Troy Noordenbos

All Publications

• Multimodal discovery of distinct tumor ecosystems for classic Hodgkin lymphoma Su, S., Subramanian, A., Flerlage, T., Flerlage, J., Rossi, C., Alig, S., Younes, S., Silva, O., Luna-Fineman, S., Park, N., Noordenbos, T., Schroers-Martin, J., Moding, E., Hoppe, R., Advani, R., Natkunam, Y., Alizadeh, A., Binkley, M. ELSEVIER. 2025: 1783-1784

  View details for DOI 10.1182/blood-2025-1783

  View details for Web of Science ID 001660185400034

• CAR19 therapy drives expansion of clonal hematopoiesis and associated cytopenias. Research square Hamilton, M. P., Phillips, N., Noordenbos, T., Boegeholz, J., Sugio, T., Sworder, B. J., Alig, S. K., Good, Z., Schroers-Martin, J. G., Tamaresis, J., Esfahani, M. S., Lu, Y., Olsen, M., Liu, C. L., Ehlinger, Z., Desai, M., Muffly, L., Negrin, R. S., Arai, S., Johnston, L., Lowsky, R., Meyer, E., Rezvani, A., Shizuru, J., Weng, W. K., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Frank, M. J., Mackall, C. L., Diehn, M., Kurtz, D. M., Miklos, D. B., Alizadeh, A. A. 2025

  Abstract

  CD19-directed chimeric antigen receptor T-cell therapy (CAR19) improves survival in patients with relapsed/refractory large B-cell lymphoma (rrLBCL) compared to immunochemotherapy with intent for autologous hematopoietic cell transplantation (HCT). However, major toxicities of CAR19 therapy include prolonged cytopenias, infection, and secondary hematologic malignancies. To investigate the mechanisms underlying these toxicities we studied a cohort of lymphoma patients receiving CAR19. CAR19-treated patients exhibited impaired immune reconstitution and increased infection compared to propensity-matched HCT-treated controls. Bone marrow analysis revealed prolonged post-CAR cytopenias is associated with clonal cytopenias of undetermined significance (CCUS) and is characterized by interferon-mediated inflammation. Despite durable lymphoma remissions, clonal hematopoiesis (CH) commonly expanded following CAR19 infusion and was associated with impaired immune reconstitution and the development of treatment related myeloid malignancy (tMN). The molecular composition and clinical outcomes of post-CAR tMN were comparable to those of post-HCT tMN. Single-cell DNA analysis revealed that most post-CAR CH clones harbored a single independent mutation and that CAR integration into T cells with CH mutations may drive persistence. These findings broadly implicate CH mutation burden and CH expansion in the development of post-CAR cytopenias and malignancies as well as mechanistically suggest these expansions occur in a background of marrow inflammation. Together, our results provide insight into the origins of key CAR19-associated toxicities, including infection and tMN.

  View details for DOI 10.21203/rs.3.rs-7746241/v1

  View details for PubMedID 41282159

  View details for PubMedCentralID PMC12633523

• Distinct cell state ecosystems for nodular lymphocyte-predominant Hodgkin lymphoma. Nature communications Subramanian, A., Su, S., Flerlage, J., Alig, S., Younes, S., Marks, L. J., Pinnix, C., Vega, F., Steiner, R., Kumar, P., Mocikova, H., Sykorova, A., Prochazka, V., Milito, C., Allen, P., Paulino, D., Ramsay, A., Flerlage, T., Palese, M., West, R., Zhu, C., Noordenbos, T., Schroers-Martin, J., Zhao, S., Park, N. J., Kalbasi, A., Moding, E. J., Newman, A. M., Advani, R. H., Hoppe, R. T., Diehn, M., Natkunam, Y., Alizadeh, A. A., Binkley, M. S. 2025; 16 (1): 8473

