T-cell Therapy Research Articles

Clinical Pharmacology of Cytokine Release Syndrome with T-cell Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies

Abstract Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention is crucial in T-BiSp development. Required hospitalization for 7 of the 9 approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce healthcare burden and improve patient outcome. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre)treatment strategies, quantitative pharmacology tools employed during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through review of T-BiSp licensing applications and emerging data from conferences and publications.

Successful allogeneic CD34+ hematopoietic stem cell boost for prolonged cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. On behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)

Successful allogeneic CD34+ hematopoietic stem cell boost for prolonged cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. On behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)

Statistical operating characteristics of current early phase dose finding designs with toxicity and efficacy in oncology.

Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated dose (MTD) of the investigational cytotoxic agent based on a single toxicity outcome, assuming a monotone dose-response relationship. However, this assumption might not always hold for newly emerging therapies such as immuno-oncology therapies and molecularly targeted therapies, making conventional dose finding trial designs based on toxicity no longer appropriate. To tackle this issue, numerous early-phase dose finding clinical trial designs have been developed to identify the optimal biological dose (OBD), which takes both toxicity and efficacy outcomes into account. In this article, we review the current model-assisted dose finding designs, BOIN-ET, BOIN12, UBI, TEPI-2, PRINTE, STEIN, and uTPI to identify the OBD and compare their operating characteristics. Extensive simulation studies and a case study using a CAR T-cell therapy phase I trial have been conducted to compare the performance of the aforementioned designs under different possible dose-response relationship scenarios. The simulation results demonstrate that the performance of different designs varies depending on the particular dose-response relationship and the specific metric considered. Based on our simulation results and practical considerations, STEIN, PRINTE, and BOIN12 outperform the other designs from different perspectives.

Acute Kidney Injury Following CAR-T Cell Therapy: A Nephrologist Perspective

Abstract Chimeric antigen receptor T-cell (CAR-T cell) therapy, an emerging personalized immunotherapy for various hematologic malignancies, autoimmune diseases, and other conditions, involves the modification of patients’ T cells to express a chimeric antigen receptor which recognizes tumor or autoimmune cell antigens. Thereby CAR-T cells destroy cancerous and other target cells selectively. Despite remarkable clinical improvements in patients, multiple adverse effects have been associated with CAR-T cell therapy. Among the most recognized adverse effects are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and tumor lysis syndrome. Even though less recognized, the incidence of acute kidney injury (AKI) ranges from 5% to 33%. The wide range of reported AKI incidence rates might depend on patient population characteristics and comorbidities and specific CAR-T cell therapy features. Even though the exact pathophysiology remains unknown, several key mechanisms including cytokine release syndrome, tumor lysis syndrome, and other factors such as direct renal toxicity of CAR-T cell therapy, conditioning regimens or other medications (e.g. antibiotics), and infectious complications (e.g. sepsis) have been proposed. Risk factors for CAR-T-related AKI include lower baseline glomerular filtration rate, higher rates of allopurinol or rasburicase use, intravenous contrast material exposure, elevated baseline lactate dehydrogenase, and grade 3 or higher cytokine release syndrome. Future prospective studies with larger patient populations are needed to gain more insight regarding the pathophysiology of CAR-T-related AKI, and, more importantly, to be able to prevent as well as to develop novel and more efficient treatment modalities. In this narrative review, we discuss the underlying pathophysiology, risk factors, potential interventions, and future directions related to AKI following CAR-T cell therapy.

Case report: CD7-targeted autologous CAR-T therapy for the treatment of T-cell acute lymphoblastic leukemia undergoing allogeneic peripheral blood stem cell transplantation in the long-term follow-up

IntroductionChimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising approach for treating relapsed/refractory (r/r) T-cell acute lymphoblastic leukemia (T-ALL). However, it is mostly used as a bridging therapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, secondary allo-HSCT is costly and associated with significantly high treatment-related mortality rate than the primary transplants. In this report, we present the case of an adult T-ALL patient who underwent CD7-targeted autologous CAR-T cell therapy that was not bridged with secondary allo-HSCT.Case presentationThe adult T-ALL patient relapsed for a third time after undergoing allogeneic peripheral blood stem cell transplantation (PBSCI) and achieving the first complete remission (CR1). Therefore, the patient was administered CD7-targeted autologous CAR-T cell therapy that was not bridged with secondary allo-HSCT. Towards this, the endogenous CD7-deleted CAR (CD7-CAR7) T cells were generated using CRISPR/Cas9 gene-editing technology. However, after the first infusion, the CD7 CAR-T cells did not show significant proliferation when analyzed at two weeks and the patient became positive for peripheral measurable residual disease (MRD). Therefore, after a two-week period, an augmented dose of CAR-T cells was administered. MRD was monitored in the peripheral blood and bone marrow samples. The patient achieved complete remission and did not require targeted treatment after the completion of CD7 CAR-T-cell therapy. The current follow-up data has shown that the patient is negative for MRD and has been disease-free for more than 42 months.ConclusionThe results of this case study provide evidence for the long-term efficacy of CD7-targeted autologous CAR-T-cell therapy without requiring secondary allo-HSCT in patients with r/r T-ALL that have relapsed after previous allogeneic PBSCT.

Nurses’ reported training needs for advanced cell therapies: a survey on behalf of the Nurses Group of the EBMT

Background Advanced Therapy Medicinal Products (ATMPs) for human use have advanced globally with the rapid adoption of Chimeric Antigen Receptor T-cell (CAR-T) therapies in haemato-oncology. CAR-T cell therapy and ATMPs have unique, significant acute and chronic toxicities, and appropriate patient care is crucial. Significant challenges, including the need for nurse education and training, accompany optimal patient success and benefits. Objectives This study aimed to describe nurses’ training needs in relation to ATMP management and patient care. Methods A cross-sectional online survey was performed by the European Society for Blood and Marrow Transplantation, based on a previously tested questionnaire developed in the UK. Findings 109 complete responses from 86 different centers from 24 countries were returned (1207 distributed). Over 1/3 reported experience delivering licensed ATMPs (CAR-T). High-priority training areas included a general introduction to ATMPs, toxicity management, product-specific information, and regulatory frameworks for ATMPs. A clear need for ATMP-specific training exists and is regarded as important. Training prior to implementation is key and should be supported by ongoing competency maintenance. Counseling, patient support, and long-term follow-up are identified for future training and opportunities for nurse experience sharing in this rapidly evolving field.

"The End of the Golden Weather": therapeutic strategies for mantle cell lymphoma relapsed or refractory to covalent BTK inhibitors.

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma which is often characterised by a pattern of continued relapse after frontline chemoimmunotherapy. Although patients are usually able to regain durable disease control with covalent Bruton's tyrosine kinase inhibitors (cBTKi) at first relapse, it is now appreciated that such responses are often not sustained and the management of such patients represents a significant area of unmet need. There is an imperative to better understand resistance mechanisms and identify high-risk subsets of patients for whom cBTKi responses may be particularly short. Allogeneic stem cell transplant has an established role in appropriate candidates, however contemporary consensus is to preferentially offer chimeric antigen receptor (CAR) T-cell therapy. In this Review, we consider the available data on both existing and emerging treatment options, including non-covalent BTK inhibitors, bispecific antibodies, antibody-drug conjugates and Bcl-2 inhibitors and propose a treatment strategy prioritising clinical trials where available.

Clinical outcomes of chimeric antigen receptor T-cell therapy following autologous hematopoietic stem cell transplantation in 38 patients with refractory/relapsed primary or secondary central nervous system lymphoma.

Several reports have indicated that chimeric antigen receptor (CAR) T-cell therapy following autologous hematopoietic stem cell transplantation (ASCT) is a promising strategy for refractory/relapsed (r/r) central nervous system lymphoma (CNSL), but the number of reported cases is limited. The cohort in this retrospective study consisted of 38 patients with r/r CNSL who received CAR T-cell therapy following ASCT at our center between January 2019 and April 2024. Group comparisons of continuous variables were tested using the unpaired Student's t-test or the Mann-Whitney U-test, while categorical variables were analyzed using Fisher's exact test. The Kaplan-Meier method was employed to estimate survival curves, and group comparisons were performed using the log-rank test. The cohort comprised 38 patients with r/r CNSL, all of whom had active CNS involvement. After therapy, the best overall response rate (ORR) of all patients was 78.9%. Subgroup analysis found that a lower ORR was observed in patients with lactate dehydrogenase levels above the upper limit of normal (60.0% vs. 91.3%, P = 0.039). With a median follow-up of 37.5months, the estimated 1-year overall survival (OS) and progression-free survival (PFS) rates were 72.8% and 57.4%, respectively. The risk factors associated with PFS was no response to current therapy (adjusted hazard ratio: 22.87, P < 0.001). The incidence rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were both 13.2%. Among the 25 patients with secondary CNSL (SCNSL), the best ORRs were 91.7% for those with CNS lesions only and 61.5% for those with CNS and systemic lesions (P = 0.160), while the estimated 1-year PFS rates were 83.3% and 38.5%, respectively (P = 0.030). CAR T-cell therapy following ASCT shows promising efficacy for r/r CNSL patients. Besides, SCNSL patients with CNS and systemic lesions have inferior treatment efficacy compared to those with CNS lesions only.

