CAR-T Cell Treatment Research Articles

High-Dose Chemotherapy and Autologous or Allogeneic Transplantation in Aggressive B-Cell Lymphoma—Is There Still a Role?

Novel therapies such as CAR-T, BTK inhibitors and PD-1 inhibitors have changed the management of aggressive B-cell lymphomas. Nonetheless, these novel therapies have their own risk of late toxicities including second malignancies. They also create a subgroup of patients with relapse, treatment failure, or indefinite maintenance. We discuss the current role of autologous and allogeneic stem cell transplantation in this context. In patients with recurrent diffuse large B-cell lymphoma, CAR-T cell treatment has largely replaced autologous transplant. Autologous transplant should be considered in patients with late relapses and in selected patients with T-cell-rich B-cell lymphoma, where CAR-T cell therapy may be less effective. It also remains the treatment of choice for consolidation of patients with primary CNS lymphoma. In mantle cell lymphoma, intensive chemotherapy combined with BTK inhibitors and rituximab results in excellent outcomes, and the role of autologous transplantation is declining. In Hodgkin’s lymphoma, autologous transplant consolidation remains the standard of care for patients who failed initial chemotherapy. Allogeneic transplantation has lower relapse rates but more complications and higher non-relapse mortality than autologous transplantation. It is usually reserved for patients who fail autologous transplantation or in whom autologous stem cells cannot be collected. It may also have an important role in patients who fail CAR-T therapies. The increasing complexity of care and evolving sequencing of therapies for patients with aggressive B-cell lymphomas only emphasizes the importance of appropriate patient selection and optimal timing of stem cell transplantation.

Emerging Role of CAR-T Therapy in Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a malignant clonal disease originating from hematopoietic stem cells. In the past few decades, AML treatment has been dominated by a "3+7" regimen (anthracyclines + cytarabine), and the survival curve has stagnated. However, these procedures are associated with serious adverse effects. The development of chimeric antigen receptor (CAR)-T cell treatment provides a viable alternative, with decreased non-relapse death rates. Despite its potential, CAR-T cell therapy for AML confronts significant obstacles due to the disease's heterogeneity and accompanying toxicity. Genetic alteration strategies are being investigated to improve its safety and efficacy. Engineering CAR-T cells to express inhibitory receptors or suicide genes can help regulate T cell activity and prevent excessive immune activation. In summary, while CAR-T cell treatment has promise for AML, overcoming its hurdles through genetic modification and target refining is crucial. This review focuses on the existing landscape and future directions of CAR-T cell treatment for AML.

Dual CAR-T cell therapy for glioblastoma: strategies to cure tumour diseases based on a mathematical model

AbstractThe CAR-T cell immunotherapy entails the genetic reprogramming of T-lymphocytes, which then engage with cancer cells, triggering an anti-tumour immune response. While this treatment has gained approval for hematological cancers, addressing solid tumours presents new obstacles. Challenges include the heterogeneity of antigen expression within solid tumours, encompassing antigen-positive non-tumoural cells, the presence of immune inhibitory molecules, and the difficulty of CAR-T cell trafficking within the tumour microenvironment. In this article, we analytically study a generalisation of a mathematical model proposed by León-Triana et al. (Cancers 13(4):703, 2021a. https://doi.org/10.3390/cancers13040703, Commun Nonlinear Sci Numer Simul 94:105570). This model focuses on the dynamics of glioblastoma, the most aggressive brain tumour, and its response to CAR-T cell treatment. We study the basic properties of the model, the dynamics of the solutions of the model when the treatment is not sustained during the time, and finally we study analytically the model when the therapy is constant, periodic and/or impulsive. We derive sufficient conditions for global stability of tumour-free equilibrium, as well as necessary and sufficient conditions for local stability of the equilibrium obtaining conditions for an effective treatment. Finally, we perform different numerical simulations to find the strategies to keep the tumour under control. The obtained results are based on a combination of different analytical techniques in differential equations, dynamical systems and numerical simulations.

