New Comorbidity Index Associated with Survival After Chimeric Antigen Receptor T Cell Therapy for Large B-Cell Lymphoma.

The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T cell (CAR-T) therapy is not well-established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017-2020 were selected from the CIBMTR registry.

CD19 CAR T-Cell Therapy for Primary Mediastinal Large B-Cell Lymphoma: A CIBMTR Analysis.

T cells engineered with CD19-directed chimeric antigen receptors (CD19 CAR) T cells have become standard treatment for patients with high risk, relapsed or refractory (R/R) large B-cell lymphomas (LBCL). However, outcomes in patients with rare subsets of LBCL, such as primary mediastinal large B-cell lymphoma (PBMCL), have not been well characterized. The impact of prior immune checkpoint inhibitor (ICI) treatment, commonly used to treat R/R PMBCL, is also unknown.

NKTR-255 Enhances Complete Response Following CD19 CAR-T in Patients with Relapsed/Refractory Large B-cell Lymphoma.

Autologous T-cells engineered to express CD19-directed chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory large B-cell lymphoma (LBCL). However, more than half of patients do not attain a durable response and will eventually relapse. Thus, strategies to improve long-term efficacy of CAR T-cell products are needed.

Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: A CIBMTR Analysis.

Relapsed and/or refractory Richter transformation (RT) is generally associated with poor response to available therapies and a short survival time. As RT patients were excluded from participating in the pivotal studies of chimeric antigen receptor T cell therapy (CAR-T) for large B-cell lymphoma, there is a paucity of information about the efficacy of CAR-T in RT. Therefore, through the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed data from 140 RT patients who received anti-CD19 CAR-T between 2018 and 2023.

Opportunities to Improve Antibiotic Stewardship, and Identification of Blood Biomarkers Associated with Bacteremia Following CAR-T Cell Therapy.

Cytokine release syndrome (CRS) is frequent after chimeric antigen receptor T-cell therapy (CAR-T). CRS and bacteremia share clinical features, making it difficult to distinguish between the two and deliver targeted treatment. As a result, most patients with CRS receive empiric broad-spectrum antibiotics that may adversely impact long-term outcomes.

Real-world outcomes of brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma: a CIBMTR analysis.

Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (r/r MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with r/r MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with r/r MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis.

Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia.

CD19 chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, approximately 20% of patients fail to achieve a complete remission (CR), and some develop severe, life-threatening toxicities. Understanding the biological mechanisms underlying both dysfunctional responses and severe toxicity is essential for optimizing patient management and improving therapeutic efficacy.

Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma.

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity.

A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up.

FCARH143, an autologous B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, which incorporates a fully human BCMA-specific single chain variable fragment and 4-1BB costimulatory domain, was evaluated in a phase 1 trial for relapsed/refractory multiple myeloma (RRMM). Patients were stratified by bone marrow plasma cell involvement (10%-30% or >30%) and received lymphodepleting chemotherapy followed by escalating CAR-T doses (50 × 106 to 450 × 106). The primary end point was safety; secondary end points were overall response rate (ORR), duration of response, and progression-free survival (PFS).

Cytokine-mediated increase in endothelial-leukocyte interaction mediates brain capillary plugging during CAR T cell neurotoxicity.

CD19-directed CAR T cells treat cancer, but also cause immune effector cell associated neurotoxicity syndrome (ICANS). Despite strong epidemiologic links between cytokine release syndrome and ICANS, it is uncertain how elevated systemic cytokines and activated immune cells cause brain dysfunction. We previously showed that leukocytes plug brain capillaries in an immunocompetent mouse model of CD19-CAR neurotoxicity.

Outcome correlates of approved CD19-targeted CAR T cells for large B cell lymphoma.

CD19-targeted chimeric antigen receptor (CAR) T cells have provided a breakthrough in the treatment of patients with relapsed and/or refractory large B cell lymphoma (LBCL). Currently, three CD19-targeted CAR T cell products are approved by the FDA and various other regulators for the treatment of patients with LBCL: axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel. Response rates following infusion of these CD19-targeted CAR T cells have been promising; however, approximately half of treated patients show relapse within 2 years.

