Cytokine Release Syndrome Research Articles

First-in-Human Phase 1 study of a CD16A bispecific innate cell engager, AFM24, targeting EGFR-expressing solid tumors.

Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on natural killer (NK) cells/macrophages and EGFR on tumor cells, redirecting antitumor activity towards tumors. The safety and tolerability of AFM24 was evaluated in this Phase 1/2a dose escalation/dose expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR. The main objective in Phase 1 was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints included the incidence of treatment emergent adverse events and pharmacokinetics. In the dose escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a DLT of Grade 3 infusion-related reaction (IRR). IRRs were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics were dose-proportional and CD16A receptor occupancy on NK cells approached saturation between 320-480 mg. Paired tumor biopsies demonstrated activation of innate and adaptive immune responses within the tumor. Best objective response was stable disease in 10/35 patients; four had stable disease for 4.3-7.1 months. AFM24 was well tolerated with 480 mg established as the RP2D. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.

HSP-CAR30 WITH A HIGH PROPORTION OF LESS-DIFFERENTIATED T CELLS PROMOTES DURABLE RESPONSES IN REFRACTORY CD30+ LYMPHOMA.

CD30-directed CART cell therapy (CART30) has limited efficacy in relapsed or refractory patients with CD30+ lymphoma, with a low proportion of durable responses. We have developed an academic CART30 cell product (HSP-CAR30) by combining strategies to improve performance. HSP-CAR30 targets a proximal epitope within the non-soluble part of CD30, and the manufacturing process includes a modulation of ex vivo T cell activation, as well as the addition of interleukin-21 to IL-7 and IL-15 to promote stemness of T cells. We translated HSP-CAR30 to a phase 1 clinical trial of 10 patients with relapsed/refractory classical Hodgkin lymphoma (HL) or CD30+ T cell lymphoma (T-NHL). HSP-CAR30 was mainly composed of memory stem-like (TSCM-LIKE) and central memory (TCM) CAR30+ T cells (87.5%±5%). No dose-limiting toxicities were detected. Six patients had grade 1 cytokine release syndrome, and no patient developed neurotoxicity. The overall response rate was 100%, and 5 out of 8 patients with HL achieved complete remission (CR). An additional HL patient achieved CR after a second HSP-CAR30 infusion. Remarkably, 60% of patients have ongoing CR after a mean follow-up of 34 months. Of note, CAR30+ T cells at expansion peak had a predominance of TSCM and TCM cells, and CAR30+ T cells remained detectable in 3 of 5 evaluable patients at least 12 months after infusion. Our study shows that selection of the epitope targeting CD30 and ex vivo preservation of less-differentiated memory T cells may enhance the efficacy of CART30 in patients with refractory HL. This trial is registered at www.clinicaltrials.gov (NCT04653649).

Evaluation and comparison of infusion reactions related to prophylactic medication timing for taxane administration.

Taxane medications, paclitaxel, and docetaxel, are chemotherapy agents that have a higher incidence of reported hypersensitivity and infusion reactions. To help classify these reactions, the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) is utilized. Prophylactic medications have been used to decrease the incidence and severity of these events. At our institution, medications that patients can receive prior to the initiation of a taxane infusion are a histamine 1 receptor antagonist (H1RA), histamine 2 receptor antagonist (H2RA), a steroid or a combination of these medications. The purpose of this retrospective review was to compare the rates and severity of infusion reactions based on the timing of prophylactic medication administration in the first and second doses of taxane infusions. Patients who received paclitaxel or docetaxel from January 30th, 2022, through January 30th, 2023, were included in the analysis. To assist in the identification of a reaction, taxane administrations were flagged for review if a rescue medication was administered after the start of a paclitaxel or docetaxel infusion. The rates and severity of infusion reactions were analyzed based on the timing of prophylactic medication administration. A sub-group analysis comparing infusion reaction characteristics between taxanes given, was performed. Of the 1486 taxane infusions that were completed within the year, 249 infusion reactions were confirmed and graded utilizing the NCI CTCAE. When examining the first and second doses of a taxane (N = 536), we identified 222 infusions reactions. The odds of a patient having an infusion reaction, during the first and second doses, was found to be less likely for patients given a prophylactic medication 30 min prior to receiving a taxane compared to those who did not receive a pre-medication (p = 0.037). This multisite retrospective study showed that administration of prophylactic medications 30 to 80 min prior to the first and second infusion of a taxane was the optimal timing to decrease the likelihood of patients having an infusion reaction. No difference in the severity of the reaction was seen. Most patients were able to complete the entire infusion, regardless of what rescue medications were used following the infusion reaction.