CD19-Directed CAR T-Cells in a Patient With Refractory MOGAD: Clinical and Immunologic Follow-Up for 1 Year.

In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells. CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis and infused after a conventional lymphodepleting regimen. A 18-year-old man developed 2 episodes of myelitis associated with serum MOG-IgG, which were followed by 6 episodes of left optic neuritis (ON) and sustained the presence of MOG-IgG over 6 years despite multiple immunotherapies. After the sixth episode of ON, accompanied by severe residual visual deficits, CAR T-cell treatment was provided without complications. Follow-up of cell counts showed complete depletion of CD19+ B cells at day +7; reconstituted B cells at day +141 showing a naïve B-cell phenotype, and low or absent memory B cells and plasmablasts for 1 year. MOG-IgG titers have remained undetectable since CAR T-cell infusion. The patient had an early episode of left ON at day +29, when MOG-IgG was already negative, and since then he has remained free of relapses without immunotherapy for 1 year. This clinical case shows that CD19-directed CAR T-cell therapy is well-tolerated and is a potential treatment for patients with refractory MOGAD. This provides Class IV evidence. It is a single observational study without controls.

Évaluation en vie réelle du parcours de soins des patients éligibles à un traitement par axicabtagene ciloleucel : cohorte multicentrique IMPA-CT

The arrival of CAR-T cell treatments in Europe in 2018 has considerably changed the clinical and logistical management of lymphoma patients. The aim of this study is to evaluate pathways of patients eligible for axicabtagene ciloleucel (axi-cel), particularly previously and afterwards of its administration, stages that are currently poorly documented in the literature. Ninety-eight patients from eleven French qualified centers eligible for axi-cel treatment between June 2020 and February 2021 were retrospectively included. Of all the stages in the care pathway evaluated, the median time observed between relapse after the previous line and prescription of axi-cel was 27days, and the median time between the multidisciplinary consultation meeting and axi-cel administration was 63days. The two main methods of discharge from hospital were a return home (65% of cases) or hospitalisation in a rehabilitation unit (20% of cases). Among all the geographical and organizational characteristics assessed, no factor was found to have a significant impact on the time length of the patient's journey, apart from the patient capacity of the qualified center, and the origin of the patient's referral (coming from a qualified or a referral center). Since the study was carried out, the number of qualified centers has continued to rise, improving territorial coverage and access to treatment.

Revolutionizing Immunotherapy: Unveiling New Horizons, Confronting Challenges, and Navigating Therapeutic Frontiers in CAR-T Cell-Based Gene Therapies.

The CAR-T cell therapy has marked the dawn of new era in the cancer therapeutics and cell engineering techniques. The review emphasizes on the challenges that obstruct the therapeutic efficiency caused by cell toxicities, immunosuppressive tumor environment, and decreased T cell infiltration. In the interest of achieving the overall survival (OS) and event-free survival (EFS) of patients, the conceptual background of potential target selection and various CAR-T cell design techniques are described which can minimize the off-target effects, reduce toxicity, and thus increase the resilience of CAR-T cell treatment in the haematological malignancies as well as in solid tumors. Furthermore, it delves into cutting-edge technologies like gene editing and synthetic biology, providing new opportunities to enhance the functionality of CAR-T cells and overcome mechanisms of immune evasion. This review provides a comprehensive understanding of the complex and diverse aspects of CAR-T cell-based gene treatments, including both scientific and clinical aspects. By effectively addressing the obstacles and utilizing the capabilities of cutting-edge technology, CAR-T cell therapy shows potential in fundamentally changing immunotherapy and reshaping the approach to cancer treatment.

CAR-T Cells Therapy in Glioblastoma: A Systematic Review on Molecular Targets and Treatment Strategies.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.

Abstract PO-001: GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance

Abstract Chimeric antigen receptor (CAR)-T cell therapies can be curative for CD19+ hematological malignancies, though are limited by frequent patient relapse and response failures. Here, we identify GPR65 as a tumor-specific determinant of responsiveness to CAR-T cell therapy. In patients and an immune competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) response to CAR-T cell therapy, high GPR65 is associated with a complete tumor response. In mice, GPR65 knockout (GPR65 KO) tumors are resistant to CAR-T cell therapy in vivo, without antigen loss. Single-cell network analyses reveal that GPR65 deficiency remodels tumor interactions with host macrophages, partially through increasing tumor VEGFA. This leads to increased macrophage numbers and preferential M2 macrophage polarization. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restores responsiveness to CAR-T cell treatment. Anti-VEGFA therapy in combination with CAR-T cell administration also prolongs the survival of GPR65 KO tumor-bearing mice. Our results indicate that tumor GPR65 expression is important for B-ALL responses to CAR-T cell therapy through its impact on the tumor microenvironment and supports new approaches to identify and overcome CAR-T cell resistance. Citation Format: Jayadev Mavuluri. GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-001.

The Fate(s) of CAR T-Cell Therapy: Navigating the Risks of CAR+ T-Cell Malignancy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy represents a landmark advancement in treating resistant forms of cancer such as leukemia, lymphoma, and myeloma. However, concerns about long-term safety have emerged following an FDA investigation into reports of second primary malignancies (SPM) after CAR-T cell treatment. This review offers a thorough examination of how genetically modified T cells might transform into CAR+ SPM. It explores genetic and molecular pathways leading to T-cell lymphomagenesis, the balance between CAR T-cell persistence, stemness, and oncogenic risk, and the trade-off of T-cell exhaustion, which may limit therapy efficacy but potentially reduce lymphomagenesis risk. Significance: An FDA probe into 22 cases of second primary T-cell malignancies following CAR T-cell therapy stresses the need to investigate their origins. Few may arise from preexisting genetic and epigenetic alterations and those introduced during therapeutic engineering. Technological advances, regulatory oversight, and patient monitoring are essential to mitigate potential risks.

Influence of gender on acute kidney injury among patients undergoing chimeric antigen receptor T-cell (CAR-T cell) therapy: Insights from National Inpatient Sample.

e14524 Background: Chimeric antigen receptor T-cell (CAR-T Cell) immunotherapy has shown promising results in patients with B-cell leukemia and lymphoma and multiple myeloma. The side effect profile is still being studied and acute kidney injury (AKI) following treatment has been a commonly reported outcome in the context of cytokine release syndrome. In most cases, the kidney injury is reversible with adequate hydration and treatment of the underlying cytokine release syndrome when needed. This study aimed to investigate the outcomes of gender in patients undergoing CAR-T cell therapy along with the protective variables and independent predictors of AKI in this patient population. Methods: This was a retrospective analysis of data the National Inpatient Sample (NIS) between January 2019 and December 2020 to identify patients who underwent CAR-T cell therapy. We stratified the data based on gender and studied the incidence of AKI in patient admitted to the hospital primarily for CAR-T cell treatment. The primary endpoint was in-hospital mortality, AKI, average age, length of stay (LOS), and total charge by hospital. Additionally, we explored independent predictors and protective variables for AKI in patients receiving the treatment. Results: A total of 4010 patients underwent CAR-T Cell therapy from January 2019 to December 2020. Among these patients, females comprised 41.1% (n=1650). The mean age at the time of CAR-T cell treatment for males was 57.5 and for females 56.9. The inpatient mortality rates for both groups were 3% (p=0.97). The total incidence of AKI in patients undergoing CAR-T cell therapy was 14.9%, with rates of 19% in males and 9% in females (p<0.01). LOS for males and females was 19 days, and 20 days respectively (p=0.4). Average total hospital charge for males was 958,345 and 1,017,685 for females (p=0.3642). Interestingly, there was no difference between genders in relation to the incidence of cytokine release syndrome (p=0.3). Notably, CKD, obesity, liver disease, and electrolyte imbalances were independent predictors of AKI with an adjusted odds ratio of 4.26 (p<0.01; 95% confidence interval [CI]: 1.7-10.6), 2.7 (p=0.015; 95% CI: 1.2-6.06), 2.7 (p=0.045; 95% CI: 1.02-7.23), 2.5 (p<0.01; 95% CI: 1.67-3.81). Importantly, gender was a protective variable for females when it came to AKI after CAR-T cell therapy with an adjusted odds ratio of 0.38 (p<0.01; 95% CI: 0.23-0.63). Conclusions: AKI has been documented as a common side effect in patients undergoing CAR-T cell therapy. In most cases the kidney injury is reversible with adequate hydration and CRS treatment when necessary. Our study highlights CKD, obesity, liver disease, and electrolyte imbalance as independent predictors of AKI after CAR-T cell therapy and female gender as a predictive variable against developing AKI.

