Emily Egeler

All Publications

• EVALUATION OF B7-H3 IMMUNOHISTOCHEMISTRY IN HIGH-GRADE GLIOMAS FOR CHIMERIC ANTIGEN RECEPTOR T-CELL PREDICTIVE TESTING Dyson, K., Zuraski, C., Solomon, D., Li, G., Stocksdale, B., Song, K., Mahdi, J., Tanner, K., Bertrand, S., Iv, M., Threlkeld, Z., Ramakrishna, S., Sahaf, B., Egeler, E., Tunuguntla, R., Therkelsen, K., Nagpal, S., Lim, M., Monje, M., Scott, B., Mackall, C., Charu, V., Thomas, R. OXFORD UNIV PRESS INC. 2025: v49-v50

  View details for DOI 10.1093/neuonc/noaf201.0195

  View details for Web of Science ID 001613247800006

• A phase 1 study of B7H3 CAR-T cells administered intracranially in recurrent glioblastoma. Li, G., Stocksdale, B. R., Song, K., Mahdi, J., Tanner, K., Bertrand, S., Iv, M., Threlkeld, Z., Ramakrishna, S., Sahaf, B., Egeler, E., Charu, V., Tunuguntla, R., Therkelsen, K., Nagpal, S., Lim, M., Monje, M., Scott, B., Mackall, C., Thomas, R. LIPPINCOTT WILLIAMS & WILKINS. 2025: 2018

  View details for DOI 10.1200/JCO.2025.43.16_suppl.2018

  View details for Web of Science ID 001509526200001

• Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., Barsan, V., Song, K. W., Kamens, J., Baggott, C., Kunicki, M., Rietberg, S. P., Lim, A. S., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., Erickson, C., Jacobs, A., Duh, A. K., Tunuguntla, R., Klysz, D. D., Fowler, C., Green, S., Beebe, B., Carr, C., Fujimoto, M., Brown, A. K., Petersen, A. G., McIntyre, C., Siddiqui, A., Lepori-Bui, N., Villar, K., Pham, K., Bove, R., Musa, E., Reynolds, W. D., Kuo, A., Prabhu, S., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Grant, G., Prolo, L., Ye, X., Sahaf, B., Davis, K. L., Feldman, S. A., Ramakrishna, S., Mackall, C. 2024

  Abstract

  H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I trial no. NCT04196413 (ref. 3) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg-1; DL2, 3 × 106 kg-1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10-30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

  View details for DOI 10.1038/s41586-024-08171-9

  View details for PubMedID 39537919

  View details for PubMedCentralID 5996391

• CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. Lancet (London, England) Frank, M. J., Baird, J. H., Kramer, A. M., Srinagesh, H. K., Patel, S., Brown, A. K., Oak, J. S., Younes, S. F., Natkunam, Y., Hamilton, M. P., Su, Y. J., Agarwal, N., Chinnasamy, H., Egeler, E., Mavroukakis, S., Feldman, S. A., Sahaf, B., Mackall, C. L., Muffly, L., Miklos, D. B. 2024

  Abstract

  Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

  View details for DOI 10.1016/S0140-6736(24)00746-3

  View details for PubMedID 38996463

• A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. Blood Srinagesh, H. K., Jackson, C., Shiraz, P., Jeyakumar, N., Hamilton, M. P., Egeler, E., Mavroukakis, S., Kuo, A., Cancilla, J., Sahaf, B., Agarwal, N., Kanegai, A. M., Kramer, A. M., Arai, S., Bharadwaj, S., Dahiya, S., Hosoya, H., Johnston, L. J., Kennedy, V. E., Liedtke, M., Lowsky, R., Mikkilineni, L., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J. A., Smith, M., Weng, W. K., Feldman, S. A., Frank, M. J., Lee, Z., Tagliaferri, M., Marcondes, A. M., Miklos, D. B., Mackall, C. L., Muffly, L. 2024

  Abstract

  While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

  View details for DOI 10.1182/blood.2024024952

  View details for PubMedID 38968138

• CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia Schultz, L. M., Jeyakumar, N., Kramer, A. M., Sahaf, B., Srinagesh, H., Shiraz, P., Agarwal, N., Hamilton, M., Erickson, C., Jacobs, A., Moon, J., Baggott, C., Arai, S., Bharadwaj, S., Johnston, L. J., Liedtke, M., Lowsky, R., Meyer, E., Negrin, R., Rezvani, A., Shizuru, J., Sidana, S., Egeler, E., Mavroukakis, S., Tunuguntla, R., Gkitsas-Long, N., Retherford, A., Brown, A. K., Gramstrap-Petersen, A. L., Ibañez, R. M., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L., Frank, M., Ramakrishna, S., Muffly, L. 2024

  Abstract

  Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

  View details for DOI 10.1038/s41375-024-02220-y

  View details for PubMedID 38491306

  View details for PubMedCentralID 4993814

• Discovery and Preclinical Work A Practical Guide to Drug Development in Academia - The SPARK Approach edited by Mochly-Rosen, D., Grimes, K. Springer. 2013; 1: 31–77
• Validation of a Pre-Infusion Prediction Model for IEC-HS in Children and Young Adults with B-Acute Lymphoblastic Leukemia McNerney, K. O., Kwon, S., Naik, S., Fabrizio, V. A., Llaurador, G., Sanchez-Pinto, L., Talleur, A. C., Zeng, X., Baggott, C., Vatsayan, A., Verneris, M. R., Prabhu, S., Rossoff, J., Pacenta, H. L., Phillips, C. L., Talano, J. A., Moskop, A., Myers, D., Karras, N., Bonifant, C. L., Qayed, M. D., Satwani, P., Temple, W. C., Krupski, C., Keating, A. K., Baumeister, S., Egeler, E., Curran, K. J., Mackall, C. L., Laetsch, T. W., Gardner, R. A., Schultz, L. ELSEVIER SCIENCE INC. 2026

  View details for Web of Science ID 001709434400025

• Overlap of post-CAR T HLH toxicity definitions and their prognostic significance in children and young adults with B-acute lymphoblastic leukemia McNerney, K., Kwon, S., Naik, S., Fabrizio, V., Caraballo, G., Sanchez-Pinto, L., Talleur, A., Zeng, X., Baggott, C., Vatsayan, A., Verneris, M., Prabhu, S., Rossoff, J., Pacenta, H., Phillips, C., Talano, J., Moskop, A., Myers, D., Karras, N., Bonifant, C., Qayed, M., Satwani, P., Temple, W., Krupski, C., Keating, A., Baumeister, S., Egeler, E., Mavroukakis, S., Curran, K., Mackall, C., Laetsch, T., Gardner, R., Schultz, L. ELSEVIER. 2025: 4501-4502

  View details for DOI 10.1182/blood-2025-4501

  View details for Web of Science ID 001669341000001

• SINGLE-CELL LANDSCAPE OF B7H3-CAR T THERAPY IN GLIOMA: MECHANISMS OF RESISTANCE AND SIGNATURES OF LONG-TERM RESPONSE Chen, Y., Song, K., Desai, M., Ehlinger, Z., Daghagh, H., Rietberg, S., Feeney, A., Tanner, K., Dyson, K., Stockdale, B., Dhapola, G., Lohman, C., Patil, S., Kuo, A., Good, Z., Prabhu, S., Kong, K., Egeler, E., Beebe, B., Carr, C., Mahdi, J., Bertrand, S., Iv, M., Threlkeld, Z., Charu, V., Tunuguntla, R., Therkelsen, K., Nagpal, S., Monje, M., Scott, B., Li, G., Lim, M., Sotillo, E., Sahaf, B., Ramakrishna, S., Thomas, R., Mackall, C. OXFORD UNIV PRESS INC. 2025: v13

  View details for DOI 10.1093/neuonc/noaf201.0044

  View details for Web of Science ID 001612039700001

• HUMANIZED ANTI-CAR ANTIBODIES AFFECT DURABLE RESPONSE TO GD2-CAR T-CELLS IN DIFFUSE MIDLINE GLIOMA Chen, Y., Song, K., Huang, Y., Iswari, N., Desai, M., Ehlinger, Z., Daghagh, H., Reynolds, K., Mahdi, J., Majzner, R., Richards, B., Kamens, J., Barsan, V., Campen, C., Partap, S., Madhav, D., Moon, J., Baggott, C., Fujimoto, M., Li, A., Jariwala, S., Mavroukakis, S., Egeler, E., Jacobs, A., Erickson, C., Kaur, A., Soundaranayagi, S., Rietberg, S., Schultz, L., Davis, K., Feldman, S., Heitzeneder, S., Yamada-Hunter, S., Sotillo, E., Good, Z., Sahaf, B., Monje, M., Ramakrishna, S., Mackall, C. OXFORD UNIV PRESS INC. 2025: v114

  View details for DOI 10.1093/neuonc/noaf201.0462

  View details for Web of Science ID 001613237000002

• Characterization and prediction of hematotoxicity in pediatric patients receiving tisagenlecuecel. Blood advances Naik, S., Selukar, S., Talleur, A. C., Deshpande, S., Llaurador Caraballo, G., Fabrizio, V. A., Rouce, R. H., Zeng, X. L., Vatsayan, A., Rossoff, J., Pacenta, H. L., John, S., Phillips, C. L., Talano, J. M., Moskop, A., Verneris, M. R., Myers, G. D., Hall, E. M., Karras, N. A., Bonifant, C. L., Qayed, M., Bakinowski, E., Keating, A., Baumeister, S. H., Tomilson, E., Hermiston, M. L., Satwani, P., Krupski, C., Chinnabhandar, V., Stefanski, H. E., Egeler, E., Curran, K. J., Laetsch, T. W., Mackall, C. L., Prabhu, S., Nguyen, K., Baggott, C., Schultz, L. M., McNerney, K. O. 2025