Cardiotoxic Effects Following CAR-T Cell Therapy: A Literature Review.

This paper reviewed the current literature on incidence, clinical manifestations, and risk factors of Chimeric Antigen Receptor T-cell (CAR-T) cardiotoxicity. CAR-T therapy has emerged as a groundbreaking treatment for hematological malignancies since FDA approval in 2017. CAR-T therapy is however associated with a few side effects, among which cardiotoxicity is of significant concern. There were only a few studies on CAR-T cardiotoxicity published to date with limited sample sizes, and their findings were heterogeneous. It was difficult to reach generalizable conclusions. CAR-T therapy was associated with significant risks for acute and subacute cardiotoxicity, as measured by echocardiograms, EKG, and blood biomarkers. Patients with cytokine release syndrome (CRS) grade 2 or higher were more likely to exhibit cardiotoxicity. The most prevalent cardiac events included hypotension-requiring inotropic or vasopressor support, tachycardia, heart failure/decompensation, atrial fibrillation, new or worsening cardiomyopathy, arrhythmia, myocarditis, cardiac arrest, and cardiovascular death. The most prevalent echocardiographic changes were systolic dysfunction and diastolic dysfunction, and abnormal echocardiogram findings. There were differences in findings between adult and pediatric patients. The long-term effects beyond a year post treatment remain largely unknown and long-term follow-up studies are warranted.

Letetresgene Autoleucel in Advanced/Metastatic Myxoid/Round Cell Liposarcoma.

The cancer/testis antigen New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a promising target in myxoid/round cell liposarcoma (MRCLS). In this pilot study, we assessed the adoptive T-cell therapy NY-ESO-1c259T letetresgene autoleucel (lete-cel) in patients with human leukocyte antigen (HLA)-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-positive advanced/metastatic NY-ESO-1-expressing MRCLS. Patients underwent a reduced-dose (cohort 1) or standard-dose (cohort 2) lymphodepletion regimen (LDR). The primary end point was investigator-assessed overall response rate (ORR). Safety was assessed through adverse event (AE) reports. Correlative biomarker analyses were performed post hoc. The trial is registered at ClinicalTrials.gov (identifier: NCT02992743). Of 23 enrolled patients, 10 in cohort 1 and 10 in cohort 2 received lete-cel. Investigator-assessed ORR was 20% (95% CI, 2.5 to 55.6) and 40% (95% CI, 12.2 to 73.8), median duration of response was 5.3 months (95% CI, 1.9 to 8.7) and 7.5 months (95% CI, 6.0 to not estimable [NE]), and median progression-free survival was 5.4 months (95% CI, 2.0 to 11.5) and 8.7 months (95% CI, 0.9 to NE) in cohorts 1 and 2, respectively. AEs included cytokine release syndrome and cytopenias, consistent with T-cell therapy/LDR. Post hoc correlative biomarkers showed T-cell expansion and persistence in both cohorts. To our knowledge, this study is the first demonstrating the clinical promise of lete-cel in HLA-/NY-ESO-1-positive patients with advanced MRCLS.

Cardiovascular Complications of Immune Effector Cell Therapies in Pediatric Hematological and Solid Tumors.

Immune effector cell (IEC) therapies, including chimeric antigen receptor (CAR)-modified T-cell therapy, have shown efficacy in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and are being investigated for other malignancies. A common toxicity associated with IEC therapy is cytokine release syndrome (CRS), which can lead to cardiovascular decompensation due to systemic inflammation. Data are limited regarding cardiovascular adverse effects in children. This study aims to describe the cardiovascular adverse effect profile of IEC therapies in pediatric patients with hematologic and solid tumor malignancies. We retrospectively reviewed patients who received IECs directed towards various targets in patients with hematologic, solid, and brain tumor malignancies from January 2014 to June 2023 at Texas Children's Hospital. The primary end point was hypotension requiring vasoactive support and/or heart failure within 30 days of infusion. A total of 203 patients met inclusion criteria. Pretreatment echocardiogram was available for 142 (70%) pediatric patients, of whom 140 (96%) had normal baseline systolic function. Hypotension requiring vasoactive support occurred in 26 (13%) patients. Hematologic malignancy indications (p = 0.002), total body irradiation (TBI) (p = 0.002), and allogenic hematopoietic stem cell transplants (HCT) (p = 0.035) were associated with increased risk of hypotension requiring vasoactive support. Follow-up echocardiograms were available for 14 patients who met the primary end point, and all showed return to baseline within 6 months. Significant hemodynamic compromise occurred in a minority of patients treated with IEC therapies. All experiencing cardiac dysfunction had recovery of function, and there was no cardiovascular-related mortality.

Herpesvirus Infections After Chimeric Antigen Receptor T-Cell Therapy and Bispecific Antibodies: A Review.

In this narrative review, we explore the burden and risk factors of various herpesvirus infections in patients receiving chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies (BsAb) for the treatment of hematologic malignancies. Antiviral prophylaxis for herpes simplex/varicella zoster viruses became part of the standard of care in this patient population. Breakthrough infections may rarely occur, and the optimal duration of prophylaxis as well as the timing of recombinant zoster immunization remain to be explored. Clinically significant cytomegalovirus (CMV) infections can affect up to 10% of patients after CAR-T, depending on the CAR-T product target, post-CAR-T complications such as cytokine release syndrome and the need for glucocorticoid therapy. Surveillance and prophylactic strategies for CMV need to be developed, whereas the risk factors for and the burden of CMV infections after BsAb are not yet well-defined. Human herpes virus 6 reactivation and end organ disease such as encephalitis are rarely reported after CAR-T and have not yet been reported after BsAb; additional research is needed.

Epcoritamab-Induced fatal pleural effusion in diffuse large B-Cell lymphoma: a case report and literature review.

Epcoritamab, a bispecific T-cell engager (BiTE) antibody targeting CD3 and CD20, has shown significant efficacy in treating refractory diffuse large B-cell lymphoma (DLBCL). However, its use can lead to severe side effects, such as tumor flare. Here, we report the case of an 84-year-old male with relapsed DLBCL who developed fatal unilateral pleural effusion following Epcoritamab treatment. Initially, the patient showed a favorable response, but later developed significant pleural effusion with elevated interleukin-6 (IL-6) levels, indicating a severe inflammatory response. This suggests that Epcoritamab directly affected the pleural lesions and caused a local cytokine release syndrome (L-CRS). Despite aggressive management, including Tocilizumab and Dexamethasone, the patient's condition worsened, leading to his death. This case underscores the importance of regular lab tests and imaging follow-ups to monitor and manage severe inflammatory reactions based on tumor location. Comprehensive monitoring protocols are needed to mitigate risks associated with novel immunotherapies. To our knowledge, this is the first reported case of fatal unilateral pleural effusion in a patient with relapsed DLBCL following Epcoritamab treatment.

Cytokine release syndrome induced by dabrafenib and trametinib therapy in BRAF V600E-mutant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) with BRAF V600E mutations is responsive to targeted therapies, such as dabrafenib and trametinib. However, these treatments can lead to serious adverse events, including cytokine release syndrome (CRS). Herein, we report the case of a 75-year-old man with stage IVB NSCLC and a BRAF V600E mutation who developed severe CRS, manifesting hepatic and renal dysfunction, following treatment with dabrafenib and trametinib. Despite initial fever management, the patient's renal function deteriorated rapidly, necessitating hemodialysis. Elevated cytokine levels, including interleukin-6, interferon-γ, and tumor necrosis factor α, were detected. The patient was treated with steroid pulse therapy, which resulted in fever resolution, and his renal function gradually improved. Hemodialysis was discontinued as renal function recovered. This case underscores the importance for early recognition and management of CRS in patients receiving targeted therapies. Prompt intervention with steroids may prevent CRS progression and mitigate associated organ dysfunction. Further investigation is required to clarify the mechanisms of CRS in patients receiving targeted therapy, particularly in the absence of prior immune checkpoint inhibitor use.

Comprehensive Review of Early and Late Toxicities in CAR T-Cell Therapy and Bispecific Antibody Treatments for Hematologic Malignancies.

Chimeric antigen receptor T-cell (or CAR-T) therapy and bispecific antibodies (BsAbs) have revolutionized the treatment of hematologic malignancies, offering new options for relapsed or refractory cases. However, these therapies carry risks of early complications, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and delayed issues like graft-versus-host disease (GVHD), infections, and secondary cancers. Effective management requires early diagnosis using advanced biomarkers and imaging, along with prompt interventions involving immunosuppressants, corticosteroids, and cytokine inhibitors. A multidisciplinary approach is essential, integrating hematologists, oncologists, and infectious disease specialists, with emerging strategies like targeted biologics and personalized medicine showing promise in balancing efficacy with toxicity management. Ongoing research is critical to refine diagnostics and treatments, ensuring that these therapies not only extend survival but also improve patients' quality of life. This review provides critical insights for healthcare professionals to quickly recognize and treat complications of CAR-T and BsAbs therapies. By focusing on early detection through biomarkers and imaging and outlining timely therapeutic interventions, it aims to equip the multidisciplinary care team with the knowledge necessary to manage the challenges of these advanced treatments effectively, ultimately optimizing patient outcomes.

Clinical Benefit of Pegylated Liposomal Doxorubicin and High Prevalence of Pre-Existing Psychiatric Conditions in Patients with Desmoid-Type Fibromatosis.

Background/Objectives: Desmoid-type fibromatosis (DTF) is a locally invasive tumor composed of myofibroblast-like cells and collagen; it does not metastasize but can cause significant local morbidity. Most sporadic cases are associated with mutations in the CTNNB1 gene, which encodes beta-catenin. Various treatments have been used with differing efficacy and toxicity profiles. At our institution, pegylated liposomal doxorubicin (PLD) has become the preferred treatment for patients with DTF. We aim to describe our experience using PLD in patients with DTF who require treatment. Methods: A retrospective review of 61 DTF patients (41 females, 20 males) treated between 2000 and 2023 was conducted to assess the efficacy and toxicity of PLD. Results: Of the 26 patients treated with PLD, 23 had follow-up clinical data to assess benefit. Twenty-one showed clinical benefit, and only one progressed. Two patients did not benefit from PLD due to infusion reactions and chose alternative therapies. The primary side effect of PLD was hand-foot syndrome (HFS), but dose reduction and extended intervals allowed most patients to tolerate treatment. Other treatments, such as methotrexate, vinblastine/vinorelbine, and sorafenib, also showed activity but had significant toxicities, including severe HFS, malaise, and hypertension. Interestingly, 31 out of 61 patients had a pre-existing history of psychiatric conditions (primarily depression and anxiety), and 6 of 41 women had personal or family history of polycystic ovary syndrome (PCOS). Additionally, 15 patients had obesity, and 4 had hypothyroidism. Conclusions: PLD is an effective and well-tolerated treatment for DTF, with good clinical responses at lower, tolerable doses. The association of pre-existing psychiatric diagnoses, PCOS, and obesity warrants further investigation.

