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1. Bridging Therapy in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Receiving Standard of Care Brexucabtagene Autoleucel: Results from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA)

Author

Lin, Chenyu, Tsai, Dr. Stephanie B., Roloff, Gregory, Zhang, Amy, Aldoss, Ibrahim, Kopmar, Noam E., Dekker, Simone E., Jeyakumar, Nikeshan, Gupta, Vishal, O'Connor, Timothy E, Dykes, Kaitlyn C, Ahmed, Mohamed, Dholaria, Dr. Bhagirathbhai, Zambrano, Hector, Bradshaw, Danielle, Logan, Aaron C., Tracy, Sean, Kubiak, Michal, Solh, Melhem M, Mercadal, Santiago, Schwartz, Marc, Mukherjee, Akash, Battiwalla, Minoo, Shaughnessy, Paul J., Majhail, Navneet S., Mountjoy, Luke, Malik, Shahbaz, Mathews, John, Ladha, Dr. Abdullah, Advani, Anjali S., Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T, Hilal, Talal, Moore, Jozal W., O'Dwyer, Kristen M, Sasine, Joshua P, Lee, Catherine J, Kota, Vamsi, Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Oliai, Caspian, Bachanova, Veronika, Stock, Wendy, Pullarkat, Vinod, Cassaday, Ryan D., Miller, Katharine, Muffly, Lori S, Galal, Ahmed, Shah, Bijal D., and Faramand, Rawan G

Abstract

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). The optimal bridging therapy is unknown in this setting.

Published
2024
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2. Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Shows Rapid Primary Engraftment with CD33-Negative Hematopoiesis in Patients with High-Risk Acute Myeloid Leukemia (AML) and Avoids Hematopoietic Toxicity during Gemtuzumab Ozogamicin (GO) Maintenance Post-Hematopoietic Cell Transplant (HCT).

Author

DiPersio, John F., Cooper, Brenda, Suh, Hyung C., Koura, Divya, Bernard, Léa, Shah, Nirali N., Walter, Roland B., Perales, Miguel-Angel, Mapara, Markus Y., Tamari, Roni, Loken, Michael, Breitschwerdt, Kyle, Nath, Sritama, Raffel, Glen D, and Koehne, Guenther

Abstract

Maintenance therapy intended to control post-alloHCT relapse is often limited by hematopoietic toxicity towards normal engrafted cells. GO (MylotargTM) is an antibody-drug conjugate targeting CD33+ AML, but its use is limited by on-target, off-tumor hematopoietic toxicity. Trem-cel (formerly VOR33) is manufactured from CD34+ cells isolated from matched-donor apheresis and modified by CRISPR/Cas9 gene-editing to remove CD33, with the goal of protecting normal hematopoietic cells from post-HCT CD33-directed therapies.

Published
2024
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3. Trial in Progress: Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Author

Shah, Nirali N., Azzi, Jacques, Cooper, Brenda, Deol, Abhinav, DiPersio, John F., Koura, Divya, Magenau, John, McClune, Brian, Muffly, Lori S, Mushtaq, Muhammad Umair, Narayan, Rupa, Suh, Hyung C., Nath, Sritama, Whangbo, Jennifer, and Koehne, Guenther

Abstract

Relapse after allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML) is associated with a 2-year post-relapse survival rate of less than 20%. Though chimeric antigen receptor (CAR) T cells targeting tumor-associated antigens have demonstrated efficacy in several hematologic malignancies, the CAR T cell experience for relapsed/refractory (R/R) AML is limited. Challenges for autologous AML CAR T cell therapy include inadequate numbers of functional, undifferentiated T cells in the starting material, and the potential presence of AML blasts that may interfere with T cell proliferation and function during the manufacturing process. VCAR33 is a CD33-directed CAR T cell product generated using lymphocytes from each patient's prior allogeneic stem cell donor. CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (>80%) of AML blasts. Manufacturing CAR T cells from healthy starting material will likely eliminate delays and production failures due to lymphopenia and may also improve T cell function.