Protection of CD33-modified hematopoietic stem cell progeny from CD33-directed CAR T cells in rhesus macaques.

The treatment of monogenetic disorders, such as hemoglobinopathies and lysosomal storage diseases, has markedly improved with the advent of cell and gene therapies, particularly allogeneic or gene-modified autologous stem cell transplantations. However, therapeutic efficacy is reliant on maintaining engraftment above a critical threshold. To maintain such engraftment levels, we and others have pursued approaches to shield edited cells from antibody or chimeric antigen receptor (CAR) T-cell-mediated selection.

Real-world outcomes with tisagenlecleucel in aggressive B-cell lymphoma: subgroup analyses from the CIBMTR registry.

Background: Tisagenlecleucel, a CD19 chimeric antigen receptor T-cell therapy, is approved for adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL) after ≥2 lines of therapy. When used in real-world settings, tisagenlecleucel has shown similar efficacy and improved safety compared with previous clinical trials. However, long-term data on real-world outcomes are lacking.

Phase 1 study of CD19 CAR T-cell therapy harboring a fully human scFv in CAR-naïve adult patients with B-ALL.

CD19-directed chimeric antigen receptor-engineered (CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial, we observed anti-CAR immune responses associated with impaired in vivo CAR T-cell expansion after second infusions. Because these CD8+ T-cell responses were predominantly directed at peptides derived from the murine single-chain variable fragment (scFv) in the CAR, we conducted a clinical trial investigating the safety and efficacy of CD19 CAR T-cells engineered with a CAR incorporating a fully human scFv (JCAR021) in adults with R/R B-ALL (NCT03103971).

Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia.

Introduction: Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by an aggressive clinical course and limited efficacious treatment options in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy is an investigational treatment strategy for R/R AML that has shown some promise. However, obstacles to successful CAR-T cell immunotherapy for AML remain.

Targeting the membrane-proximal C2-set domain of CD33 for improved CAR T cell therapy.

Current CD33-targeted immunotherapies typically recognize the membrane-distal V-set domain of CD33. Here, we show that decreasing the distance between T cell and leukemia cell membrane increases the efficacy of CD33 chimeric antigen receptor (CAR) T cells. We therefore generated and optimized second-generation CAR constructs containing single-chain variable fragments from antibodies raised against the membrane-proximal C2-set domain, which bind CD33 regardless of whether the V-set domain is present (CD33 antibodies).

PD-L1 macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B-cell lymphoma microenvironment impact CD19 CAR-T cell immunotherapy efficacy.

CD19-targeted chimeric antigen receptor T-cell (CAR-T) immunotherapy has transformed the management of relapsed/refractory large B-cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR-T therapy outcomes. Using NanoString nCounter transcriptome profiling ( = 24) and multiplex immunohistochemistry (mIHC,  = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR-T therapy.

qPCR assay for detection of Woodchuck Hepatitis Virus Post-Transcriptional Regulatory Elements from CAR-T and TCR-T cells in fresh and formalin-fixed tissue.

As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product.

Stealth transgenes enable CAR-T cells to evade host immune responses.

Background: Adoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing.

A stochastic framework for evaluating CAR T cell therapy efficacy and variability.

Based on a deterministic and stochastic process hybrid model, we use white noises to account for patient variabilities in treatment outcomes, use a hyperparameter to represent patient heterogeneity in a cohort, and construct a stochastic model in terms of Ito stochastic differential equations for testing the efficacy of three different treatment protocols in CAR T cell therapy. The stochastic model has three ergodic invariant measures which correspond to three unstable equilibrium solutions of the deterministic system, while the ergodic invariant measures are attractors under some conditions for tumor growth. As the stable dynamics of the stochastic system reflects long-term outcomes of the therapy, the transient dynamics provide chances of cure in short-term.