HD-CAR-1 / Heidelberg University Hospital - LARVOL DELTA

Patterns, risk factors and management of CD19-directed chimeric antigen receptor T-cell therapy failure in CNS lymphoma (ASH 2025) - "Notably,peripheral CD19+-B-cell aplasia suggested persistence of CD19-CAR T-cells in 93% of patients at PD.Salvage immune checkpoint inhibition (pembrolizumab, nivolumab), and lenalidomide with rituximab ortafasitamab yielded prolonged responses in a subset of patients, often exceeding 5 months... Our study identifies novel radiological risk factors for CD19-CAR failure in patients withCNSL, namely peripheral CE and LMD prior to CD19-CAR, which may guide prognostic stratification atbaseline. Outcome after CD19-CAR failure remains poor, underlining the need for rational salvagetreatments. In patients progressing after CD19-CAR therapy, we noted encouraging responses aftersalvage ICI and lenalidomide combined with rituximab/tafasitamab, which warrant further investigationin prospective studies."

CAR T-Cell Therapy • Clinical • IO biomarker • CNS Disorders • CNS Lymphoma • Hematological Malignancies • Lymphoma

Impact of prior B-cell-directed immunotherapy on the outcome of CD19 CAR T-cell therapy in aggressive B-cell lymphoma - an analysis of the EBMT and the GoCART coalition (ASH 2025) - "Introduction:Treatment outcomes of diffuse large B-cell lymphoma (DLBCL) and related large B-cell lymphoma (LBCL)have been revolutionized by novel B-cell-directed immunotherapies (BCDI), such as CD19-targetingchimeric antigen receptor T-cell therapy (CAR-T), polatuzumab vedotin (pola), and bispecific antibodies(BSA)...Here, wecompare outcomes of patients (pts) receiving BCDI (excluding rituximab) versus conventional treatmentsprior to CD19 CAR-T in a large European multicenter cohort.We collected retrospective data on the use and type of BCDI, as well as outcomes from 1154 adult ptsacross 38 European centers who received CD19 CAR-T between 2018 and 2023 for LBCL, identified in theEuropean Group for Blood and Marrow Transplantation (EBMT) registry...Twenty-four of 380 pts (6.3%) received BSA, 305 (80.3%)pola-based regimens, and 51 (13.4%) other BCDI (including obinutuzumab, 26 pts; brentuximab, 16 pts).The BCDI and non-BCDI groups were balanced for lymphoma diagnosis and..."

CAR T-Cell Therapy • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Infectious Disease • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Primary Mediastinal Large B-Cell Lymphoma

Fcγ-receptor-activation by circulating immune complexes in systemic autoimmune diseases and its reduction by CD19-CAR T-cell therapy. (PubMed, Rheumatology (Oxford)) - "Our study reveals the presence of FcyR-engaging cICs in CTDs and demonstrates that the bioactivity of cICs is correlated with clinical phenotypes and treatment outcomes."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Interstitial Lung Disease • Psoriatic Arthritis • Pulmonary Disease • Respiratory Diseases • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Sjogren's Syndrome • Systemic Sclerosis • TOP1

Clinical Presentation, Management and Outcome of Tumor inflammation-associated neurotoxicity (TIAN) in CNS lymphoma treated with CD19-CAR T-cell therapy (SNO 2025) - "Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to pre-existing CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management."

CAR T-Cell Therapy • Clinical • Brain Cancer • CNS Lymphoma • CNS Tumor • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Clinical Presentation, Management and Outcome of Tumor inflammation-associated neurotoxicity (TIAN) in CNS lymphoma treated with CD19-CAR T-cell therapy (WFNOS 2025) - "Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to pre-existing CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management."

CAR T-Cell Therapy • Clinical • Brain Cancer • CNS Lymphoma • CNS Tumor • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Clinical Presentation, Management and Outcome of Tumor inflammation-associated neurotoxicity (TIAN) in CNS lymphoma treated with CD19-CAR T-cell therapy (WFNOS 2025) - "Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to pre-existing CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management."