Published
2024
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4. Trial in Progress: A First-in-Human Phase 1/2 Study of Hematopoietic Stem Cell Transplantation (HCT) with VOR33 (CD33-Deleted Allograft) Followed By Treatment with Gemtuzumab Ozogamicin (GO) in Patients with CD33+ Acute Myeloid Leukemia (AML) Who Are at High-Risk of Post-HCT Relapse

Author

Cooper, Brenda W., Suh, Hyung C., Koura, Divya, Koehne, Guenther, Cho, Christina, Bambace, Nadia M., Bernard, Léa, Shah, Nirali N., Walter, Roland B., DiPersio, John F., Nath, Sritama, Lee-Sundlov, Melissa M., Lacy, Ali, Stanizzi, Darren, Kuhn, Karen, Whangbo, Jennifer S., Slapak, Christopher, and Raffel, Glen D.

Published
2022
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5. Trial in Progress: A First-in-Human Phase 1/2 Study of Hematopoietic Stem Cell Transplantation (HCT) with VOR33 (CD33-Deleted Allograft) Followed By Treatment with Gemtuzumab Ozogamicin (GO) in Patients with CD33+ Acute Myeloid Leukemia (AML) Who Are at High-Risk of Post-HCT Relapse

Author

Cooper, Brenda W., Suh, Hyung C., Koura, Divya, Koehne, Guenther, Cho, Christina, Bambace, Nadia M., Bernard, Léa, Shah, Nirali N., Walter, Roland B., DiPersio, John F., Nath, Sritama, Lee-Sundlov, Melissa M., Lacy, Ali, Stanizzi, Darren, Kuhn, Karen, Whangbo, Jennifer S., Slapak, Christopher, and Raffel, Glen D.

Published
2022
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6. The Impact of Social Determinants of Health on Brexucabtagene Autoleucel Outcomes in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Author

O'Connor, Timothy E, Lin, Chenyu, Roloff, Gregory, Zhang, Amy, Aldoss, Ibrahim, Faramand, Rawan G, Kopmar, Noam E., Dykes, Kaitlyn C, Jeyakumar, Nikeshan, Dekker, Simone E., Gupta, Vishal, Ahmed, Mohamed, Logan, Aaron C., Zambrano, Hector, Bradshaw, Danielle, Mercadal, Santiago, Schwartz, Marc, Tracy, Sean, Kubiak, Michal, Mukherjee, Akash, Majhail, Navneet S., Battiwalla, Minoo, Mountjoy, Luke, Malik, Shahbaz, Mathews, John, Shaughnessy, Paul J., Ladha, Abdullah, Advani, Anjali S., Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T, Hilal, Talal, Moore, Jozal W., O'Dwyer, Kristen M, Sasine, Joshua P, Solh, Melhem M, Lee, Catherine J., Kota, Vamsi, Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Oliai, Caspian, Bachanova, Veronika, Stock, Wendy, Pullarkat, Vinod, Cassaday, Ryan D., Shah, Bijal D., Miller, Katharine, Muffly, Lori S, Galal, Ahmed, Tsai, Dr. Stephanie B., and Dholaria, Dr. Bhagirathbhai

Abstract

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR-T) cell therapy approved for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). How social determinants of health (SDoH) affect outcomes of adults receiving brexu-cel is unknown.

Published
2024
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7. Impact of prior inotuzumab ozogamicin treatment on brexucabtagene autoleucel outcomes in adults with B-cell ALL

Author

Aldoss, Ibrahim, Roloff, Gregory W., Faramand, Rawan, Kopmar, Noam E., Lin, Chenyu, Advani, Anjali S., Dekker, Simone E., Gupta, Vishal K., O'Connor, Timothy E., Jeyakumar, Nikeshan, Muhsen, Ibrahim N., Valtis, Yannis, Zhang, Amy, Miller, Katharine, Sutherland, Katherine, Dykes, Kaitlyn C., Ahmed, Mohamed, Chen, Evan, Zambrano, Hector, Bradshaw, Danielle, Mercadal, Santiago, Schwartz, Marc, Tracy, Sean, Dholaria, Bhagirathbhai, Kubiak, Michal, Mukherjee, Akash, Majhail, Navneet, Battiwalla, Minoo, Mountjoy, Luke, Malik, Shahbaz A., Mathews, John, Shaughnessy, Paul, Logan, Aaron C., Ladha, Abdullah, Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T., Hilal, Talal, Moore, Jozal, Connor, Matthew, O'Dwyer, Kristen M., Hill, LaQuisa C., Tsai, Stephanie B., Sasine, Joshua, Solh, Melhem M., Lee, Catherine J., Kota, Vamsi K., Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Oliai, Caspian, Leonard, Jessica T., Frey, Noelle V., Park, Jae H., Luskin, Marlise R., Bachanova, Veronika, Galal, Ahmed, Bishop, Michael R., Stock, Wendy, Cassaday, Ryan D., Pullarkat, Vinod, Shah, Bijal D., and Muffly, Lori S.

Abstract

•InO-exposed patients with r/r B-ALL have inferior outcomes after brexu-cel, particularly those who were nonresponders to InO.•The negative association is unrelated directly to InO per se; rather, it reflects selection of patients with intrinsically adverse-risk ALL.

Published
2024
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8. Impact of Prior Response to Blinatumomab on Outcomes of Brexucabtagene Autoleucel (Brexu-cel) in Adult Patients with Relapsed or Refractory (r/r) B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA)

Author

Gupta, Vishal K, Roloff, Gregory W, Muffly, Lori S., Aldoss, Ibrahim, Kopmar, Noam E., Lin, Chenyu, Dekker, Simone E., Jeyakumar, Nikeshan, O'Connor, Timothy E, Zhang, Amy, Miller, Katharine, Dykes, Kaitlyn C, Ahmed, Mohamed, Bradshaw, Danielle, Mercadal, Santiago, Schwartz, Marc, Tracy, Sean, Dholaria, Bhagirathbhai, Kubiak, Michal, Mukherjee, Akash, Majhail, Navneet, Battiwalla, Minoo, Mountjoy, Luke, Malik, Shabaz, Mathews, John, Shaughnessy, Paul, Logan, Aaron C., Ladha, Abdullah, Yaghmour, George, Advani, Anjali S., Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T., Hilal, Talal, Moore, Jozal, O'Dwyer, Kristen M., Tsai, Stephanie B., Sasine, Joshua, Lee, Catherine J., Kota, Vamsi K., Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Stock, Wendy, Galal, Ahmed, Pullarkat, Vinod, Cassaday, Ryan D, Shah, Bijal D., Faramand, Rawan, and Oliai, Caspian H.

Abstract

Introduction:Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a CD19-directed bispecific T-cell engager that is also approved for r/r B-ALL, and often used as early salvage therapy. Data in the pediatric/AYA population suggest that patients who did not respond to blinatumomab may have inferior outcomes to CD19-directed CAR-T products compared to those who have achieved a response to blinatumomab or were blinatumomab-naïve (Myers et al. J Clin Oncol 2022). In this study, we evaluate the response to blinatumomab and subsequent response to brexu-cel in adults with r/r B-ALL.

Published
2023
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9. Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Author

Shah, Nirali N., Azzi, Jacques, Cooper, Brenda W, Deol, Abhinav, DiPersio, John, Koura, Divya, McClune, Brian, Muffly, Lori S., Mushtaq, Muhammad Umair, Narayan, Rupa, Suh, Hyung Chan, Yanik, Gregory, Nath, Sritama, Whangbo, Jennifer, and Koehne, Guenther

Abstract

Background and Significance:

Published
2023
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10. Bridging Therapy in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Receiving Standard of Care Brexucabtagene Autoleucel: Results from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA)

Author

Lin, Chenyu, Tsai, Stephanie B., Roloff, Gregory W, Zhang, Amy, Aldoss, Ibrahim, Kopmar, Noam E., Dekker, Simone E., Jeyakumar, Nikeshan, Gupta, Vishal K, O'Connor, Timothy E, Dykes, Kaitlyn C, Ahmed, Mohamed, Dholaria, Bhagirathbhai, Zambrano, Hector, Bradshaw, Danielle, Logan, Aaron C., Tracy, Sean, Kubiak, Michal, Solh, Melhem M., Mercadal, Santiago, Schwartz, Marc, Mukherjee, Akash, Battiwalla, Minoo, Shaughnessy, Paul, Majhail, Navneet, Mountjoy, Luke, Malik, Shahbaz A., Mathews, John, Ladha, Abdullah, Advani, Anjali S., Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T., Hilal, Talal, Moore, Jozal, O'Dwyer, Kristen M., Sasine, Joshua, Lee, Catherine J., Kota, Vamsi K., Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Oliai, Caspian H., Bachanova, Veronika, Stock, Wendy, Pullarkat, Vinod, Cassaday, Ryan D, Miller, Katharine, Muffly, Lori S., Galal, Ahmed, Shah, Bijal D., and Faramand, Rawan

Abstract

Introduction:

Published
2023
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11. The Impact of Social Determinants of Health on Brexucabtagene Autoleucel Outcomes in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Author

O'Connor, Timothy E, Lin, Chenyu, Roloff, Gregory W, Zhang, Amy, Aldoss, Ibrahim, Faramand, Rawan, Kopmar, Noam E., Dykes, Kaitlyn C, Jeyakumar, Nikeshan, Dekker, Simone E., Gupta, Vishal K, Ahmed, Mohamed, Logan, Aaron C., Zambrano, Hector, Bradshaw, Danielle, Mercadal, Santiago, Schwartz, Marc, Tracy, Sean, Kubiak, Michal, Mukherjee, Akash, Majhail, Navneet, Battiwalla, Minoo, Mountjoy, Luke, Malik, Shabaz, Mathews, John, Shaughnessy, Paul, Ladha, Abdullah, Yaghmour, George, Advani, Anjali S., Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T., Hilal, Talal, Moore, Jozal, Sasine, Joshua, Solh, Melhem M., Lee, Catherine J., Kota, Vamsi K., Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Oliai, Caspian H., Bachanova, Veronika, Stock, Wendy, Cassaday, Ryan D, Shah, Bijal D., Miller, Katharine, Muffly, Lori S., Galal, Ahmed, Tsai, Stephanie B., and Dholaria, Bhagirathbhai

Abstract

Background

Published
2023
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12. Toxicity Profile of Brexucabtagene Autoleucel (brexu-cel; CD19-directed CAR T-cell therapy) in Adult Patients (pts) with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from a Multicenter Real-World Outcomes Study

Author

Kopmar, Noam E., Gooley, Ted, Roloff, Gregory W, Aldoss, Ibrahim, Lin, Chenyu, Dekker, Simone E., Gupta, Vishal K, Jeyakumar, Nikeshan, O'connor, Timothy, Dykes, Kaitlyn C, Ahmed, Mohamed, Zambrano, Hector, Bradshaw, Danielle, Mercadal, Santiago, Schwartz, Marc, Tracy, Sean, Dholaria, Bhagirathbhai, Kubiak, Michal, Mukherjee, Akash, Majhail, Navneet, Battiwalla, Minoo, Mountjoy, Luke, Malik, Shabaz, Shaughnessy, Paul, Mathews, John, Logan, Aaron C., Ladha, Abdullah, Yaghmour, George, Advani, Anjali S., Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T., Hilal, Talal, Moore, Jozal, O'Dwyer, Kristen M., Tsai, Stephanie B., Sasine, Joshua, Solh, Melhem M., Lee, Catherine J., Kota, Vamsi K., Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Oliai, Caspian H., Bachanova, Veronika, Stock, Wendy, Galal, Ahmed, Pullarkat, Vinod, Shah, Bijal D., Faramand, Rawan, Muffly, Lori S., and Cassaday, Ryan D

Abstract

Introduction:

Published
2023
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13. Trem-Cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Shows Rapid Primary Engraftment with CD33-Negative Hematopoiesis in Patients with High-Risk Acute Myeloid Leukemia (AML) and Avoids Hematopoietic Toxicity during Gemtuzumab Ozogamicin (GO) Maintenance Post-Hematopoietic Cell Transplant (HCT)

Author

DiPersio, John, Cooper, Brenda W, Suh, Hyung C, Koura, Divya, Bernard, Lea, Shah, Nirali N., Walter, Roland B., Perales, Miguel-Angel, Mapara, Markus, Tamari, Roni, Loken, Michael R., Breitschwerdt, Kyle, Nath, Sritama, Raffel, Glen D, and Koehne, Guenther

Abstract

Background:Allogeneic HCT is the standard of care for eligible patients with AML harboring high-risk features such as adverse-risk cytogenetics or measurable residual disease (MRD), however, the majority of these patients still relapse post-HCT and have very poor outcomes. The use of maintenance therapies intended to control post-HCT relapse is often limited by hematopoietic toxicity towards normal engrafted cells. GO (tradename: Mylotarg TM) is an anti-CD33 antibody-drug conjugate targeting CD33+ AML, but its use is limited by on-target, off-tumor hematopoietic toxicity toward CD33+ myeloid and progenitor cells. Tremtelectogene empogeditemcel (trem-cel; formerly VOR33) is a hematopoietic stem and progenitor cell product, manufactured from CD34+ cells isolated from a patient-matched donor, that has been modified by CRISPR/Cas9 gene-editing to lack CD33. Trem-cel was developed to protect normal hematopoietic cells from post-HCT CD33-directed therapies and allow exclusive targeting of residual leukemia.

Published
2023
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14. The Impact of Inotuzumab Ozogamicin (InO) Treatment on Brexucabtagene Autoleucel (Brexu-cel) Outcomes in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Author

Aldoss, Ibrahim, Roloff, Gregory W, Advani, Anjali S., Kopmar, Noam E., Lin, Chenyu, Dekker, Simone E., Gupta, Vishal K, Jeyakumar, Nikeshan, O'Connor, Timothy E, Zhang, Amy, Miller, Katharine, Dykes, Kaitlyn C, Ahmed, Mohamed, Zambrano, Hector, Bradshaw, Danielle, Mercadal, Santiago, Schwartz, Marc, Tracy, Sean, Dholaria, Bhagirathbhai, Kubiak, Michal, Mukherjee, Akash, Majhail, Navneet, Battiwalla, Minoo, Mountjoy, Luke, Malik, Shahbaz A., Mathews, John, Shaughnessy, Paul, Logan, Aaron C., Ladha, Abdullah, Yaghmour, George, Stefan, Maryann, Guzowski, Caitlin, Hoeg, Rasmus T., Hilal, Talal, Moore, Jozal, O'Dwyer, Kristen M., Tsai, Stephanie B., Sasine, Joshua, Solh, Melhem M., Lee, Catherine J., Kota, Vamsi K., Koura, Divya, Veeraputhiran, Muthu, Blunk, Betsy, Leonard, Jessica T., Oliai, Caspian H., Bachanova, Veronika, Stock, Wendy, Galal, Ahmed, Pullarkat, Vinod, Cassaday, Ryan D, Shah, Bijal D., Faramand, Rawan, and Muffly, Lori S.

Abstract

Cellular Immunotherapies: Late Phase and Commercially Available Therapies

Published
2023
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15. A Prospective Randomized Clinical Trial Comparing a Calcineurin-Free Gvhd Prophylaxis Regimen with Post-Transplant Cyclophosphamide and Abatacept to Methotrexate and Tacrolimus

Author

Koura, Divya, Mirocha, James, Dykes, Kaitlyn C, Hamdan, Ayad, Goodman, Aaron, Tanaka, Tiffany N, Mulroney, Carolyn M., Costello, Caitlin L., Mangan, James K., Ball, Edward D., Jeong, Ah-Reum, Maroge, Joseph, Padilla, Michelle, and Tzachanis, Dimitrios

Abstract

Background: Chronic Graft Versus Host Disease (GVHD) is one of the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we could induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy can eliminate most host-reactive donor T cells. Abatacept (CTLA4Ig) blocks the costimulatory signals given to naïve T cells during immune reconstitution, thus favoring an anergic phenotype and promoting tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and has therefore the ability to preserve the graft-versus-tumor effect.

Published
2023
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16. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Author

Suessmuth, Yvonne, Mukherjee, Rithun, Watkins, Benjamin, Koura, Divya T., Finstermeier, Knut, Desmarais, Cindy, Stempora, Linda, Horan, John T., Langston, Amelia, Qayed, Muna, Khoury, Hanna J., Grizzle, Audrey, Cheeseman, Jennifer A., Conger, Jason A., Robertson, Jennifer, Garrett, Aneesah, Kirk, Allan D., Waller, Edmund K., Blazar, Bruce R., Mehta, Aneesh K., Robins, Harlan S., and Kean, Leslie S.

Abstract

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+ effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31+/CD4+ putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.

Published
2015
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17. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

Author

Suessmuth, Yvonne, Mukherjee, Rithun, Watkins, Benjamin, Koura, Divya T., Finstermeier, Knut, Desmarais, Cindy, Stempora, Linda, Horan, John T., Langston, Amelia, Qayed, Muna, Khoury, Hanna J., Grizzle, Audrey, Cheeseman, Jennifer A., Conger, Jason A., Robertson, Jennifer, Garrett, Aneesah, Kirk, Allan D., Waller, Edmund K., Blazar, Bruce R., Mehta, Aneesh K., Robins, Harlan S., and Kean, Leslie S.

Abstract

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31+/CD4+putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8+Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.govas #NCT01012492.

Published
2015
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18. Inherited predisposition to multiple myeloma

Author

Koura, Divya and Langston, Amelia

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma. Family pedigree analyses of high-risk families, case-control studies and racial disparities in disease incidence all point to a potential inherited predisposition to MM. Genome-wide association studies (GWASs) have identified susceptibility loci in a number of cancers and such studies are currently underway in MM. To date, GWASs in MM have identified several potential regions of interest for further study on chromosomes 3p22, 7p15.3, 8q24 and 2p23.3. In addition, several targets of paraproteins (so called ‘paratargs’) in MM have been identified. Hyperphosphorylation of the paratarg protein, which is inherited in an autosomal dominant manner, appears a common mechanism underlying the antigenicity of these proteins. One particular protein, hyperphosphorylated paratarg-7 (pP-7) is a common target in persons with myeloma and has also been identified in affected members of several high-risk MM families. It appears that the frequency of pP-7 as an antigenic target may be particularly high in African American patients with MM, which could be part of the explanation for observed racial disparities in the incidence of MM. In this review we focus on available data in the area of inherited predisposition to MM, and highlight future research directions.

Published
2013
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19. A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care

Author

Koura, Divya, Tzachanis, Dimitrios, Ball, Edward D., Costello, Caitlin, Goodman, Aaron M, Mangan, James K., Mulroney, Carolyn, Maroge, Joseph, Padilla, Michelle, Breslin, Peggy, Garrett, Jodi, and McConnell, Kimberly

Abstract

Background: Graft versus host disease (GVHD) is one the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we can induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy when given on Days +3 and +4 can eliminate host-reactive donor T cells. CTLA4Ig blocks the costimulatory signals given through CD28 to naïve donor T cells thus favoring an anergic phenotype that promotes tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and therefore has the ability to preserve the graft-versus-tumor effect.

Published
2021
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20. A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care

Author

Koura, Divya, Tzachanis, Dimitrios, Ball, Edward D., Costello, Caitlin, Goodman, Aaron M, Mangan, James K., Mulroney, Carolyn, Maroge, Joseph, Padilla, Michelle, Breslin, Peggy, Garrett, Jodi, and McConnell, Kimberly

Abstract

Tzachanis: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Partner: Consultancy; Fate Therapeutics: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Magenta: Consultancy; Kyowa Kirin: Consultancy. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Mangan: Elevate Bio: Other: ad board.abatacept: using as part of graft versus host disease prophylaxis

Published
2021
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