The MAGIC Composite Response: A Novel Endpoint Integrating Clinical and Biomarker Parameters for Acute GVHD.

Changes in the clinical symptoms of acute graft versus host disease (GVHD) are currently used to assess responses to treatment. The MAGIC consortium has recently shown that the integration of serum biomarkers with clinical symptoms at the onset of treatment in a MAGIC Composite Score (MCS) more accurately predicts response to treatment and 6-month non-relapse mortality (NRM) than clinical symptoms alone. In this study we evaluated whether the integration of serum biomarkers and clinical symptoms on day 28 (D28) would also better predict NRM than clinical response only (CRO).

Life-Threatening Cytopenias in a Jehovah's Witness Following CD19-Directed Chimeric Antigen Receptor T Cell Therapy.

Here we report on a Jehovah's Witness (JW) patient who experienced profound and prolonged life-threatening cytopenias following CD19-targeted CAR T cell therapy, successfully managed with bloodless medicine strategies. This case highlights the potential risks of CAR T therapy, even in patients without known hematotoxicity risk factors. By implementing tailored bloodless strategies, the patient received CAR T therapy without significant infectious, cardiac, or bleeding complications.

Sequential Targeting in Multiple Myeloma: Talquetamab, a GPRC5D bispecific antibody, as a Bridge to BCMA CAR-T cell therapy.

Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two BCMA-directed chimeric antigen receptor T cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma (RRMM); however, the 6-8 weeks manufacturing time risks disease progression or death in up to 10% of patients, highlighting the need for effective bridging strategies. Talquetamab, a GPRC5D-targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 US, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel.

Electroencephalography in patients with immune effector cell-associated neurotoxicity syndrome (ICANS).

Background & Objectives: Seizures are a recognized complication of immune effector cell-associated neurotoxicity syndrome (ICANS) from chimeric antigen receptor T cell therapy (CAR-T). Our objective was to characterize continuous (electroencephalogram) EEG data during ICANS to understand EEG patterns in the broader clinical context.

Methods: Clinical and EEG data was collected retrospectively from 2018 to 2023 in patients who underwent CAR-T for cancer and subsequently developed ICANS.

Spatiotemporal Single-Cell Analysis Reveals T Cell Clonal Dynamics and Phenotypic Plasticity in Human Graft-versus-Host Disease.

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for various hematologic diseases but often leads to acute graft-versus-host disease (GVHD), a potentially life-threatening complication. We leverage GVHD as a uniquely tractable disease model to dissect complex T-cell-mediated pathology in 27 alloHCT recipients. We integrate pre-transplant identification of alloreactive T-cells with longitudinal tracking across blood and gut, using mixed lymphocyte reaction-based clonal "fingerprinting", TCR clonotyping, single-cell RNA/TCR sequencing, and spatial transcriptomics.

Surviving Grade 4 ICANS: A Case Report and Discussion of Emerging Management Strategies.

Chimeric antigen receptor (CAR) T-cell therapy is increasingly used in both oncologic and nononcologic conditions. Although low-grade neurotoxicity may be easily treated, severe neurotoxicity remains clinically challenging and many times fatal. We present the case of a young adult with relapsed acute lymphoblastic leukemia who developed grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS), manifesting as severe cerebral edema refractory to first-line therapies.

Impact of posttransplant cyclophosphamide-based GVHD prophylaxis in patients 70 years and older: an update from BMT CTN 1703.

Allogeneic hematopoietic cell transplant (allo-HCT) is underutilized in adults aged ≥70 years. Morbidity, often driven by graft-versus-host disease (GVHD), is considered a major barrier to its use. The BMT CTN 1703 trial (ClinicalTrials.

Emapalumab for severe cytokine release syndrome in solid tumor CAR-T: a case report.

Chimeric Antigen Receptor T (CAR-T) cell therapy significantly and rapidly changed the treatment paradigm for lymphoma, myeloma and leukemia, and the recent approvals of the first cellular immunotherapies in melanoma and synovial sarcoma demonstrate the potential success of this approach in solid tumors. Though the therapeutic potential of CAR-T is impressive, severe cytokine release syndrome (CRS) remains an ongoing challenge. Here we report a patient who received an investigational CAR-T product for metastatic castration-resistant prostate cancer who developed multi-drug refractory, life-threatening CRS, which was successfully treated with the interferon (IFN)-γ antagonist emapalumab.