  Abstract

  Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and few studies have comprehensively investigated the immune microenvironment and rare lymphocyte-predominant (LP) cells. Here we develop a NLPHL specific lymphocyte-predominant ecotype (LPE) model to identify 34 distinct cell states across 14 cell types that co-occur within 3 LPEs for 171 cases. LPE1 and LPE2 were characterized by immunosuppressive microenvironments with high expression of B2M on LP cells, CD8 T-cell exhaustion, immune checkpoint genes expressed by follicular T-cells, and an improved freedom from progression compared to LPE3 in training (n = 109, with 65% LPE1/2) and validation cohorts (n = 62, with 61% LPE1/2). We validate the co-occurrence and co-localization of cell states using spatial transcriptomics. Protein expression of HLA-I and HLA-II on LP cells and SSTR2 on dendritic cells was predictive of LPE1 (C-statistic=0.69), LPE2 (C-statistic=0.79), and LPE3 (C-statistic=0.60). This study establishes a clinically relevant biologic categorization for NLPHL.

  View details for DOI 10.1038/s41467-025-63339-9

  View details for PubMedID 41006203

  View details for PubMedCentralID PMC12475200

• Superior survival in diffuse large B cell lymphoma of the bone with immune rich tumor microenvironment. Blood cancer journal de Groen, R. A., de Groot, F. A., Böhringer, S., Kret, E. J., de Haan, L. M., Noordenbos, T., Blommers, S., Jansen, R. E., van Wezel, T., van Eijk, R., Raghoo, R., Ruano, D., Boome, L. T., Terpstra, V., Levenga, H., Ahsmann, E., Posthuma, E. F., Focke-Snieders, I., Hardi, L., den Hartog, W. C., van den Berg, A., Mutsaers, P., Lam, K., van der Poel, M. W., Hamid, M. A., Woei-A-Jin, F. J., Janssens, A., Tousseyn, T., Bovée, J. V., Koens, L., Diepstra, A., Cleven, A. H., Kersten, M. J., Jansen, P. M., Veelken, H., Nijland, M., Dekker, T. J., Vermaat, J. S. 2025; 15 (1): 82

  Abstract

  With tumor genomic and gene-expression profiling (GEP), this study investigated the immune-molecular signatures of a unique cohort of diffuse large B-cell lymphoma of the bone (bone-DLBCL), including primary bone (PB-DLBCL, n = 52) and polyostotic-DLBCL (n = 20), in comparison to nodal DLBCLs with germinal center B-cell (GCB) phenotype (nodal-DLBCL-GCB, n = 34). PB-DLBCL and polyostotic-DLBCL shared similar genomic profiles and transcriptomic signatures, justifying their collective analysis as bone-DLBCL. Differential incidences of EZH2, HIST1H1E, and MYC aberrations (p < 0.05) confirmed the distinct oncogenic evolution between bone-DLBCL and nodal-DLBCL-GCB. Differentially expressed genes were identified between bone-DLBCL and nodal-DLBCL-GCB (p < 0.001), substantiated by distinct gene-set enrichment analysis (GSEA). In contrast to a more 'depleted' phenotype for nodal-DLBCL-GCB, bone-DLBCL primarily exhibited an 'intermediate/rich' tumor microenvironment (TME) signature (p = 0.001), as determined by a previously published gene set. Unsupervised clustering defined two distinct groups that aligned with previously reported immune-enriched TME clusters: an 'immune-rich' cluster largely consisting of bone-DLBCLs (75%, p = 0.002) with superior survival (p = 0.030), and a poor-prognostic 'immune-low' cluster, including mostly nodal-DLBCL-GCB (61%). Single-sample (ss)GSEA showed higher scores for regulatory T cells, immunosuppressive/prolymphoma cytokines, and vascular endothelial cells in immune-rich samples (p < 0.001). Additionally, CIBERSORTx revealed a higher abundance of regulatory T cells and activated mast cells in the immune-rich cluster (p < 0.001). These findings were confirmed at protein level, where CD3 and FOXP3 immunochemistry showed significant overlap with the gene-expression data (p < 0.001). Conclusively, PB-DLBCL and polyostotic-DLBCL share immune-molecular TME characteristics, supporting their classification as a unified bone-DLBCL entity. The distinct immune-rich TME profile of bone-DLBCL associated with superior survival potentially shapes emerging immunomodulatory strategies.

  View details for DOI 10.1038/s41408-025-01291-z

  View details for PubMedID 40301298

  View details for PubMedCentralID 3958453

• Distinct Molecular Aberrations of Classic Hodgkin Lymphoma in Older Adults Identified By Comprehensive Genomic Profiling Rossi, C., Boegeholz, J., Goldstein, J. S., Shi, S., Su, S., Tessoulin, B., Alig, S. K., Garofalo, A., Esfahani, M., Schroers-Martin, J. G., Liu, C., Olsen, M., Kang, X., Tian, F., Kurtz, D., Sugio, T., Noordenbos, T., Andre, M., Fornecker, L., Julia, E., Traverse-Glehen, A., Casasnovas, O., Binkley, M. S., Diehn, M., Ghesquieres, H., Alizadeh, A. A. ELSEVIER. 2024: 853-854

  View details for DOI 10.1182/blood-2024-201644

  View details for Web of Science ID 001412608600046

• Integrating Genomic & Transcriptomic Features for Noninvasive Detection, Characterization, and Monitoring of T-Cell Lymphomas Sugio, T., Nesselbush, M., Shukla, N., Garofalo, A., Mutter, J. A., Esfahani, M., Alig, S. K., Shi, S., Noordenbos, T., Hamilton, M. P., Rossi, C., Tian, F., Liu, C., Olsen, M., Kang, X., Russler-Germain, D. A., Horwitz, S., Kato, K., Ito, A., Yamagishi, M., Fukuda, T., Akashi, K., Uchimaru, K., Khodadoust, M. S., Diehn, M., Mehta-Shah, N., Alizadeh, A. A. ELSEVIER. 2024: 454-455

  View details for DOI 10.1182/blood-2024-206518

  View details for Web of Science ID 001415654100004

• Resolving the Microarchitecture of Classic and Transformed Follicular Lymphoma By Single Cell Alignment to Spatial Transcriptomes Noordenbos, T., Schroers-Martin, J. G., Hamilton, M. P., Jun, S., Sugio, T., Sworder, B. J., Steen, C., Olsen, M., Liu, C., Newman, A., Howitt, B., Natkunam, Y., Miklos, D. B., Diehn, M., Frank, M. J., Alizadeh, A. A. ELSEVIER. 2024: 2993-2994

  View details for DOI 10.1182/blood-2024-199300

  View details for Web of Science ID 001412630600038

• Immunosuppressed Tumor Microenvironment in <i>MYC</i>-Rearranged High-Grade B-Cell Lymphomas Compared to Diffuse Large B-Cell Lymphomas, Not Otherwise Specified De Jonge, A., Noordenbos, T., De Groen, R. A. L., De Groot, F. A., De Haan-Treurniet, L. M., Jansen, P. M., Fu, L., de Heer, K., Klerk, C., Sandberg, Y., Fijnheer, R., Mutsaers, P., Beeker, A., Bohmer, L. H., Wang, S., Strobbe, L., Boersma, R., Oosterveld, M., Koene, H. R., De Miranda, N., van den Berg, A., Nijland, M., Roemer, M. G. M., Mutis, T., Chamuleau, M. E. D., Vermaat, J. S. P. ELSEVIER. 2024: 4380-4381

  View details for DOI 10.1182/blood-2024-205968

  View details for Web of Science ID 001409330600015

• Comprehensive Characterization of the Cell States and Ecosystems in Classic Hodgkin Lymphoma Using Single-Cell RNA-Seq, Digital Deconvolution, and Machine Learning Su, S., Subramanian, A., Flerlage, T., Flerlage, J. E., Rossi, C., Noordenbos, T., Schroers-Martin, J. G., Moding, E. J., Hoppe, R. T., Advani, R. H., Natkunam, Y., Alizadeh, A. A., Binkley, M. S. ELSEVIER. 2024: 4369-4370

  View details for DOI 10.1182/blood-2024-212013

  View details for Web of Science ID 001409330600004

• Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. The New England journal of medicine Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., Frank, M. J., Sahaf, B., Mackall, C. L., Gratzinger, D., Diehn, M., Alizadeh, A. A., Miklos, D. B. 2024; 390 (22): 2047-2060

  Abstract

  The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

  View details for DOI 10.1056/NEJMoa2401361

  View details for PubMedID 38865660