Role of procalcitonin, C reactive protein and ferritin in cytokine release syndrome after CAR T-cell therapy in children and young adults

ABSTRACT Purpose Chimeric antigen receptor (CAR) T-cell CD19 therapy has changed the treatment paradigm for patients with relapsed/refractory B-cell acute lymphoblastic leukemia. It is frequently associated with potentially severe toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and admission to PICU is often required. Some biomarkers seem to correlate with CRS severity. Our goal is to elucidate the role of procalcitonin (PCT), C-reactive protein (CRP) and ferritin in the context of CRS following CAR T-cell infusion to predict its severity and PICU admission. Methods Prospective observational study (2016-2022) in children and young adult who received CAR T-cell therapy (Tisagenlecleucel/ARI-0001). We collected epidemiologic data, specific CAR T-cell toxicities, PICU admission, biomarker results (procalcitonin, CRP and ferritin), length of stay and mortality. Biomarkers were analyzed considering two values: the highest value during ward admission, and the highest overall value including PICU admission. Results Seventy-seven patients were included. Median age at infusion was 9.1 years (IQR 6-13), 49.4% were females. Before CAR T-cell infusion, the median bone marrow blast was 9% (IQR 0-59). The most frequent toxicity was CRS in 62 patients (80.5%), it was severe in 18 cases (23.4%). Fourteen patients (18.1%) had ICANS. Thirty-one patients (40.3%) required admission to the PICU. PCT and ferritin were higher in patients admitted to PICU (PCT 0.8 ng/ml vs 0.15 ng/ml, p < 0.001, ferritin 5490 vs. 2900 ug/l, p < 0.019). The proposed cut-off for PCT to predict admission to PICU is 0.55 ng/mL, presenting a sensitivity of 67.7% and a specificity of 86.7%. The maximum value of the three biomarkers was higher in those who presented any primary outcome: development of a severe CRS, the need for admission to PICU, and in-hospital mortality. Biomarkers were higher in those who needed inotropic or respiratory support. Conclusions PCT levels increase after CAR-T cell therapy in the setting of systemic inflammation and could be a predictor of PICU admission and evolution to death. Further research studying its role in the context of CRS and the differential diagnosis between infection and CRS is needed to better understand the biology of this biomarker and to define its value in clinical practice.

Horse antithymocyte globulin test doses and infusion reactions in adults with aplastic anemia: A multicenter retrospective experience

Introduction Horse antithymocyte globulin carries a black box warning for life-threatening anaphylactic reactions, and prescribing information recommends test doses to identify patients at highest risk of this adverse effect. The predictive value of such test doses is not well validated, and practicality of use is unclear. Methods This was a planned secondary analysis of a multicenter, retrospective cohort study in adults with severe aplastic anemia being managed with horse antithymocyte globulin as part of their treatment regimen. Qualitative and quantitative descriptions of test doses and infusion reactions are summarized, alongside key institutional administration practices. Results Of 49 patients who received intradermal test doses, two experienced positive reactions and went onto receive their full horse antithymocyte globulin course through prolonged infusion time or desensitization. Infusion reaction rate in patients with negative test doses was 61%, corresponding to a negative predictive value of 39%. Premedication, infusion time, and infusion reaction management were similar across institutions. Conclusion Horse antithymocyte globulin has a high risk of infusion reactions that must be monitored and managed closely. However, test doses do not consistently predict who will experience an infusion reaction, and their practicality may be limited with current administration practices.

Post-transplant cyclophosphamide plus anti-thymocyte globulin decreased serum IL-6 levels when compared with post-transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation

BackgroundPost-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common prophylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.MethodThe clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from January 2019 to February 2023.ResultsForty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).ConclusionSerum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.

Donor-derived GD2-specific CAR T cells in relapsed or refractory neuroblastoma.

Allogeneic chimeric antigen receptor (CAR) T cells targeting disialoganglioside-GD2 (ALLO_GD2-CART01) could be a therapeutic option for patients with relapsed or refractory, high-risk neuroblastoma (r/r HR-NB) whose tumors did not respond to autologous GD2-CART01 or who have profound lymphopenia. We present a case series of five children with HR-NB refractory to more than three different lines of therapy who received ALLO_GD2-CART01 in a hospital exemption setting. Four of them had previously received allogeneic hematopoietic stem cell transplantation. All patients experienced grade 2 or 3 cytokine release syndrome and one grade 2 neurotoxicity. Moderate acute graft-versus-host-disease occurred in four patients. ALLO_GD2-CART01 persisted for >6 weeks. Post-treatment, two complete responses were achieved and one maintained; in addition, one partial response and one stable disease were observed. Comparing the transcriptomic profiles obtained by RNA sequencing analyses of drug products with patient-matched, peripheral blood ALLO_GD2-CART01 collected at expansion, we found upregulation of genes associated with T cell activation and migration. In addition, after infusion, transcriptomic signaling analysis showed enrichment of genes involved in response to decreased oxygen levels, humoral immune response, cell polarization and immune-synapse formation. In comparison to autologous CAR T cells, ALLO_GD2-CAR T cells were characterized by pathways associated with T cell proliferation, immune-synapse formation and cell chemotaxis. The safety and efficacy of ALLO_GD2-CART01 in children with r/r HR-NB deserve further investigation in a prospective trial.

CRISPR/Cas9-Enhanced CAR-T Cell Therapy for Hematological Malignancies

CRISPR/Cas9 technology has brought revolution to the field of gene editing, offering precise and efficient tools for genetic modifications. One of its most promising applications lies in improving CAR-T cell therapy for treating hematological malignancies. Among approaches to treating blood cancers, CAR-T therapy, which programs T cells to recognize and eliminate cancer cells, has shown some success for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (ALL). However, challenges such as immune evasion, cytokine release syndrome (CRS), neurotoxicity, and limited CAR-T persistence remain significant barriers. CRISPR/Cas9 can optimize CAR-T therapy by precisely inserting CAR genes into specific loci, knocking out inhibitory genes like PD-1 to enhance persistence, and enabling multi-targeting strategies to overcome tumor immune escape. Clinical trials demonstrate the feasibility and potential of CRISPR-edited CAR-T cells, showing improved safety, durability, and efficacy. This study explores the synergistic application of CRISPR/Cas9 in CAR-T therapy, addressing its current limitations and providing a pathway to safer and more effective treatments for hematological malignancies

A phase 1 trial of prizloncabtagene autoleucel, a CD19/CD20 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma.

Prizloncabtagene autoleucel (prizlon-cel), a novel bispecific chimeric antigen receptor (CAR) T-cell, targets and eliminates CD19/CD20 positive tumor cells. This phase 1, open-label study investigated the safety and efficacy of prizlon-cel in patients with relapsed/refractory B-cell non-Hodgkin Lymphoma (r/r B-NHL). Patients with CD19 and/or CD20-positive r/r B-NHL received a 3-day lymphodepletion (cyclophosphamide: 300 mg/m2/d; fludarabine: 30 mg/m2/d) followed by an intravenous dose of prizlon-cel. The primary endpoints were dose-limiting toxicity (DLT) and incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of the 48 patients infused prizlon-cel, 44 had large B-cell lymphoma (LBCL). No patient experienced DLT. Cytokine release syndrome occurred in 93.8% of patients, with only one case of grade 3. Immune effector cell-associated neurotoxicity syndrome occurred in 6.3% of patients, with no grade 3 or higher events. The most common grade 3 or higher TEAEs were neutropenia (83.3%) and leukopenia (50%). The ORR and complete response (CR) rates in all patients were 91.5% and 85.1%, respectively, and in LBCL patients, ORR was 90.7% with 86.0% CR. With median follow up of 30.0 months, median DOR, PFS, and OS were all not reached. The Kaplan-Meier estimate of 2-year DOR, PFS and OS rates were 66.0%, 62.6%, and 76.5%, respectively. Prizlon-cel showed a favorable safety profile and a high and durable response in patients with r/r B-NHL, suggesting a promising treatment option for patients with r/r B-NHL. (ClinicalTrials.gov number: NCT04317885, NCT04655677, NCT04696432, NCT04693676).

Case report: The case of T-cell acute lymphoblastic leukemia treated with chemotherapy followed by anti-CD7 CAR-T cells using retroviral vector

CD7-targeted chimeric antigen receptor-T (CAR-T) cell therapy has shown great promise in the treatment of relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL). In this study, we reported a case of a 34-year-old male patient with T-ALL who finally developed multi-line drug resistance and refractoriness after multiple lines of high-intensity chemotherapy. After physician evaluation, this patient received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Then, The patient remained in complete remission (CR) for four months before a relapse with 26.64% chimerism rate, so he was treated with allogeneic anti-CD7 CAR-T cells after chemotherapy reducing the tumor burden. The CAR-T product was a novel anti-CD7 CAR-T based on retroviral vectors (RV). After infusion, the patient achieved CR within 1 month after anti-CD7 CAR-T infusion and the remission has been ongoing for 9 months to date. Cytokine release syndrome (CRS) 1 was experienced while no immune effector cell-associated neurotoxicity syndrome (ICANS) was found. In addition, CAR copy number peaked at 350, 758 copies/μg on day 6. This case report of clinical treatment of T-ALL with anti-CD7 CAR-T cells prepared using a retroviral vector without gene editing and combined with chemotherapy, which demonstrated that the RV-based anti-CD7 CAR-T cells had good therapeutic effect and high safety in triple-refractory T-ALL patients.

Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy

There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and -3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. ClinicalTrials.gov Identifier: NCT02510261.

Anti-Tumor Necrosis Factor-α Use in Pediatric Inflammatory Bowel Disease-Reports from a Romanian Center.

Background/Objectives: The introduction of anti-tumor necrosis factor-α (anti-TNF-α) agents, particularly infliximab (IFX) and adalimumab (ADA), has significantly expanded the therapeutic arsenal for inflammatory bowel disease (IBD). While these biologics have demonstrated substantial efficacy, they are associated with a spectrum of potential adverse events (AEs). This study aims to evaluate and document these AEs to facilitate optimal patient selection and monitoring strategies of patients undergoing these therapies. Methods: This retrospective, single-center study examined pediatric IBD patients receiving anti-TNF-α therapy at the "Grigore Alexandrescu" Emergency Hospital for Children in Bucharest, Romania, from January 2015 to October 2024. AEs were categorized into non-infectious complications (acute infusion reactions, anti-drug antibody formation), dermatological effects (erythema nodosum, vasculitis), neurological effects (Guillain-Barré syndrome), and infections. AEs were analyzed in relation to the specific anti-TNF-α agent administered and comprehensively characterized. Results: Of 40 patients enrolled, 22 (55%) had Crohn's disease (CD). The median (IQR) age at diagnosis was 14.8 years [10.8-15.9]. IFX was used in 34 (85%) patients while 6 (15%) patients received either ADA or IFX/ADA sequential therapy. Twenty-seven AEs were documented in 19 (47.5%) patients, the most prevalent being antidrug antibody formation (44.4%), infections (22.2%), and acute infusion reactions (22.2%). All ADA-exposed patients experienced at least one AE, compared to 41.2% (n = 14) patients treated with IFX, p = 0.01. Conclusions: AEs were observed in approximately half of the study cohort, with anti-drug antibody formation emerging as the most frequent complication. ADA therapy was associated with a significantly higher rate of AEs compared to IFX. These findings underscore the critical importance of vigilant monitoring for patients undergoing anti-TNF-α therapy in pediatric IBD management.