Autologous T cell therapy for PRAME advanced solid tumors in HLA-A*02 patients: a phase 1 trial.

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02 patients with PRAME recurrent and/or refractory solid tumors, including melanoma and sarcoma.

Itacitinib for the prevention of IEC therapy-associated CRS: results from the 2-part phase 2 INCB 39110-211 study.

Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common complications after IEC therapy for hematologic malignancies. This 2-part phase 2 study (INCB 39110-211) investigated the safety and efficacy of itacitinib, a potent, highly selective Janus kinase 1 inhibitor with broad anti-inflammatory activity, for the prevention of CRS and ICANS in patients who received commercial CD19-directed IEC therapy. Patients in part 1 received 200 mg itacitinib once daily 3 days before IEC therapy (axicabtagene ciloleucel [axi-cel], brexucabtagene autoleucel, or tisagenlecleucel) through day 26 with guidelines for use of other CRS/ICANS interventions.

CAR T-cell therapy chest CT manifestations.

Purpose: CAR T-cell therapy is an emerging anti-cancer therapeutic using modified T cells to attack a patient's cancer. The purpose of this study was to assess chest CT findings in patients undergoing CAR T-cell therapy to determine the most common CT manifestations.

Methods: We performed a retrospective test-retest study analyzing cases of patients who received CAR T-cell therapy who underwent chest CT prior to therapy and after therapy; a total of 349 patients were identified.

Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma.

Purpose: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel.

Methods: Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions.

Novel Risk Factors for Predicting Immune Effector Cell-Associated Neurotoxicity Syndrome.

Unlabelled: ICANS is a common form of neurological immunotoxicity from CAR T-cell therapy (CAR-T). While high tumor burden, product type and cell dose are established risk factors, there are many unknowns. Our objective was to characterize novel neurological and non-neurological risk factors for the development of ICANS in subjects who received CAR-T.

Improved Patient-Reported Outcomes With Post-Transplant Cyclophosphamide: A Quality-of-Life Evaluation and 2-Year Outcomes of BMT CTN 1703.

The BMT CTN 1703 phase III trial confirmed that graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) results in superior GVHD-free, relapse-free survival (GRFS) compared with Tac/methotrexate (MTX) prophylaxis. This companion study assesses the effect of these regimens on patient-reported outcomes (PROs). Using the Lee Chronic GVHD Symptom Score and PROMIS subscales (physical function, GI symptoms, social role satisfaction) as primary end points and hemorrhagic cystitis symptoms and Lee subscales as secondary end points, responses from English and Spanish speakers were analyzed at baseline and days 100, 180, and 365 after transplant.

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Intratumoral CXCL12 Gradients Contextualize Tumor Cell Invasion, Migration and Immune Suppression in Breast Cancer.

Although the CXCL12/CXCR4 pathway has been prior investigated for its prometastatic and immuno- suppressive roles in the tumor microenvironment, evidence on the spatiotemporal regulation of these hallmarks has been lacking. Here, we demonstrate that CXCL12 forms a gradient specifically around cancer cell intravasation doorways, also known as Tumor Microenvironment of Metastasis (TMEM) doorways, thus facilitating the chemotactic translocation of prometastatic tumor cells expressing CXCR4 toward the perivascular TMEM doorways for subsequent entry into peripheral circulation. Fur- thermore, we demonstrate that the CXCL12-rich micro-environment around TMEM doorways may cre- ate immunosuppressive niches, whereby CD8 T cells, despite being attracted to these regions, often exhibit reduced effector functions, limiting their efficacy.

Differences in Acute Graft-Versus-Host Disease (GVHD) Severity and Its Outcomes Between Black and White Patients.

Acute graft-versus-host disease (GVHD) is a significant complication following hematopoietic stem cell transplantation (HCT). Although recent advancements in GVHD prophylaxis have resulted in successful HCT across HLA barriers and expanded access to HCT for racial minorities, less is known about how race affects the severity and outcomes of acute GVHD. This study examines differences in the clinical course of acute GVHD and the prognostic value of GVHD biomarkers for Black and White recipients.

Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD.

Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts.