Impact of Previous Allogeneic Hematopoietic Stem Cell Transplantation on Chimeric Antigen Receptor (CAR) T Cell Treatment for Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Anti-BCMA-directed chimeric antigen receptor (CAR) T cells are effective treatment for patients with refractory/relapsed multiple myeloma (RRMM). However, little is known about the impact of previous allogeneic hematopoietic stem cell transplantation (allo-HSCT) on lymphocyte collection for production of CAR T cells and subsequent treatment with CAR T cells. PATIENTS AND METHODS: We performed a retrospective analysis of cellular composition of lymphocyte collections, CAR T cell expansion and treatment outcomes of RRMM patients undergoing therapy with idecabtagene vicleucel (ide-cel) with and without history of allo-HSCT. 27 patients (11/27 female) with median age 63 (range 39-75) years were analyzed. Five patients (19%) had the history of allo-HSCT median of 5.5 years before ide-cel. RESULTS: Prior to apheresis, the white blood cell, absolute lymphocyte counts, CD3+ cells and monocytes did not differ in patients with and without prior allo-HSCT. We also noticed no differences in the collected CD3+ yields or cellular compositions of lymphocyte collections. One year after ide-cel infusion, the progression-free survival and overall survival of patients with and without previous allo-HSCT did not differ with 60% and 45% respectively (P = .58) and 66.7% and 74% respectively (P = .84). The highest expansion of CAR T was detected between day 7 after infusion and showed no difference regarding previous allo-HSCT (P = .71). No graft-versus-host disease during the follow-up was detected. CONCLUSION: Our data confirm that the treatment with ide-cel is feasible for patients with prior allo-HSCT. Furthermore, allo-HSCT did not influence cellular composition of lymphocyte collections, clinical outcome or in vivo expansion of ide-cel.

Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma.

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.

Impact of Clonal Hematopoiesis in Patients With Cardiogenic Shock Complicating Acute Myocardial Infarction.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is common in elderly individuals and is associated with an increased risk of both hematologic malignancies and cardiovascular disease. The impact of CHIP on the outcomes for patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) remains undetermined. OBJECTIVES: The purpose of this study was to determine the prognostic impact of CHIP in CS after AMI. METHODS: Blood samples were obtained at randomization from 446 patients included in the CULPRIT-SHOCK (Culprit Lesion Only vs Multivessel Percutaneous Coronary Intervention in Cardiogenic Shock; NCT01927549) trial. CHIP was assessed using a next-generation sequencing approach targeting the most commonly mutated genes; the primary outcome at 30 days comprised all-cause mortality and renal replacement therapy. RESULTS: CHIP variants at ≥2% variant allele frequency were detected in 29% (n = 129), most commonly in the DNMT3A or TET2 genes, which harbored 47% and 36% of all mutations, respectively. Compared to non-CHIP patients, CHIP carriers were older and had decreased renal function and increased levels of N-terminal pro-B-type natriuretic peptide and inflammatory biomarkers. CHIP carriers had worse short-term outcomes measured either as mortality or as the combined clinical endpoint of mortality or severe renal failure within 30 days. Association of CHIP with the combined endpoint was independent of age and biomarkers reflecting kidney function, heart failure severity, and inflammation (OR: 1.83; 95% CI: 1.05-3.21; P = 0.03) but not significant regarding all-cause mortality (OR: 1.67; 95% CI: 0.96-2.90; P = 0.069). CONCLUSIONS: CHIP is frequent among AMI and CS patients and is associated with impaired clinical outcome. CHIP assessment may facilitate risk stratification in patients with CS and imply novel treatment targets. (Culprit Lesion Only vs Multivessel Percutaneous Coronary Intervention in Cardiogenic Shock [CULPRIT-SHOCK]; NCT01927549).

Aconitase B is required for optimal growth of Xanthomonas campestris pv. vesicatoria in pepper plants.

The aerobic plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) colonizes the intercellular spaces of pepper and tomato. One enzyme that might contribute to the successful proliferation of Xcv in the host is the iron-sulfur protein aconitase, which catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle and might also sense reactive oxygen species (ROS) and changes in cellular iron levels. Xcv contains three putative aconitases, two of which, acnA and acnB, are encoded by a single chromosomal locus. The focus of this study is aconitase B (AcnB). acnB is co-transcribed with two genes, XCV1925 and XCV1926, encoding putative nucleic acid-binding proteins. In vitro growth of acnB mutants was like wild type, whereas in planta growth and symptom formation in pepper plants were impaired. While acnA, XCV1925 or XCV1926 mutants showed a wild-type phenotype with respect to bacterial growth and in planta symptom formation, proliferation of the acnB mutant in susceptible pepper plants was significantly impaired. Furthermore, the deletion of acnB led to reduced HR induction in resistant pepper plants and an increased susceptibility to the superoxide-generating compound menadione. As AcnB complemented the growth deficiency of an Escherichia coli aconitase mutant, it is likely to be an active aconitase. We therefore propose that optimal growth and survival of Xcv in pepper plants depends on AcnB, which might be required for the utilization of citrate as carbon source and could also help protect the bacterium against oxidative stress.