Phase I clinical trial of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of advanced breast cancer.

1089 Background: In the treatment of breast cancer, the therapeutic efficacy of CAR-T cell therapy remains unsatisfactory. A possible approach to enhance the efficacy of CAR-T therapy is to combine CAR-T with PD-1 inhibition. This clinical trial was designed to assess the safety and tolerability of PD-1 knockout MUC1-targeted CAR-T cells in advanced breast cancer. Methods: Patients with advanced breast cancer were recruited according to the criteria in NCT05812326. PD-1 gene knockout (KO) MUC1-targeted CAR-T cells were prepared in 2 steps. MUC1-specific CARs were first constructed using 5E5 scFv in patient-derived T cells, and then PD-1 gene KO was achieved in these CAR positive T cells using the CRISPR-Cas9 system. Efficiency and validation were confirmed by sequencing and flow cytometry. MUC1-CAR+/PD-1-T cells were infused at a starting dose of 1-2x106 CAR+ cells/kg and then escalated to 0.9-1.8x107 CAR+ cells/kg. The safety and tolerability of therapeutic cells were evaluated using CTCAE v5.0. Patients’ general condition, levels of lymphocytes, and serum cytokines (IL-1β, IL-2R, IL-6, IL-8, TNF and IL-10) were monitored. Circulating CAR-T cells were checked regularly. Changes in tumor size were examined by MRI/CT scans. The primary endpoint was to assess the safety of this treatment. We also compared the responses in patients who received single and multiple cycles of infusion of therapeutic CAR-T cells. Results: A total of 12 patients (aged 34 to 61) diagnosed with recurrent/metastatic breast cancer were included in this study. All participants received at least 1 cycle of CAR-T cell treatment. Among the 12 patients, 8 received 1 cycle, 3 received 2 cycles, 1 received 3 cycles. Adverse events (AEs) included elevated AST level (7/12, 58.3%), acute fever (6/12), elevated ALT level (5/12), skin rash (5/12), chills (4/12), anemia (4/12), lymphopenia (4/12), diarrhea, vomiting and urinary tract infection (2/12). The most serious AE was lymphopenia (grade 4 lasting 1 day in 1 patient). No grade 3-5 CRS was observed. No patients experienced neurotoxicity. No predefined dose-limiting toxicities (DLT) or serious AEs were observed. Furthermore, there were no AEs resulting in discontinuation of treatment. Of the 12 patients evaluated, 5 had stable disease (SD), indicating that MUC1 CAR-T cell therapy can control the progression of some advanced breast cancers, despite the fact that the efficacy assessment is quite preliminary. The pharmacokinetic study indicated that improved clinical outcomes are associated with a high level of circulating CAR+ copy on day 7. Conclusions: Our data suggest that treatment of patients with advanced breast cancer with PD-1 disrupted MUC1-targeted CAR-T cells is safe and well-tolerated by all patients in this phase 1 clinical trial. No serious CRS or other EA was observed throughout the study. The efficacy of this unique combined therapy is currently being assessed. Clinical trial information: NCT05812326 .

CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival

ABSTRACT Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.

Potential and pitfalls of repurposing the CAR-T cell regimen for the treatment of autoimmune disease

Chimeric antigen receptors (CARs) are synthetic proteins designed to direct an immune response toward a specific target and have been used in immunotherapeutic applications through the adoptive transfer of T...

Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis

Background Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. Methods The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. Conclusion Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.

BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism

Altered Branched Chain Amino Acids (BCAA), including leucine, isoleucine and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of Chimeric Antigen Receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and deceasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cells treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and the increasing proportion of CAR-T cells in peripheral circulation. BCKDK-KO CAR-T cells treatment resulted in shorter survival and decreasing percentage of CAR-T cells in peripheral circulation. In conclusion, BCKDK engineered CAR-T cells exert distinct phenotype for the superior anticancer efficiency.

Changes in T-cell subsets, preexisting cytopenias and hyperferritinaemia correlate with cytopenias after BCMA targeted CAR T-cell therapy in relapsed/refractory multiple myeloma: Results from a prospective comprehensive biomarker study.

Biomarkers for cytopenias following CAR T-cell treatment in relapsed/refractory (RR) multiple myeloma (MM) are not completely defined. We prospectively analysed 275 sequential peripheral blood (PB) samples from 58 RRMM patients treated with BCMA-targeted CAR T cells, and then divided them into three groups: (i) baseline (before leukapheresis), (ii) ≤day+30, and (iii) >day+30 after CAR T-cell therapy. We evaluated laboratory data and performed flow cytometry to determine the (CAR) T-cell subsets. Baseline hyperferritinaemia was a risk factor for long-lasting grade ≥3 anaemia (r = 0.47, p < 0.001) and thrombocytopenia (r = 0.44, p = 0.002) after CAR T-cell therapy. Low baseline haemoglobin (Hb) and PLT were associated with long-lasting grade ≥3 anaemia (r = -0.56, p < 0.001) and thrombocytopenia (r = -0.44, p = 0.002) respectively. We observed dynamics of CAR-negative T-cell subsets following CAR T-cell infusion. In the late phase after CAR T-cell therapy (>day+30), CD4Tn frequency correlated with anaemia (r = 0.41, p = 0.0014) and lymphocytopenia was related to frequencies of CD8+ T cells (r = 0.72, p < 0.001) and CD8Teff (r = 0.64, p < 0.001). CD4Tcm frequency was correlated with leucocytopenia (r = -0.49, p < 0.001). In summary, preexisting cytopenias and hyperferritinaemia indicated long duration of grade ≥3 post-CAR T-cell cytopenias. Prolonged cytopenia may be related to immune remodelling with a shift in the CAR-negative T-cell subsets following CAR T-cell therapy.

Global research trends in CAR-T cell therapy for solid tumors: A comprehensive visualization and bibliometric study (2012–2023)

ABSTRACT CAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.

Effective bridging strategies prior to infusion with tisagenlecleucel results in high response rates and long-term remission in relapsed/refractory large B-cell lymphoma: findings from a German monocentric study

BackgroundIncorporating chimeric antigen receptor (CAR)-T cell therapy into relapsed or refractory large B-cell lymphoma (rr LBCL) treatment algorithms has yielded remarkable response rates and durable remissions, yet a substantial portion of patients experience progression or relapse. Variations in outcomes across treatment centers may be attributed to different bridging strategies and remission statuses preceding CAR-T cell therapy.PatientsTwenty-nine consecutive adult patients receiving tisagenlecleucel (tisa-cel) for rr LBCL from December 2019 to February 2023 at Jena University Hospital were analyzed.ResultsThe median age was 63, with a median of 3 prior treatments. Twenty patients (69%) were refractory to any systemic therapy before CAR-T cell treatment. Following leukapheresis, 25 patients (86%) received bridging therapy with the majority undergoing chemotherapy (52%) or combined modality therapy (32%). Radiotherapy (RT) was part of the bridging strategy in 44%, with moderately hypofractionated involved site RT (30.0 Gy/2.5 Gy) being applied most frequently (64%). Post-CAR-T infusion, the objective response rate at 30 days was 83%, with 55% achieving complete response. Twelve-month progression-free (PFS) and overall survival (OS) were 60% and 74%, respectively, with a median follow up of 11.1 months for PFS and 17.9 months for OS. Factors significantly associated with PFS were chemotherapy sensitivity pre-leukapheresis and response to bridging.ConclusionThe study underscores the importance of minimal tumor burden at CAR-T initiation, emphasizing the need for suitable bridging regimens. The findings advocate for clinical trials and further real-world analyses to optimize CAR-T cell therapy outcomes by identifying the most effective bridging strategies.

Advantages of high cell concentration prior to cryopreservation of initial leukapheresis in CAR-T cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy is increasingly used in patients affected by B-cell lymphoma and acute lymphoblastic leukemia. For logistical reasons, initial apheresis products may be cryopreserved for shipment to manufacturing centers. Due to the characteristics of these patients, cells are often collected in large volumes, meaning more bags must be cryopreserved. This requires increased storage, time and monetary costs. In this context, we aimed to evaluate a high cell concentration cryopreservation protocol by centrifugation to standardize the initial CAR-T manufacturing procedure. Sixty-eight processes of leukapheresis of 57 patients affected by refractory/relapsed B cell lymphoma and 9 patients affected by acute lymphoblastic leukemia who were eligible for anti-CD19 CAR-T cell treatment performed between June 2019 and October 2022 were analyzed. Whole blood count, percentage and number of T cells were assessed on the apheresis final product. The apheresis product, which was alternatively stored overnight at 4°C, was centrifuged, adjusting the volume to approximately 40 mL. The product was immediately cryopreserved to achieve a final cell concentration of 50-200×106 cells/ml for cryopreservation. Leukapheresis volume was reduced by almost fivefold (median: 185 to 40 mL), resulting in a higher product concentration in one bag. In addition, the number of non-target cells (monocytes, platelets and erythrocytes) was also reduced during the development of CAR-T cell therapy, thereby maintaining T lymphocyte levels and providing a purer starting material. The advantages of the protocol include reducing economic costs, saving storage space, simplifying the manufacturing process, and facilitating shipping logistics. In conclusion, we present a validated, simple, and cost-effective cell enrichment processing protocol that provides high-quality cryopreserved products as starting material for the CAR-T cell manufacturing process.

Construction of Switch Modules for CAR-T Cell Treatment Using a Site-Specific Conjugation System.

Chimeric antigen receptor T-cell (CAR-T cell) therapy has become a promising treatment option for B-cell hematological tumors. However, few optional target antigens and disease relapse due to loss of target antigens limit the broad clinical applicability of CAR-T cells. Here, we conjugated an antibody (Ab) fusion protein, consisting of an Ab domain and a SpyCatcher domain, with the FITC-SpyTag (FITC-ST) peptide to form a bispecific safety switch module using a site-specific conjugation system. We applied the safety switch module to target CD19, PDL1, or Her2-expressing tumor cells by constructing FMC63 (anti-CD19), antiPDL1, or ZHER (anti-Her2)-FITC-ST, respectively. Those switch modules significantly improved the cytotoxic effects of anti-FITC CAR-T cells on tumor cells. Additionally, we obtained the purified CD8+ T cells by optimizing a shorter version of the CD8-binding aptamer to generate anti-FITC CD8-CAR-T cells, which combined with the CD4-FITC-ST switch module (anti-CD4) to eliminate the CD4-positive tumor cells in vitro and in vivo. Overall, we established a novel safety switch module by site-specific conjugation to enhance the antitumor function of universal CAR-T cells, thereby expanding the application scope of CAR-T therapy and improving its safety and efficacy.