63 scFv, which binds to the membrane-distal region of CD19. We developed a novel anti-CD19 antibody clone (1218) binding to a membrane-proximal epitope of CD19 with fast on/off kinetics. AT101 is an autologous CAR-T cell transduced with a lentiviral vector encoding CAR comprised of a humanized scFv of 1218, 4-1BB costimulatory, and CD3zeta domain. Methods: In the phase 1 trial, patients (n=3 per dose level; up to n=18 in total) are treated with AT101 in 3 dose-escalation cohorts based on a standard 3 + 3 design. Each patient received a single intravenous dose of AT101 at dose level (DL) 1 (0.2 x 106 cells/kg), DL2 (1.0 x 106 cells/kg), or DL3 (5.0 x 106 cells/kg). The primary objective is to determine the safety, the maximum tolerated dose, and the recommended phase 2 dose of AT101. Key eligibility criteria include patients aged ≥19 with histologically confirmed relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Tumor responses were evaluated using Lugano 2014 criteria at 4 weeks before AT101 infusion as well as at 4 weeks and 3, 6, 9, 12, and 18 months after AT101 infusion. Results: From March 2022 to December 2022, fourteen patients were enrolled and 12 patients were treated, who were their median age of 62.5 years (range 39 to 84) and received a median of three prior lines of therapy (range 2-9). Their subtypes were as follows: diffuse large B cell lymphoma (DLBCL; n=7, 58.3%), follicular lymphoma (FL; n=3, 25.0%), mantle cell lymphoma (MCL; n=1, 8.3%), or marginal zone lymphoma (MZL; n=1, 8.3%)). The data collection cut-off date was January 31, 2024. Based on the best overall response up to three months, eleven patients responded with an overall response rate (ORR) of 91.7%, and a complete response (CR) was observed in nine patients (75%). Remarkably, in DL2 and DL3 groups, the CR was 100.0%. Among nine patients who achieved CR, seven patients have remained in CR during the median follow-up of 13.6 months (1.6-22.3 months). One patient experienced relapse and another one died from septic shock. The median duration of response (DOR), progression-free survival (PFS), overall survival (OS), and event-free survival (EFS) were 19.5, 17.2, 18.9 and 17.2 months, respectively. The median DOR, PFS, OS and EFS were not reached. Conclusions: In this first-in-human phase 1 trial, AT101 was tolerable with limited and manageable toxicities. In comparison to current FMC63 scFv-based CD19 CAR-T therapies, AT101 exhibited potent and more enduring efficacy with a remarkable suppression of relapse after CR. A phase 2 clinical trial is currently under-going for DLBCL patients. Clinical trial information: NCT05338931 .

Chemoimmunotherapy is currently the preferred first-line treatment option for the majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most of these patients, however, will experience disease progression within the first year after treatment initiation and both patients and their physicians will be confronted with the dilemma of the optimal second-line treatment. Identification of molecular targets, such as KRASG12C, BRAFV600X, METexon14, and human epidermal growth factor receptor 2 mutations, and RET rearrangements offer therapeutic opportunities in pretreated patients with corresponding alterations. For those tumors that do not harbor oncogenic drivers, second-line treatment with docetaxel remains the current standard of care despite modest efficacy. Strategies to challenge docetaxel include the combination of immune checkpoint inhibitors (ICIs) with tyrosine inhibitors of multiple kinases or with DNA damage response inhibitors, antibody-drug conjugates, and locoregional treatments for oligoprogressive disease. Next-generation immunotherapy strategies, such as T-cell engagers, immune-mobilizing monoclonal T-cell receptors, chimeric antigen receptor cell therapy, tumor infiltrating lymphocytes, and T-cell receptor cell therapy are being currently investigated in the quest to reverse resistance to ICIs. Importantly, the advent of these new agents heralds a novel spectrum of toxicities that require both the physician's and the patient's education. Herein, we review current and future strategies aiming to outperform docetaxel after chemoimmunotherapy failure, and we provide practical information on how to best communicate to our patients the unique toxicity aspects associated with immunotherapy.

T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs). Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 107 cells/m2), and subsequent cohorts received C7R-GD2.CARTs at two dose levels (1 × 107 cells/m2; 3 × 107 cells/m2). Standard lymphodepletion with cyclophosphamide and fludarabine was included at all dose levels. Eleven patients (age 4-18 years) received therapy without dose-limiting toxicity. The GD2.CART cohort did not experience toxicity, but had disease progression after brief improvement of residual neurologic deficits (≤3 weeks). The C7R-GD2.CART cohort developed grade 1 tumor inflammation-associated neurotoxicity in seven of eight (88%) cases, controllable with anakinra. Cytokine release syndrome was observed in six of eight (75%, grade 1 in all but one patient) and associated with increased circulating IL-6 and IP-10 (P < .05). Patients receiving C7R-GD2.CARTs experienced temporary improvement from baseline neurologic deficits (range, 2 to >12 months), and seven of eight (88%) remained eligible for additional treatment cycles (range 2-4 cycles). Partial responses by iRANO criteria were observed in two of seven (29%) patients with DMG treated by C7R-GD2.CARTs. Intravenous GD2.CARTs with and without C7R were well tolerated. Patients treated with C7R-GD2.CARTs exhibited transient improvement of neurologic deficits and increased circulating cytokines/chemokines. Treatment with C7R-GD2.CARTs represents a novel approach warranting further investigation for children with these incurable CNS cancers.