CAR T-Cell Therapy • Clinical • Brain Cancer • CNS Lymphoma • CNS Tumor • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

The Ig Superfamily Ligand B7H6 Subjects Activated T Cells to NK Cell Surveillance and Limits CAR T Cell Persistence (ASH 2023) - P2 | "We then co-injected CD19.CAR T cells and patient-autologous NK cells in leukemia-engrafted mice and observed reduced CAR T cell persistence in the peripheral blood of mice with NK cell co-injection...We therefore analyzed tissue of patients that were treated with nivolumab and ipilimumab (NCT03416244)...We therefore suggest an alternative immune checkpoint that limits T cell expansion and persistence in physiological and cellular engineering contexts. Targeting the B7H6-NKp30 axis may offer a means to modulate T cell immunity across multiple disease entities."

CAR T-Cell Therapy • Clinical • IO biomarker • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Leukemia • Lymphoma • Multiple Sclerosis • Oncology • T Cell Non-Hodgkin Lymphoma • CD4 • CD8 • GZMB • NCR3LG1

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma (ASH 2023) - "Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi)...Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi...Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented."

Acute Graft versus Host Disease • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Lymphoma • Mantle Cell Lymphoma • Oncology • Transplantation

The CAR-Hematotox As a Risk Model to Predict Early Complications and Outcome after Bispecific T-Cell Engager Therapy in Relapsed/Refractory Multiple Myeloma (ASH 2024) - "The CAR-HEMATOTOX (HTX) score was originally developed to predict long-lasting neutropenia following anti-CD19 CAR T-cell therapy, but has since then emerged as a risk model for other immune-related toxicities, infections and survival across cellular immunotherapies...Methods : This retrospective observational study included 128 RRMM patients who had received at least one step-up dose of either standard-of-care teclistamab (n=70) or talquetamab (n=58) at two major German myeloma centers until June 2024...Moreover, a HTX ≥ 2 was associated with a significantly increased rate of CRS grade ≥ 2 (36% vs. 12%; OR 4.33; 95% CI 1.59-11.53; p=0.004) and tocilizumab administration (43% vs. 17%; OR 3.55; 95% CI 1.43-8.16; p=0.004)...Conclusion : Our study provides first evidence for the HTX score as a suitable model for risk stratification prior to BTCE therapy. Such scores can potentially influence clinical decision-making regarding inpatient step-up dosing, frequency of clinical..."

IO biomarker • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

Clonal Evolution of Lymphoid Malignancies Following the Mutagenic Impact of Radiotherapy (ASH 2024) - "Finally, we validated and refined the indel landscape of chemoRT by exposing TP53-mutant lymphoma cells (DHL-4) to cisplatin and RT, then performing 30x bulk WGS of 15 single-cell-derived colonies...All of these RT-unexposed cases had evidence of platinum/melphalan mutagenesis...One LBCL case had an irradiated neck node prior to CD19 CART...Here, we see that even a single resistant tumor cell from an RT-exposed lesion can seed systemic relapse. further underscoring the need to eradicate disease in entirety to avoid propagation of resistant subclones."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Large B Cell Lymphoma • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Plasmacytoma • RB1 • SOCS1 • TNFAIP3 • TP53

Characterizing Environmental Adaption and Virulence of Gut Microbiome Enterococcus Spp. from Patients Receiving CD19-Targeted CAR-T Cell Therapy (ASH 2024) - "Methods 59 patients with B cell malignancies who underwent treatment with CD19-CAR-T cells at two university cancer centers in Germany (Munich and Heidelberg) were included, where we collected serial clinical data and stool samples...Results In vitro testing showed an increase in ampicillin resistance for E. faecium and E. faecalis from pre- to post-CAR-T time points (Fisher's exact test p-value = 0.08754 and p-value = 0.06234, respectively)...These findings suggest the need to perform strain-specific phenotyping in future microbe – host interaction studies in patients undergoing cell-based immunotherapies. Ultimately enabling future microbiome-based patient assessment and monitoring."

CAR T-Cell Therapy • Clinical • Graft versus Host Disease • Immunology • IL6

In-depth analysis of CD19.CAR T cells to elucidate the impact of cryopreservation on function, viability and frequency of subpopulations in these cells (DGHO 2025) - "Manufacturers have to be aware of this as all (commercially available CAR T) final products are stored frozen. Different surface marker expression has been observed in T cell subpopulations which could unveil factors that determine the cellular composition of these preparations and the actual CAR T cell product."