  Abstract

  Hematotoxicity is the most frequent severe toxicity following chimeric antigen receptor (CAR) T therapy. However, limited data exist on risk factors and outcomes for hematotoxicity for children and young adults (CAYA) with B-acute lymphoblastic leukemia (B-ALL) treated with tisagenlecleucel. We conducted a multi-institutional study involving 326 CAYA, with 144 evaluable in an initial training cohort and 141 evaluable in a validation cohort, through the Pediatric Real World CAR Consortium to characterize the incidence and outcomes of prolonged severe neutropenia (PSN) and to develop a predictive risk score for PSN, tailored for use in this population. The incidence of PSN, defined as an absolute neutrophil count (ANC) of <500 cells/µL for ≥ 30 days, was 15.3% in the initial training cohort and 21% in the validation cohort. Development of PSN was associated with inferior overall survival (p<0.001), relapse-free survival (p=0.01), higher non-relapse mortality (p=0.003), and a greater risk of infections within 30 days (p=0.03). Multivariable penalized regression analysis identified key risk factors for PSN which included pre-infusion C-reactive protein and bone marrow disease burden, and post-infusion peak ferritin and occurrence of severe CRS, which were used to create the CytoRisk score. In the validation cohort, the CytoRisk score discriminated between patients with and without PSN (area under the curve: 0.90, specificity: 93%, sensitivity: 71%, positive predictive value: 74%, negative predictive value: 92%). The CytoRisk score may be used to a priori identify patients at highest risk of PSN and overall worse outcomes.

  View details for DOI 10.1182/bloodadvances.2025016824

  View details for PubMedID 40690779

• Author Correction: Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature Monje, M., Mahdi, J., Majzner, R., Yeom, K. W., Schultz, L. M., Richards, R. M., Barsan, V., Song, K. W., Kamens, J., Baggott, C., Kunicki, M., Rietberg, S. P., Lim, A. S., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., Erickson, C., Jacobs, A., Duh, A. K., Tunuguntla, R., Klysz, D. D., Fowler, C., Green, S., Beebe, B., Carr, C., Fujimoto, M., Brown, A. K., Petersen, A. G., McIntyre, C., Siddiqui, A., Lepori-Bui, N., Villar, K., Pham, K., Bove, R., Musa, E., Reynolds, W. D., Kuo, A., Prabhu, S., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Grant, G., Prolo, L., Ye, X., Sahaf, B., Davis, K. L., Feldman, S. A., Ramakrishna, S., Mackall, C. 2024

  View details for DOI 10.1038/s41586-024-08452-3

  View details for PubMedID 39613972

• MYELOID POPULATIONS MODULATE GD2 CAR T CELL ACTIVITY IN DIFFUSE MIDLINE GLIOMA Ramakrishna, S., Geraghty, A., Good, Z., Desai, M., Mancusi, R., Mahdi, J., Song, K., Ehlinger, Z., Chen, Y., Hamilton, M., Rietberg, S., Majzner, R., Schultz, L., Richards, B., Kamens, J., Barsan, V., Campen, C., Partap, S., Moon, J., Baggott, C., Kunick, M., Fujimoto, M., Li, A., Jariwala, S., Mavroukakis, S., Egeler, E., Jacobs, A., Erickson, C., Prabhu, S., Davis, K., Feldman, S., Sahaf, B., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0652

  View details for Web of Science ID 001362581000011

• Role of B Cell Recovery in Relapse Risk and CD19 Phenotype Following Real-World Use of Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia: A Multi-Institutional Retrospective Study Zeng, X., Kwon, S., Vatsayan, A., Baggott, C., Prabhu, S., John, S., Pacenta, H. L., Phillips, C. L., Rossoff, J., Talano, J., Moskop, A., Verneris, M. R., Myers, D. D., Hall, E., Karras, N. A., Bonifant, C. L., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Keating, A. K., Baumeister, S. H. C., Fabrizio, V. A., Chinnabhandar, V., Egeler, E., Mavroukakis, S., Nguyen, K., Curran, K. J., Mackall, C. L., Laetsch, T. W., Schultz, L., McNerney, K. O. ELSEVIER. 2024: 2817-2819

  View details for DOI 10.1182/blood-2024-211231

  View details for Web of Science ID 001422229700006

• Safe and Effective Combination of Donor-Derived, Allogeneic CD19/CD22-CAR T Cells with Myeloablative Graft-Engineered Allo-HCT for High-Risk B-ALL Muffly, L., Ananth, S., Danley, L., Wagner, C., Kordek, D., Denoble, K., Fraser, A., Egeler, E., Molina, A., Ehlinger, Z., Desai, M., Daghagh, H., Tunuguntla, R., Brown, A. K., Ibanez, R., Kramer, A., Good, Z., Arai, S., Johnston, L., Lowsky, R., Rezvani, A. R., Shizuru, J., Mikkilineni, L., Shiraz, P., Sidana, S., Weng, W., Kennedy, V. E., Bharadwaj, S., Dahiya, S., Frank, M. J., Meyer, E. H., Negrin, R. S., Feldman, S. A., Mackall, C. L., Sahaf, B., Miklos, D. B., Smith, M. ELSEVIER. 2024: 680

  View details for DOI 10.1182/blood-2024-211959

  View details for Web of Science ID 001415676400028

• CD22-Directed CAR T-Cell Therapy for Large B-Cell Lymphomas Progressing after CD19-Directed CAR T-Cell Therapy: Continued Durable Remissions at 3-Year Follow-up Kramer, A., Baird, J. H., Srinagesh, H., Egeler, E., Levine, K., Brown, A. K., Mavroukakis, S., Cunanan, K., Su, Y., Agarwal, N., Hamilton, M. P., Bharadwaj, S., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shizuru, J., Mikkilineni, L., Hosoya, H., Shiraz, P., Sidana, S., Weng, W., Kennedy, V. E., Smith, M., Dahiya, S., Davis, K. L., Ramakrishna, S., Schultz, L., Tunuguntla, R., Feldman, S. A., Muffly, L., Mackall, C. L., Miklos, D. B., Frank, M. J. ELSEVIER. 2024: 70-71

  View details for DOI 10.1182/blood-2024-198544

  View details for Web of Science ID 001410860600018

• SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS Monje, M., Mahdi, J., Majzner, R. G., Yeom, K., Schultz, L. M., Richards, R., Barsan, V., Song, K., Kamens, J., Baggott, C., Kunicki, M., Lim, A., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., Erickson, C., Jacobs, A., Duh, A. K., Rietberg, S. P., Tunuguntla, R., Klysz, D., Fowler, C., Green, S., Beebe, B., Carr, C., Fujimoto, M., Brown, A., Peterson, A. G., Mcintyre, C., Siddiqui, A., Lepori-Bui, N., Villar, K., Pham, K., Bove, R., Musa, E., Reynolds, W., Kuo, A., Prabhu, S., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Grant, G., Prolo, L., Ye, X., Sahaf, B., Davis, K. L., Feldman, S. A., Ramakrishna, S., Mackall, C. L. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae064.100

  View details for Web of Science ID 001252720000169

• Risk Factors and Outcomes for Hematotoxicity Following Tisagenlecleucel for Pediatric BAcute Lymphoblastic Leukemia McNerney, K. O., Fabrizio, V. A., Talleur, A. C., Lim, S., Dreyzin, A., Baggott, C., Vatsayan, A., Rossoff, J., Prabhu, S., Pacenta, H. L., Phillips, C. L., Talano, J., Moskop, A., Verneris, M. R., Myers, D., Karras, N., Bonifant, C. L., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Keating, A., Baumeister, S. H. C., Chinnabhandar, V., Egeler, E., Curran, K. J., Mackall, C. L., Laetsch, T. W., Schultz, L., Naik, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-189921

  View details for Web of Science ID 001159306708106

• HLH-like toxicities predict poor survival following use of tisagenlecleucel in children and young adults with B-ALL. Blood advances McNerney, K. O., Si Lim, S., Ishikawa, K., Dreyzin, A., Vatsayan, A., Chen, J. J., Baggott, C., Prabhu, S., Pacenta, H. L., Phillips, C. L., Rossoff, J., Stefanski, H. E., Talano, J. A., Moskop, A., Verneris, M. R., Myers, D., Karras, N. A., Brown, P. A., Bonifant, C. L., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Keating, A. K., Baumeister, S. H., Fabrizio, V. A., Chinnabhandar, V., Egeler, E., Mavroukakis, S., Curran, K. J., Mackall, C. L., Laetsch, T. W., Schultz, L. M. 2023

  Abstract

  Chimeric antigen-receptor (CAR)-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities involving hyperferritinemia, multi-organ dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-acute lymphoblastic leukemia (B-ALL) who develop HLH-like toxicities, although larger outcomes analyses of children and young adults (CAYA) with B-ALL who develop these toxicities following commercial tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYA with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-like toxicities, high grade CRS without HLH-like toxicities, or no to low grade CRS without HLH-like toxicities. Primary objectives included characterizing the incidence, outcomes, and pre-infusion factors associated with HLH-like toxicities. Among 185 CAYA infused with tisagenlecleucel, 26 (14.1%) met criteria for HLH-like toxicities. One-year overall survival and relapse-free survival were 25.7% and 4.7% in those with HLH-like toxicities, compared with 80.1% and 57.6% in those without. In multivariable analysis for death, meeting criteria for HLH-like toxicities carried a hazard ratio of 4.61 (95% confidence interval: 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-like toxicities had higher pre-tisagenlecleucel disease burden, ferritin, C-reactive protein levels, and lower platelet and absolute neutrophil counts than patients with high grade or no/low grade CRS without HLH-like toxicities. Overall, CAYA with B-ALL who developed HLH-like toxicities following tisagenlecleucel experienced high rates of relapse and non-relapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-like toxicities following tisagenlecleucel.

  View details for DOI 10.1182/bloodadvances.2022008893

  View details for PubMedID 36857419

• CAR-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (carHLH) IS ASSOCIATED WITH PRE-INFUSION INFLAMMATION AND HIGH DISEASE BURDEN AND PREDICTS POOR OUTCOMES FOLLOWING TISAGENLECLEUCEL IN PEDIATRIC B-ALL McNerney, K. O., Lim, S., Ishikawa, K., Dreyzin, A., Vatsayan, A., Chen, J. J., Baggott, C., Prabhu, S., Pacenta, H., Philips, C., Rossoff, J., Stefanski, H., Talano, J., Moskop, A., Verneris, M., Myers, D., Karras, N. A., Brown, P., Qayed, M., Hermiston, M., Satwani, P., Krupski, C., Keating, A. K., Wilcox, R., Baumeister, S., Fabrizio, V. A., Chinnabhandar, V., Egeler, E., Mavroukakis, S., Curran, K. J., Mackall, C. L., Laetsch, T. W., Schultz, L. M. WILEY. 2023: S32-S33

  View details for Web of Science ID 000904088900069

• Long-Term Follow-up of CD19/22 CAR Therapy in Children and Young Adults with B-ALL Reveals Efficacy, Tolerability and High Survival Rates When Coupled with Hematopoietic Stem Cell Transplantation Schultz, L. M., Ramakrishna, S., Baskar, R., Richards, R. M., Moon, J., Baggott, C., Fujimoto, M., Kunicki, M., Li, A., Jariwala, S., Erickson, C., Jacobs, A., Yamabe, K., Barsan, V., Majzner, R. G., Egeler, E. L., Mavroukakis, S., Ehlinger, Z., Reynolds, W. D., Sahaf, B., Muffly, L., Frank, M. J., Gramstrup, A., Chinnasamy, H., Patel, S., Miklos, D. B., Feldman, S. A., Mackall, C. L., Davis, K. L. AMER SOC HEMATOLOGY. 2022: 10300-10302

  View details for DOI 10.1182/blood-2022-167789

  View details for Web of Science ID 000893230303140

• Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Schultz, L. M., Eaton, A., Baggott, C., Rossoff, J., Prabhu, S., Keating, A. K., Krupski, C., Pacenta, H., Philips, C. L., Talano, J., Moskop, A., Baumeister, S. H., Myers, G. D., Karras, N. A., Brown, P. A., Qayed, M., Hermiston, M., Satwani, P., Wilcox, R., Rabik, C. A., Fabrizio, V. A., Chinnabhandar, V., Kunicki, M., Mavroukakis, S., Egeler, E., Li, Y., Mackall, C. L., Curran, K. J., Verneris, M. R., Laetsch, T. W., Stefanski, H. 2022: JCO2201076

  Abstract

  PURPOSE: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival.METHODS: We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches.RESULTS: The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19-; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19- relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19- 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches.CONCLUSION: We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19- relapse is distinctly associated with decreased survival outcomes.

  View details for DOI 10.1200/JCO.22.01076

  View details for PubMedID 36108252

• Higher doses of tisagenlecleucel associate with improved outcomes: a report from the pediatric real-world CAR consortium. Blood advances Stefanski, H., Eaton, A., Baggott, C., Rossoff, J., Verneris, M. R., Keating, A. K., Prabhu, S., Pacenta, H. L., Phillips, C. L., Talano, J., Moskop, A., Margossian, S. P., Myers, G. D., Karras, N. A., Brown, P. A., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Wilcox, R., Rabik, C. A., Fabrizio, V. A., Chinnabhandar, V., Goksenin, A. Y., Egeler, E., Mavroukakis, S., Curran, K. J., Mackall, C. L., Laetsch, T. W., Schultz, L. M. 2022

  Abstract

  Tisagenlecleucel, chimeric antigen receptor T cell (CART) therapy targeting CD19, has shown remarkable complete response (CR) rates for patients up to the age of 26 with refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL), and is FDA-approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2- 5.0 x 106 CAR T cells/kg for patients ≤ 50 kg, or 0.1- 2.5 x 108 CAR T cells for patients > 50 kg. The effect of cell dose on survival and remission has yet to be well-established. Our primary goal was to determine if CART cell dose impacts overall survival (OS), event-free survival (EFS) and relapse-free-survival (RFS) in tisagenlecleucel-recipients. Retrospective data were collected from the Pediatric Real World CAR Consortium (PRWCC) member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 x106 CAR T cells/kg. To assess the impact of cell dose, we divided the responders into dose quartiles: 0.134-1.300 x 106 (D1; n=48 (27%), 1.301-1.700 x 106 (D2; n=46 (26%), 1.701-2.400 x 106(D3; n=43 (24%) and 2.401-5.100 x 106 (D4; n=43 (24%). OS, EFS, and RFS were improved in patients that received higher doses of Tisagenlecleucel (p=0.031, 0.0079 and 0.0045 respectively). Moreover, higher doses of tisagenlecleucel were not associated with increased toxicity. As the current tisagenlecleucel package insert dose-range remains broad, this work has implications in regard to targeting higher cell doses to optimize patients for long-standing remission.

  View details for DOI 10.1182/bloodadvances.2022007246

  View details for PubMedID 35938863

• Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells Majzner, R. G., Mahdi, J., Ramakrishna, S., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Barsan, V., Richards, R., Campen, C., Reschke, A., Toland, A., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Jacobs, A., Yamabe-Kwong, K., Rasmussen, L., Nie, E., Green, S., Kunicki, M., Fujimoto, M., Ehlinger, Z., Reynolds, W., Prabhu, S., Warren, K. E., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Monje, M., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509500153

• MAJOR TUMOR REGRESSIONS IN H3K27M-MUTATED DIFFUSE MIDLINE GLIOMA (DMG) FOLLOWING SEQUENTIAL INTRAVENOUS (IV) AND INTRACEREBROVENTRICULAR (ICV) DELIVERY OF GD2-CAR T-CELLS Monje, M., Majzner, R., Mahdi, J., Ramakrishna, S., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Barsan, V., Richards, R., Campen, C., Reschke, A., Toland, A., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Jacobs, A., Yamabe-Kwong, K., Rasmussen, L., Nie, E., Green, S., Kunicki, M., Fujimoto, M., Ehlinger, Z., Reynolds, W., Prabhu, S., Warren, K. E., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Mackall, C. OXFORD UNIV PRESS INC. 2022: 20-21

  View details for Web of Science ID 000840122400074

• GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature Majzner, R. G., Ramakrishna, S., Yeom, K. W., Patel, S., Chinnasamy, H., Schultz, L. M., Richards, R. M., Jiang, L., Barsan, V., Mancusi, R., Geraghty, A. C., Good, Z., Mochizuki, A. Y., Gillespie, S. M., Toland, A. M., Mahdi, J., Reschke, A., Nie, E., Chau, I. J., Rotiroti, M. C., Mount, C. W., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Erickson, C., Green, S., Kunicki, M., Fujimoto, M., Ehlinger, Z., Reynolds, W., Kurra, S., Warren, K. E., Prabhu, S., Vogel, H., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Filbin, M. G., Grant, G., Sahaf, B., Davis, K. L., Feldman, S. A., Mackall, C. L., Monje, M. 2022

  Abstract

  Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMG) are universally lethal paediatric central nervous system tumours1. We previously discovered that the disialoganglioside GD2 is highly expressed on H3K27M-mutant glioma cells and demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutant DIPG/DMG treated with GD2-CAR T cells (GD2-CART) at dose level 1 (1e6 GD2-CAR T cells/kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T infusions administered intracerebroventricularly3. Toxicity was largely related to tumor location and reversible with intensive supportive care. On-target, off-tumor toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Proinflammatory cytokines were increased in plasma and cerebrospinal fluid (CSF). Transcriptomic analyses of 65,598 single cells from CAR T cell products and CSF elucidate heterogeneity in response between subjects and administration routes. These early results underscore the promise of this approach for H3K27M+ DIPG/DMG therapy.

  View details for DOI 10.1038/s41586-022-04489-4

  View details for PubMedID 35130560

• Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Schultz, L. M., Baggott, C., Prabhu, S., Pacenta, H. L., Phillips, C. L., Rossoff, J., Stefanski, H. E., Talano, J., Moskop, A., Margossian, S. P., Verneris, M. R., Myers, G. D., Karras, N. A., Brown, P. A., Qayed, M., Hermiston, M., Satwani, P., Krupski, C., Keating, A. K., Wilcox, R., Rabik, C. A., Fabrizio, V. A., Rouce, R. H., Chinnabhandar, V., Kunicki, M., Barsan, V. V., Goksenin, A. Y., Li, Y., Mavroukakis, S., Egeler, E., Curran, K. J., Mackall, C. L., Laetsch, T. W. 2021: JCO2003585

  Abstract

  PURPOSE: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel.METHODS: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity.RESULTS: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively.CONCLUSION: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.

  View details for DOI 10.1200/JCO.20.03585

  View details for PubMedID 34882493

• CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy Frank, M. J., Baird, J. H., Patel, S., Craig, J., Spiegel, J. Y., Ehlinger, Z., Chinnasamy, H., Younes, S. F., Oak, J. S., Natkunam, Y., Reynolds, W. D., Iglesias, M., Crawford, E., Srinagesh, H. K., Egeler, E. L., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shiraz, P., Sidana, S., Weng, W., Schultz, L. M., Ramakrishna, S., Davis, K. L., Sahaf, B., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffl, L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-152145

  View details for Web of Science ID 000736398803041

• Tisagenlecleucel Outcomes in Relapsed/Refractory Extramedullary ALL: A Pediatric Real World CAR Consortium Report. Blood advances Fabrizio, V. A., Phillips, C. L., Lane, A., Baggott, C., Prabhu, S., Egeler, E., Mavroukakis, S., Pacenta, H. L., Rossoff, J., Stefanski, H., Talano, J. A., Moskop, A., Margossian, S. P., Verneris, M. R., Myers, G. D., Karras, N. A., Brown, P. A., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Keating, A. K., Wilcox, R., Rabik, C. A., Chinnabhandar, V., Kunicki, M., Goksenin, A. Y., Curran, K. J., Mackall, C. L., Laetsch, T. W., Schultz, L. M. 2021

  Abstract

  Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell ALL. Data for CAR therapy in extramedullary (EM) involvement is limited. Retrospective data was abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (CR) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both CNS3 and non-CNS EM) were compared to bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease prior to CAR (n=40 CNS3; n=15 non-CNS EM). The median age at infusion in CNS cohort was 10 years (range <1-25) and the non-CNS EM cohort was 13 years (2-26). In patients with CNS disease, 88% (35/40) achieved a CR, versus only 66% (10/15) with non-CNS EM disease. Patients with CNS disease (both with and without marrow involvement) had comparable 24-month OS outcomes to non-CNS EM or BM only (p=0.41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM only patients (p=0.92). No increased toxicity was seen with CNS or non-CNS EM disease (p=0.3). Active CNS disease at time of infusion did not impact outcomes. Isolated (iCNS) disease trended towards improved OS when compared to combined CNS and BM (p=0.12). R/R EM disease can be effectively treated with tisagenlecleucel with toxicity, relapse rates and survival rates comparable to patients with BM only. Outcomes for iCNS relapse are encouraging.

  View details for DOI 10.1182/bloodadvances.2021005564

  View details for PubMedID 34794180

• Optimal fludarabine lymphodepletion is associated with improved outcomes following CAR T-cell Therapy. Blood advances Fabrizio, V. A., Boelens, J. J., Mauguen, A., Baggott, C., Prabhu, S., Egeler, E., Mavroukakis, S., Pacenta, H. L., Phillips, C. L., Rossoff, J., Stefanski, H., Talano, J. A., Moskop, A., Margossian, S. P., Verneris, M. R., Myers, G. D., Karras, N. A., Brown, P. A., Qayed, M., Hermiston, M. L., Satwani, P., Krupski, C., Keating, A. K., Wilcox, R., Rabik, C. A., Chinnabhandar, V., Kunicki, M., Goksenin, A. Y., Mackall, C. L., Laetsch, T. W., Schultz, L. M., Curran, K. J. 2021

  Abstract

  Chimeric antigen receptor (CAR) T-cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy prior to CAR T-cell therapy would improve outcomes. In a retrospective analysis of relapsed/refractory B-cell acute lymphoblastic leukemia patients undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated the fludarabine exposure as area-under-the-curve (AUC;mg*hr/L) using a validated population-pharmacokinetic model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite endpoint (loss of B-cell aplasia (BCA) or relapse). Eligible patients (n=152) had a median age of 12.5 years (range <1-26), response rate of 86% (131/152), 12-month OS of 75.1% (95%-CI: 67.6-82.6%), and 12-month CIR of 36.4% (95%-CI: 27.5-45.2%). Optimal fludarabine-exposure was determined as an AUC≥13.8mg*hr/L. In multivariable analyses patients with an AUC<13.8mg*hr/L had a 2.5-fold higher CIR (HR=2.45 [1.34-4.48]; P=0.005) and a twofold higher risk of relapse or loss of BCA (HR=1.96 [1.19-3.23]; P=0.01) compared to those with optimal fludarabine exposure. High preinfusion disease burden was also associated with an increased risk of relapse (HR=2.66 [1.45-4.87]; P=0.001) and death (HR=4.77 [2.10-10.9]; p<0.001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and based on this analysis may reduce disease relapse after CAR T-cell therapy.