IMMU-39. CAR T CELLS TARGETING ICAM-1 SHOW A SURVIVAL BENEFIT IN BOTH SYNGENEIC AND XENOGRAFT GLIOMA MOUSE MODELS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy, while effective against hematological malignancies, has faced significant hurdles in its application to solid tumors. Challenges in CAR T-cell therapy for glioblastoma include the immunosuppressive tumor microenvironment, the limited infiltration of CAR T-cells into the tumor, heterogeneous target expression and antigen escape. In this study, we focused on targeting Intracellular adhesion molecule-1 (ICAM-1), a protein expressed on both glioma cells and tumor-associated cells like macrophages and endothelial cells. METHODS Glioblastoma and normal brain tissue microarray sections (TMA) were immunohistochemically analyzed for ICAM-1 expression. Second-generation human and murine ICAM-1-targeting CAR T cells were generated by lentiviral or retroviral transduction of T cells from healthy human donors or murine splenocytes. Their efficacy was evaluated in co- culture assays with human and murine glioma and endothelial cell lines. Syngeneic and xenograft orthotopic glioma mouse models were used to assess the in vivo activity of CAR T cells. Ex vivo analysis of these tumors included examination of changes in the tumor microenvironment using high-dimensional flow cytometry. RESULTS Immunohistochemical staining of TMA revealed a significant upregulation of ICAM-1 in human glioblastoma tissue compared to normal brain tissue. Single-cell RNA sequencing data from glioblastoma specimens showed a high level of ICAM-1 expression in tumor- associated macrophages. Human and murine ICAM-1-targeting CAR T cells displayed strong lysis of ICAM-1-expressing glioma and endothelial cells in vitro. Intratumoral application of CAR T cells resulted in a survival benefit in both syngeneic and xenograft glioma mouse models. Ex vivo analysis of the tumor microenvironment revealed treatment-induced changes from our CAR T cell therapy and indicates potential for further enhancements. CONCLUSION Our study demonstrates that ICAM-1-targeting CAR T cells improve survival in human and murine glioma mouse models. Flow cytometry of the tumor microenvironment reveals therapy-induced changes, for future improvements of the CAR T cell therapy.

INNV-30. TOXICITIES AND OUTCOME AFTER CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR NEUROLYMPHOMATOSIS

Abstract BACKGROUND Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. METHODS Neurolymphomatosis treated with CD19-CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification. Management, and response rates were recorded. RESULTS Eleven neurolymphomatosis cases, who had received a median 2 prior PNS-directed treatments (range: 1-3) before CD19-CAR T-cell exposure, were identified. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome was detected in 8/11 (73%; grade 1: N = 7; grade 2: N =1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions were achieved in three cases (27%), of which two are still sustained now 9 and 46 months after CD19-CAR T-cell infusion. All radiographic responses were associated with remission of neurological symptoms. CONCLUSIONS CD19-CAR T-cell treatment was well tolerated and yielded promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier, and toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.

TMIC-59. ENTANGLED: THE INTERPLAY OF CELLULAR PLASTICITY AND NEURONAL SIGNALING IN BRAIN CANCER PROGRESSION

Abstract The interplay between two recently proposed hallmarks of cancer, namely dedifferentiation/transdifferentiation and altered neuronal signaling, may dictate the spatiotemporal coupling between neurons and astrocytes. Synaptic activity correlates with brain cancer progression and further influences the directionality of metabolites. Through phenotypic plasticity, brain parenchymal cells may dedifferentiate in a manner that determines the directionality of metabolites, thereby altering plasticity and exerting selective pressure on the immune microenvironment within the brain. Therapeutic advancements in brain cancers, including maximizing surgical resection margins and Chimeric Antigen Receptor (CAR) T-cell therapy, have their own limitations. Thus, understanding the interplay between dedifferentiation/transdifferentiation and its role in dictating altered neuronal signaling to modulate the brain tumor microenvironment may provide novel targets for improving prognosis and limiting therapeutic toxicity.

IMMU-29. B7-H3-TARGETED CAR-T AND CAR-NK CELLS AGAINST HUMAN GLIOBLASTOMA

Abstract Glioblastoma multiforme (GBM) is the most lethal primary brain tumor, necessitating novel therapies. Chimeric antigen receptor (CAR) T-cell therapy has recently shown efficacy against GBM. However, this approach is costly and time-consuming due to its personalized nature. Alternatively, CAR-transduced natural killer (NK) cells offer a potential “off-the-shelf” immunotherapy option, as they do not cause graft-versus-host disease. This study aimed to assess the anti-GBM efficacy of CAR T and NK cells targeting B7-H3, a protein highly expressed in GBM. To achieve this, CAR T cells targeting B7-H3 were developed using known anti-B7-H3 scFv sequences. Additionally, cord blood-derived NK cells were transduced with the B7-H3 CAR. Both types of CAR-modified cells were tested for their anti-GBM activity in vitro. Moreover, their anti-tumor effects were evaluated in an in vivo xenograft model using patient-derived GBM cells. The results demonstrated that both B7-H3 CAR T cells and CAR NK cells exhibited significant cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of these CAR-modified cells into the xenograft model significantly reduced tumor growth. In conclusion, B7-H3 targeted CAR T cells and cord blood-derived CAR NK cells both show potential in eliminating GBM cells, suggesting promising avenues for future GBM treatment strategies.

EXTH-51. ENHANCING GLIOBLASTOMA TREATMENT: ALLOGENEIC CAR-T CELLS OVERCOMES FUNCTIONAL DEFICITS OF PATIENT-DERIVED AUTOLOGOUS PRODUCTS

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults, with a dismal prognosis despite an intensive standard of care. Recently, chimeric antigen receptor T-cell (CAR-T) therapy has shown promising outcomes in treating liquid malignancies. However, clinical trials targeting various tumor antigens in GBM failed to show durable clinical benefit. Though this may stem from various tumor-intrinsic immune evasion strategies typical of GBM, there has been little work investigating whether the problem lies in the quality of the CAR-T products treatment itself. Currently, CAR-T cells for clinical studies are produced in an autologous setting, where T-cells are extracted from patients, engineered ex-vivo, and then re-infused. However, peripheral T-cells taken from GBM patients have shown qualitative and functional deficits, which may contribute to suboptimal treatment outcomes. Thus, we aimed to explore whether CAR-Ts generated from GBM patients had any functional deficits in comparison to healthy donors, utilizing our previously validated CD133 CAR-T. In this study, we show pre-treatment exhaustion, poor tumor control, and reduced survival advantage in autologous, patient-derived CD133-targeting CAR-T cell products using an orthotopic xenograft model of human GBM. To address the functional and logistical considerations of autologous therapy, we also sought to generate an “off-the-shelf” allogeneic CD133 CAR-T. Using CRISPR gene editing technology, we generated TCR-knockout CAR-T cells with comparable pre-clinical efficacy to our healthy donor derived autologous models. Ultimately, this work highlights the need to reevaluate autologous CAR-T therapy for GBM and consider allogeneic approaches as biologically-informed therapeutic alternatives.

NCMP-09. SPONTANEOUS RESOLUTION OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) DEVELOPED AFTER RITUXIMAB TREATMENT FOR LOW-GRADE B-CELL LYMPHOMA

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare viral infection caused by the reactivation of the JC virus, which causes significant morbidity and mortality. Rituximab, a CD20 inhibitor used for B-cell neoplasms as well as autoimmune diseases, is associated with the development of PML. Here, we report a case of a 74-year-old woman with a history of low-grade B-cell lymphoma with biopsy-proven PML with spontaneous immune reconstitution with clinical and radiographic improvement. For her low-grade B-cell lymphoma, she received six cycles of rituximab and bendamustine, followed by one cycle of maintenance rituximab, which was discontinued due to intolerance. Ten months later, she developed progressive left-sided paresthesias, paresis, and incoordination. Brain MRI revealed a large right subcortical frontal-parietal FLAIR hyperintense and peripherally enhancing lesion with leading-edge diffusion restriction. CSF studies revealed elevated protein (385 mg/dL) and negative JCV PCR. A brain biopsy was performed with tissue staining positive for SV40, consistent with PML. Her CD4 count was 88 cells/mm3. A repeat CSF sample one month later showed near normalization CSF protein (47 mg/dL) and negative CSF JCV PCR. MRI of the brain one month later demonstrated complete enhancement resolution and decreased FLAIR abnormality, which correlated with subjective and objective clinical improvement. Her serum CD4 also increased to 134 cells/mm3. This highlights a rare case of PML related to rituximab with spontaneous improvement, which may help guide clinicians in counseling patients who may also develop this complication. Furthermore, this supports the biological rationale for continued investigation of T-cell therapies to achieve immune reconstitution.

EPCO-61. THE LANDSCAPE OF ALTERNATIVE SPLICING IN PEDIATRIC GLIOMA

Abstract Recent studies have identified alternative splicing (AS) as a novel source of neoantigens for immunotherapy. Surprisingly little is known about the AS milieu in Pediatric glioma, including diffuse intrinsic pontine glioma (DIPG), pediatric high grade glioma (pHGG) and medulloblastoma. We analyzed 20 primary DIPG, 22 pHGG and 20 medulloblastoma human specimens via RNA sequencing and re-analyzed RNA-sequencing data from non-malignant human brain tissues. From these data, we reconstructed the landscape of AS in Pediatric glioma and contrasted that to observed isoforms in non-malignant brain. We identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies in DIPG, pHGG and medulloblastoma. We also identified novel splicing events derived neoantigens in DIPG, pHGG and medulloblastoma respectively, which are potential immunotherapy targets. We found DIPG specific isoforms of Platelet-derived growth factor pathway genes which are expressed exclusively by DIPG tumor cells. Our studies shed light on the effect of immunotherapy on AS and identify novel targets for emerging immunotherapies in pediatric glioma.

A Brief Chronicle of Antibody Research and Technological Advances

This review briefly traces the historical development of antibody research and related technologies. The path from early perceptions of immunity to the emergence of modern immunotherapy has been marked by pivotal discoveries and technological advances. Early insights into immunity led to the development of vaccination and serotherapy. The elucidation of antibody structure and function paved the way for monoclonal antibody technology and its application in diagnosis and therapy. Breakthroughs in genetic engineering have enabled the production of humanized antibodies and the advances in Fc engineering, thereby increasing therapeutic efficacy. The discovery of immune checkpoints and cytokines revolutionized the treatment of cancer and autoimmune diseases. The field continues to evolve rapidly with the advent of antibody–drug conjugates, bispecific antibodies, and CAR T-cell therapies. As we face global health challenges, antibody research remains at the forefront of medical innovation and offers promising solutions for the future.

RADT-39. CENTRAL NERVOUS SYSTEM BRIDGING RADIOTHERAPY (CNS-BRT) ACHIEVES RAPID CYTOREDUCTION PRIOR TO CAR T-CELL THERAPY FOR AGGRESSIVE B-CELL LYMPHOMAS

Abstract BACKGROUND CAR T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma to improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that CNS-BRT would achieve similar, significant cytoreduction prior to CART for CNSL. METHODS We analyzed CNSL patients with non-Hodgkin B-cell lymphomas who received CNS-BRT prior to commercial CART. Best CNS response post-CART was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or RANO for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CART. RESULTS Twelve patients received CNS-BRT, with median follow up of 11.8m (IQR: 8.5–21.9). Ten had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten CNSL patients had progressive disease at the time of CNS-BRT. RT targets included whole brain (n=3), involved site (partial) brain (n=4), involved site spine (n=4), and orbits (n=1) with median dose 24Gy (range: 15-33). 1/12 patients experienced grade ≥3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95%CI: 62.0–86.0) mean reduction in lesion size from baseline (p=0.014) at a median of only 12d from BRT completion and pre-CART infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field for a 12-month estimated risk of CNS progression post-CART of 20.0% (95%CI: 3–49). CONCLUSIONS Early data suggest CNS-BRT achieves rapid cytoreduction and favorable CNS response. The rates of severe CRS/ICANS were similar to comparison series of CNSL patients treated with CART without BRT suggesting an acceptable safety profile. Our data support further study of BRT as a bridging strategy for CNSL-directed CART.

Synthetic Biology in T-cell Engineering Research

Synthetic biology has emerged as a transformative discipline, enabling precise genetic and functional reprogramming of cellular systems. In T-cell engineering, it offers groundbreaking potential to revolutionize immunotherapy by endowing T cells with enhanced specificity, adaptability, and resilience against complex diseases such as cancer and autoimmune disorders. By integrating advanced genome-editing tools like CRISPR-Cas9 with modular synthetic constructs, researchers can design T cells with bespoke functionalities, such as tunable antigen recognition, controlled cytokine release, and resistance to immunosuppressive tumor microenvironments. This approach not only overcomes the limitations of conventional T-cell therapies but also facilitates the development of novel therapeutic paradigms, including "smart" cellular systems capable of sensing and responding to dynamic biological cues. Furthermore, synthetic circuits allow for the incorporation of logic-gated mechanisms to minimize off-target effects and enhance therapeutic precision. Despite these advancements, challenges remain in optimizing safety, scalability, and regulatory compliance. This research aims to explore the intersection of synthetic biology and T-cell engineering, highlighting cutting-edge methodologies, therapeutic applications, and emerging trends. By addressing current limitations and envisioning future possibilities, this work seeks to contribute to the growing body of knowledge driving synthetic biology toward clinical and industrial breakthroughs in cellular immunotherapy.

Coinfection of EBV with other pathogens: a narrative review

The Epstein-Barr viwrus (EBV) is a common herpesvirus that affects more than 90% of people worldwide. Even while EBV infections are frequently asymptomatic, they can cause autoimmune diseases and a number of cancers, especially in those with impaired immune systems. The intricate relationships between EBV and other coinfecting pathogens, including as human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), and Plasmodium species, are examined in this study. We investigated the fundamental processes of these coinfections, their effects on the course of the disease, and their practical ramifications. The study reviewed how co-infections with EBV might modify immune responses, promote oncogenesis, and make treatment plans more challenging. In this review, we also discussed current therapeutic strategies, such as targeted molecular interventions, EBV vaccines, and adoptive T-cell therapy. The review underscores the need for more research to provide more focused and effective therapies that address the mutually reinforcing effects of numerous infections in disorders linked with EBV.

Equecabtagene Autoleucel in Patients With Relapsed or Refractory Multiple Myeloma

Equecabtagene autoleucel (eque-cel), a fully human-derived B-cell maturation antigen-targeting chimeric antigen receptor (CAR) T-cell therapy, has exhibited potential for the treatment of relapsed or refractory multiple myeloma (RRMM), and further investigation in a larger cohort is necessary. To evaluate whether eque-cel can benefit patients with RRMM and determine the overall response rate postinfusion. The FUMANBA-1 trial was a single-arm, open-label, phase 1b/2 trial that evaluated eque-cel in adult patients with RRMM. Enrollment began in April 2020, and patients who received eque-cel will be monitored for a minimum of 15 years following the infusion. As of September 2022, patients with heavily pretreated RRMM who received at least 3 prior courses of therapy from 14 centers were enrolled. Data were analyzed from April 2020 to September 2022. Patients received a single infusion of eque-cel at 1.0 × 106 CAR-positive T cells/kg after the lymphodepletion. Efficacy was the primary objective, and safety, pharmacokinetics, and pharmacodynamics were secondary objectives. Of 103 patients who received an eque-cel infusion, 55 (53.4%) were male, and the median (range) age was 58 (39-70) years. A total of 101 patients were evaluable for efficacy. At a median (range) follow-up of 13.8 (0.4-27.2) months, the overall response rate was 96.0% (97 of 101), with 74.3% (75 of 103) achieving a complete response or better. Among the 12 patients who had prior CAR T-cell treatment, 75% (9 of 12) achieved a response. The median progression-free survival was not reached, with a 12-month progression-free survival rate of 78.8% (95% CI, 68.6-86.0). A total of 96 patients (95.0%) achieved minimal residual disease negativity at a sensitivity threshold of 10-5. Adverse events were favorable: 96 of 103 patients (93.2%) experienced cytokine release syndrome (grade 1 to 2 in 95 patients [92.3%]) and 2 (1.9%) experienced immune effector cell-associated neurotoxicity syndrome (grade 1 to 2). All cases of immune effector cell-associated neurotoxicity syndrome and 94 of 96 cases of cytokine release syndrome resolved with treatment. Additionally, only 20 patients (19.4%) developed antidrug antibodies. Cellular kinetic analysis confirmed CAR-positive T cells in all patients, with the longest duration at 735 days. In this trial, eque-cel led to early, deep, and durable responses in patients with heavily pretreated RRMM with a manageable safety profile. Patients with prior CAR T-cell therapy also benefitted from eque-cel. Chinese Clinical Trial Registry Identifier: ChiCTR2000033946.