CAR T-Cell Therapy • Clinical • CD4 • CD8 • IL7

"Pathway inhibitor-refractory high-risk CLL: which cellular therapy first? A Single-Center Retrospective Study" (DGHO 2025) - "AlloHCT used matched related or unrelated donors and TBI 8Gy/fludarabine/ATG for conditioning. The 3rd generation product HD-CAR-1 was used for CART in all instances (Derigs et al, Leukemia 2024)... AlloHCT can provide long-lasting MRD eradication and disease control in patients with high-risk CLL having failed multiple lines of PI. In contrast, the curative potential of CART remains elusive. Therefore, CART provides a viable option for patients who are not alloHCT candidates, as a bridge to alloHCT, and for those who have previously failed transplantation."

Retrospective data • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Richter's Syndrome • TP53

Fcγ-receptor activation by circulating immune complexes in autoimmunity and CD19.CAR-T cell therapy (ACR Convergence 2025) - "In summary, our study closes a knowledge gap by proving the presence of FcγR-engaging cICs that can be associated with clinical parameters and treatment in systemic autoimmune diseases."

CAR T-Cell Therapy • Immunology • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Sjogren's Syndrome • Systemic Sclerosis

Bifunctional Cysteine-Engineered CAR‑T Cells Enable Thiol-Mediated Targeting to Overcome Antigen Escape in B Cell Lymphoma. (PubMed, ACS Cent Sci) - "In a pilot in vivo study, these bifunctional CD19-CysCAR-T cells suppressed tumor growth and prolonged survival of BCL-bearing mice without inducing systemic toxicity. Given that aberrant exofacial redox states are a hallmark of multiple cancers, our findings suggest a promising strategy to enhance the efficacy of anti-CD19 CAR-T cell therapy, overcome antigen escape, and reduce tumor relapse in BCL, with potential applicability to other malignancies."

IO biomarker • Journal • B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Clinical presentation, management, and outcome of TIAN in CNS lymphoma treated with CD19-CAR T-cell Therapy. (PubMed, Blood) - "Collectively, our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to pre-existing CNSL lesions and distinct from ICANS. CNS tumor volume at baseline may allow to identify patients at risk and may guide management."

Journal • Brain Cancer • CNS Lymphoma • CNS Tumor • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

Two years on persisting CD19.CAR-T cells and nintedanib: clinical response of systemic sclerosis-associated pulmonary fibrosis (EULAR 2025) - "Of note, fibrotic lesions in CT and areas of activated fibroblasts in FAPI-PET/CT further regressed in the second year of treatment, i.e. after prolonged deep B cell depletion and the achievement of serologic remission. Learning points for clinical practice: The case suggests serological remission and improvement of pulmonary fibrosis as new goals in the treatment of SSc."

CAR T-Cell Therapy • Clinical • Fibrosis • Immunology • Interstitial Lung Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis

Persisting CD19.CAR-T cells in combination with nintedanib: clinical response in a patient with systemic sclerosis-associated pulmonary fibrosis after 2 years. (PubMed, Lancet Respir Med) - No abstract available

Journal • Immunology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis

CD19.CAR-T CELL THERAPY FOR PULMONARY FIBROSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS OR RHEUMATOID ARTHRITIS (EBMT 2025) - "These three patients received i.v. a dose of 200 million CAR-T cells/sqm body surface after standard conditioning with fludarabine and cyclophosphamide...The patient had first received cyclophosphamide which was then switched to mycophenolate and nintedanib without achieving a stable disease...Serological remission and significant improvement of ILD in 68Ga-FAPI-PET/CT were achieved (increase in forced vital capacity +38%; reduction of the area of pulmonary fibrosis by more than -50%).The second patient (SSc, female, 62 y/o) finger tip ulcera and lung fibrosis and was put on nitedanib and mycophenolate mofetil (MMF) without significant improvement... In contrast to all other known patients with autoimmune diseases treated with 2nd generation 2ndGen CD19.CAR-T cell therapy, the 3rdGen CD19.CAR-T cells persisted in our patients, for up to two years now. After 6 months, the first patient responded, the two other patients were stabilized over a post treatment period of four..."