  View details for DOI 10.1182/bloodadvances.2021006418

  View details for PubMedID 34788386

• GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas. Majzner, R. G., Ramakrishna, S., Mochizuki, A., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Toland, A., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J. S., Marcy, A., Kunicki, M., Fujimoto, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Mackall, C. L., Monje, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263501014

• SINGLE CELL RNA SEQUENCING FROM THE CSF OF SUBJECTS WITH H3K27M+DIPG/DMG TREATED WITH GD2 CAR T-CELLULAR THERAPY Mochizuki, A., Ramakrishna, S., Good, Z., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Toland, A., Baggot, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J., Marcy, A., Kunicki, M., Celones, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Davis, K., Feldman, S., Sahaf, B., Majzner, R., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2021: 39

  View details for DOI 10.1093/neuonc/noab090.158

  View details for Web of Science ID 000671540600159

• GD2 CAR T-CELLS MEDIATE CLINICAL ACTIVITY AND MANAGEABLE TOXICITY IN CHILDREN AND YOUNG ADULTS WITH H3K27M-MUTATED DIPG AND SPINAL CORD DMG Majzner, R., Ramakrishna, S., Mochizuki, A., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Martin, A., Toland, S., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J., Marcy, A., Kunicki, M., Fujimoto, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2021: 49-50

  View details for DOI 10.1093/neuonc/noab090.200

  View details for Web of Science ID 000671540600201

• Intracellular Context Affects Levels of a Chemically Dependent Destabilizing Domain PLOS ONE Sellmyer, M. A., Chen, L., Egeler, E. L., Rakhit, R., Wandless, T. J. 2012; 7 (9)

  Abstract

  The ability to regulate protein levels in live cells is crucial to understanding protein function. In the interest of advancing the tool set for protein perturbation, we developed a protein destabilizing domain (DD) that can confer its instability to a fused protein of interest. This destabilization and consequent degradation can be rescued in a reversible and dose-dependent manner with the addition of a small molecule that is specific for the DD, Shield-1. Proteins encounter different local protein quality control (QC) machinery when targeted to cellular compartments such as the mitochondrial matrix or endoplasmic reticulum (ER). These varied environments could have profound effects on the levels and regulation of the cytoplasmically derived DD. Here we show that DD fusions in the cytoplasm or nucleus can be efficiently degraded in mammalian cells; however, targeting fusions to the mitochondrial matrix or ER lumen leads to accumulation even in the absence of Shield-1. Additionally, we characterize the behavior of the DD with perturbants that modulate protein production, degradation, and local protein QC machinery. Chemical induction of the unfolded protein response in the ER results in decreased levels of an ER-targeted DD indicating the sensitivity of the DD to the degradation environment. These data reinforce that DD is an effective tool for protein perturbation, show that the local QC machinery affects levels of the DD, and suggest that the DD may be a useful probe for monitoring protein quality control machinery.

  View details for DOI 10.1371/journal.pone.0043297

  View details for Web of Science ID 000308738500009

  View details for PubMedID 22984418

  View details for PubMedCentralID PMC3440426

• Ligand-switchable Substrates for a Ubiquitin-Proteasome System JOURNAL OF BIOLOGICAL CHEMISTRY Egeler, E. L., Urner, L. M., Rakhit, R., Liu, C. W., Wandless, T. J. 2011; 286 (36): 31328-31336

  Abstract

  Cellular maintenance of protein homeostasis is essential for normal cellular function. The ubiquitin-proteasome system (UPS) plays a central role in processing cellular proteins destined for degradation, but little is currently known about how misfolded cytosolic proteins are recognized by protein quality control machinery and targeted to the UPS for degradation in mammalian cells. Destabilizing domains (DDs) are small protein domains that are unstable and degraded in the absence of ligand, but whose stability is rescued by binding to a high affinity cell-permeable ligand. In the work presented here, we investigate the biophysical properties and cellular fates of a panel of FKBP12 mutants displaying a range of stabilities when expressed in mammalian cells. Our findings correlate observed cellular instability to both the propensity of the protein domain to unfold in vitro and the extent of ubiquitination of the protein in the non-permissive (ligand-free) state. We propose a model in which removal of stabilizing ligand causes the DD to unfold and be rapidly ubiquitinated by the UPS for degradation at the proteasome. The conditional nature of DD stability allows a rapid and non-perturbing switch from stable protein to unstable UPS substrate unlike other methods currently used to interrogate protein quality control, providing tunable control of degradation rates.

  View details for DOI 10.1074/jbc.M111.264101

  View details for Web of Science ID 000294487500028

  View details for PubMedID 21768107

  View details for PubMedCentralID PMC3173072

• Regulating protein stability in mammalian cells using small molecules. Cold Spring Harbor protocols Hagan, E. L., Banaszynski, L. A., Chen, L., Maynard-Smith, L. A., Wandless, T. J. 2009; 2009 (3): pdb prot5172-?

  View details for DOI 10.1101/pdb.prot5172

  View details for PubMedID 20147107

  View details for PubMedCentralID PMC3213858