CAR T-Cell Therapy • Clinical • Cardiovascular • Fibrosis • Immunology • Infectious Disease • Inflammatory Arthritis • Interstitial Lung Disease • Lupus • Novel Coronavirus Disease • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis

CD19.CAR-T CELL THERAPY FOR PULMONARY FIBROSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS OR RHEUMATOID ARTHRITIS (EBMT 2025) - "These three patients received i.v. a dose of 200 million CAR-T cells/sqm body surface after standard conditioning with fludarabine and cyclophosphamide...The patient had first received cyclophosphamide which was then switched to mycophenolate and nintedanib without achieving a stable disease...Serological remission and significant improvement of ILD in 68Ga-FAPI-PET/CT were achieved (increase in forced vital capacity +38%; reduction of the area of pulmonary fibrosis by more than -50%).The second patient (SSc, female, 62 y/o) finger tip ulcera and lung fibrosis and was put on nitedanib and mycophenolate mofetil (MMF) without significant improvement... In contrast to all other known patients with autoimmune diseases treated with 2nd generation 2ndGen CD19.CAR-T cell therapy, the 3rdGen CD19.CAR-T cells persisted in our patients, for up to two years now. After 6 months, the first patient responded, the two other patients were stabilized over a post treatment period of four..."

CAR T-Cell Therapy • Clinical • Cardiovascular • Fibrosis • Immunology • Infectious Disease • Inflammatory Arthritis • Interstitial Lung Disease • Lupus • Novel Coronavirus Disease • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis

PATHWAY INHIBITOR-REFRACTORY HIGH-RISK CLL: WHICH CELLULAR THERAPY FIRST? A SINGLE-CENTER RETROSPECTIVE STUDY (EBMT 2025) - P1/2 | "AlloHCT used matched related or unrelated donors and was largely based on TBI 8Gy/fludarabine/ATG conditioning. The 3rd generation product HD-CAR-1 was used for CART in all instances (Derigs et al, Leukemia 2024)... AlloHCT can provide long-lasting MRD eradication and disease control also in patients with high-risk CLL having failed multiple lines of PI. In contrast, the curative potential of CART remains to be demonstrated. Therefore, CART provides a viable option for patients who are not alloHCT candidates, as well as a bridge to alloHCT, and for those who have previously failed transplantation."

Retrospective data • Chronic Lymphocytic Leukemia • Richter's Syndrome • TP53

PATHWAY INHIBITOR-REFRACTORY HIGH-RISK CLL: WHICH CELLULAR THERAPY FIRST? A SINGLE-CENTER RETROSPECTIVE STUDY (EBMT 2025) - P1/2 | "AlloHCT used matched related or unrelated donors and was largely based on TBI 8Gy/fludarabine/ATG conditioning. The 3rd generation product HD-CAR-1 was used for CART in all instances (Derigs et al, Leukemia 2024)... AlloHCT can provide long-lasting MRD eradication and disease control also in patients with high-risk CLL having failed multiple lines of PI. In contrast, the curative potential of CART remains to be demonstrated. Therefore, CART provides a viable option for patients who are not alloHCT candidates, as well as a bridge to alloHCT, and for those who have previously failed transplantation."

Retrospective data • Chronic Lymphocytic Leukemia • Richter's Syndrome • TP53

Immunological effects of CD19.CAR-T cell therapy in systemic sclerosis: an extended case study. (PubMed, Arthritis Res Ther) - "This report describes for the first time the phenotypic recovery of innate Fcγ-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fcγ receptor IIIA + cells such as NK cells."

CAR T-Cell Therapy • Journal • Immunology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis

Aggressive Lymphoma after CD19 CAR T-Cell Therapy. (PubMed, N Engl J Med) - "The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis."

CAR T-Cell Therapy • IO biomarker • Journal • CNS Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Transplantation • CD34 • CD8 • DNMT3A • TET2

Toxicities and Outcome after CD19-directed Chimeric Antigen Receptor T-cell Therapy for Neurolymphomatosis (SNO 2024) - "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."

CAR T-Cell Therapy • B Cell Lymphoma • CNS Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology