348 results on '"A, Gottschalk"'
Search Results
2. Engineering naturally occurring CD7− T cells for the immunotherapy of hematological malignancies
- Author
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Freiwan, Abdullah, Zoine, Jaquelyn T., Crawford, Jeremy Chase, Vaidya, Abishek, Schattgen, Stefan A., Myers, Jacquelyn A., Patil, Sagar L., Khanlari, Mahsa, Inaba, Hiroto, Klco, Jeffery M., Mullighan, Charles G., Krenciute, Giedre, Chockley, Peter J., Naik, Swati, Langfitt, Deanna M., Mamonkin, Maksim, Obeng, Esther A., Thomas, Paul G., Gottschalk, Stephen, and Velasquez, M. Paulina
- Published
- 2022
- Full Text
- View/download PDF
3. Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs
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Steffin, David H.M., Muhsen, Ibrahim N., Hill, LaQuisa C., Ramos, Carlos A., Ahmed, Nabil, Hegde, Meenakshi, Wang, Tao, Wu, Mengfen, Gottschalk, Stephen, Whittle, Sarah B., Lulla, Premal D., Mamonkin, Maksim, Omer, Bilal, Rouce, Rayne H., Heczey, Andras, Metelitsa, Leonid S., Grilley, Bambi J., Robertson, Catherine, Torrano, Virginia, Lapteva, Natalia, Gee, Adrian P., Rooney, Cliona M., Brenner, Malcolm K., and Heslop, Helen E.
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- 2022
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4. Is immune escape in the rearview mirror?
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Naik, Swati, primary and Gottschalk, Stephen, additional
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- 2024
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5. Impact of hematopoietic cell transplantation on myocardial fibrosis in young patients with sickle cell disease
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Sharma, Akshay, Selukar, Subodh, Bi, Yu, Merlocco, Anthony, Morin, Cara E., Goode, Chris, Rai, Parul, Towbin, Jeffrey A., Hankins, Jane S., Gottschalk, Stephen, Triplett, Brandon, and Johnson, Jason N.
- Abstract
Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.clinicaltrials.govas #NCT04362293.
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- 2024
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6. EBV/LMP-specific T cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation
- Author
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McLaughlin, Lauren P., Rouce, Rayne, Gottschalk, Stephen, Torrano, Vicky, Carrum, George, Wu, Meng-Fen, Hoq, Fahmida, Grilley, Bambi, Marcogliese, Andrea M., Hanley, Patrick J., Gee, Adrian P., Brenner, Malcolm K., Rooney, Cliona M., Heslop, Helen E., and Bollard, Catherine M.
- Published
- 2018
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7. Redirecting T cells to hematological malignancies with bispecific antibodies
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Velasquez, Mireya Paulina, Bonifant, Challice L., and Gottschalk, Stephen
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- 2018
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8. Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs
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David H. M. Steffin, Ibrahim N. Muhsen, LaQuisa C. Hill, Carlos A. Ramos, Nabil Ahmed, Meenakshi Hegde, Tao Wang, Mengfen Wu, Stephen Gottschalk, Sarah B. Whittle, Premal D. Lulla, Maksim Mamonkin, Bilal Omer, Rayne H. Rouce, Andras Heczey, Leonid S. Metelitsa, Bambi J. Grilley, Catherine Robertson, Virginia Torrano, Natalia Lapteva, Adrian P. Gee, Cliona M. Rooney, Malcolm K. Brenner, and Helen E. Heslop
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Adult ,Hematologic Neoplasms ,Neoplasms ,Immunology ,Leukocytes, Mononuclear ,Humans ,Cell Biology ,Hematology ,Child ,Biochemistry ,Follow-Up Studies ,Retrospective Studies - Abstract
Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, 13 patients (3.8%) developed another cancer with a total of 16 events (4 hematologic malignancies and 12 solid tumors). The 5-year cumulative incidence of a first subsequent malignancy in the recipients of genetically modified IE cells was 3.6% (95% confidence interval, 1.8% to 6.4%). For 11 of the 16 subsequent tumors, biopsies were available, and no sample was transgene positive by polymerase chain reaction. Replication-competent retrovirus testing of peripheral blood mononuclear cells was negative in the 13 patients with subsequent malignancies tested. Rates of subsequent malignancy were low and comparable to standard chemotherapy. These results suggest that the administration of IE cells genetically modified with γ retroviral vectors does not increase the risk for subsequent malignancy.
- Published
- 2022
9. LigandCD70.CAR As a Platform for Dual-Targeting CAR T Cells for Acute Myeloid Leukemia
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Scherer, Lauren, primary, Tat, Candise, additional, Sauer, Tim, additional, Tashiro, Haruko, additional, Naik, Swati, additional, Velasquez, Mireya Paulina, additional, Gottschalk, Stephen, additional, Rooney, Cliona M., additional, Brenner, Malcolm K., additional, and Omer, Bilal, additional
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- 2022
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10. Establishing Immunocompetent Leukemia Models to Investigate the Impact of CAR T Cells on the Immune Microenvironment and Bone Marrow Niche
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Moore, Sarah E., primary, Zoine, Jaquelyn T., additional, Crawford, Jeremy Chase, additional, Langfitt, Deanna, additional, Barajas, Juan M., additional, Abdelhamed, Sherif, additional, Iacobucci, Ilaria, additional, Haydar, Dalia, additional, Krenciute, Giedre, additional, Mullighan, Charles G., additional, Klco, Jeffery M., additional, Gottschalk, Stephen, additional, Thomas, Paul G., additional, and Velasquez, Mireya Paulina, additional
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- 2022
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11. Safety and Anti-Leukemic Activity of CD123-CAR T Cells in Pediatric Patients with AML: Preliminary Results from a Phase 1 Trial
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Naik, Swati, primary, Madden, Renee M., additional, Lipsitt, Amanda, additional, Lockey, Timothy, additional, Bran, Jennyfer, additional, Rubnitz, Jeffrey E., additional, Klco, Jeffery, additional, Shulkin, Barry, additional, Patil, Sagar L., additional, Schell, Sarah, additional, Park, Jeoungeun John, additional, Riberdy, Janice, additional, Shang, Na, additional, Zoine, Jaquelyn T., additional, Wallace, Jennifer, additional, Harstead, Elaine, additional, Willis, Catherine, additional, Metais, Jean-Yves, additional, Langfitt, Deanna M., additional, Zhou, Sheng, additional, Akel, Salem M., additional, Meagher, Michael M., additional, Triplett, Brandon M., additional, Gottschalk, Stephen, additional, and Velasquez, Mireya Paulina, additional
- Published
- 2022
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12. Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies
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Abdullah Freiwan, Jaquelyn T. Zoine, Jeremy Chase Crawford, Abishek Vaidya, Stefan A. Schattgen, Jacquelyn A. Myers, Sagar L. Patil, Mahsa Khanlari, Hiroto Inaba, Jeffery M. Klco, Charles G. Mullighan, Giedre Krenciute, Peter J. Chockley, Swati Naik, Deanna M. Langfitt, Maksim Mamonkin, Esther A. Obeng, Paul G. Thomas, Stephen Gottschalk, and M. Paulina Velasquez
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7− T cells to generate CD7-CAR (CD7-CARCD7−) T cells. CD7-CARCD7− T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7− T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of nonselected (bulk) CD19-CAR and CD19-CARCD7− T cells revealed that CD19-CARCD7− T cells had enhanced antitumor activity compared with their bulk counterparts in vitro and in vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected postinfusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed postinfusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than nonresponders (NCT03573700). Thus, CARCD7− T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.
- Published
- 2022
13. Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant
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Tao Wang, Helen E. Heslop, Stephen Gottschalk, Bambi Grilley, Rammurti T. Kamble, Carlos A. Ramos, Ann M. Leen, Meng-Fen Wu, Malcolm K. Brenner, Robert A. Krance, Catherine Robertson, Manik Kuvalekar, Jasleen K. Randhawa, Spyridoula Vasileiou, Adrian P. Gee, Suhasini Lulla, Juan F. Vera, Betty Chung, Ayumi Watanabe, Premal Lulla, Ifigeneia Tzannou, Swati Naik, LaQuisa Hill, and George Carrum
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Adult ,Male ,Adolescent ,Clinical Trials and Observations ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,T-Cell Antigen Receptor Specificity ,Graft vs Leukemia Effect ,Hematopoietic stem cell transplantation ,Biochemistry ,Young Adult ,Antigen ,Antigens, Neoplasm ,Recurrence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Survivin ,medicine ,Humans ,Transplantation, Homologous ,Aged ,Salvage Therapy ,PRAME ,Errata ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Allografts ,Donor Lymphocytes ,medicine.disease ,Combined Modality Therapy ,Tissue Donors ,Leukemia, Myeloid, Acute ,Leukemia ,surgical procedures, operative ,Lymphocyte Transfusion ,Myelodysplastic Syndromes ,Cancer research ,Female ,Stem cell ,business - Abstract
Relapse after allogeneic hematopoietic stem cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor–derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen–pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.
- Published
- 2021
14. LigandCD70.CAR As a Platform for Dual-Targeting CAR T Cells for Acute Myeloid Leukemia
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Lauren Scherer, Candise Tat, Tim Sauer, Haruko Tashiro, Swati Naik, Mireya Paulina Velasquez, Stephen Gottschalk, Cliona M. Rooney, Malcolm K. Brenner, and Bilal Omer
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. Safety and Anti-Leukemic Activity of CD123-CAR T Cells in Pediatric Patients with AML: Preliminary Results from a Phase 1 Trial
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Swati Naik, Renee M. Madden, Amanda Lipsitt, Timothy Lockey, Jennyfer Bran, Jeffrey E. Rubnitz, Jeffery Klco, Barry Shulkin, Sagar L. Patil, Sarah Schell, Jeoungeun John Park, Janice Riberdy, Na Shang, Jaquelyn T. Zoine, Jennifer Wallace, Elaine Harstead, Catherine Willis, Jean-Yves Metais, Deanna M. Langfitt, Sheng Zhou, Salem M. Akel, Michael M. Meagher, Brandon M. Triplett, Stephen Gottschalk, and Mireya Paulina Velasquez
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity
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Bilal Omer, Linus Angenendt, Christoph Schliemann, Carsten Müller-Tidow, David Nikolov Sedloev, Kathan Parikh, Sandhya Sharma, Michael Schmitt, Qian Chen, Cliona M. Rooney, Tim Sauer, and Stephen Gottschalk
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Adoptive cell transfer ,Immunobiology and Immunotherapy ,THP-1 Cells ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Biology ,Immunotherapy, Adoptive ,Biochemistry ,Antigen ,medicine ,Humans ,Cytotoxic T cell ,Receptors, Chimeric Antigen ,Myeloid leukemia ,Cell Biology ,Hematology ,Immunotherapy ,Chimeric antigen receptor ,Neoplasm Proteins ,Leukemia, Myeloid, Acute ,Haematopoiesis ,HEK293 Cells ,Cancer research ,Chimeric Antigen Receptor T-Cell Therapy ,CD27 Ligand ,Single-Chain Antibodies - Abstract
The prognosis of patients with acute myeloid leukemia (AML) remains dismal, highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to patients with AML has been limited, in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML, as it is expressed on most leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CAR T cells that contained a common single-chain variable fragment (scFv) for antigen detection, but differed in size and flexibility of the extracellular spacer and in the transmembrane and the costimulatory domains. These CD70scFv CAR T cells were compared with a CAR construct that contained human CD27, the ligand of CD70 fused to the CD3ζ chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion, and cytotoxic capacities of CD70scFv-based CAR T cells, but CD27z-CAR T cells demonstrated superior proliferation and antitumor activity in vitro and in vivo, compared with all CD70scFv-CAR T cells. Although CD70-CAR T cells recognized activated virus-specific T cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells. Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.
- Published
- 2021
17. Donor-derived multiple leukemia antigen–specific T-cell therapy to prevent relapse after transplant in patients with ALL
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Naik, Swati, primary, Vasileiou, Spyridoula, additional, Tzannou, Ifigeneia, additional, Kuvalekar, Manik, additional, Watanabe, Ayumi, additional, Robertson, Catherine, additional, Lapteva, Natalia, additional, Tao, Wang, additional, Wu, Mengfen, additional, Grilley, Bambi, additional, Carrum, George, additional, Kamble, Rammurti T., additional, Hill, LaQuisa, additional, Krance, Robert A., additional, Martinez, Caridad, additional, Tewari, Priti, additional, Omer, Bilal, additional, Gottschalk, Stephen, additional, Heslop, Helen E., additional, Brenner, Malcom K., additional, Rooney, Cliona M., additional, Vera, Juan F., additional, Leen, Ann M., additional, and Lulla, Premal D., additional
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- 2022
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18. Immunotherapeutic strategies to prevent and treat human herpesvirus 6 reactivation after allogeneic stem cell transplantation
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Gerdemann, Ulrike, Keukens, Laura, Keirnan, Jacqueline M., Katari, Usha L., Nguyen, Chinh T.Q., de Pagter, Anne P., Ramos, Carlos A., Kennedy-Nasser, Alana, Gottschalk, Stephen M., Heslop, Helen E., Brenner, Malcolm K., Rooney, Cliona M., and Leen, Ann M.
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- 2013
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19. Donor-derived multiple leukemia antigen-specific T-cell therapy to prevent relapse after transplant in patients with ALL
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Swati Naik, Spyridoula Vasileiou, Ifigeneia Tzannou, Manik Kuvalekar, Ayumi Watanabe, Catherine Robertson, Natalia Lapteva, Wang Tao, Mengfen Wu, Bambi Grilley, George Carrum, Rammurti T. Kamble, LaQuisa Hill, Robert A. Krance, Caridad Martinez, Priti Tewari, Bilal Omer, Stephen Gottschalk, Helen E. Heslop, Malcom K. Brenner, Cliona M. Rooney, Juan F. Vera, Ann M. Leen, and Premal D. Lulla
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Adult ,Transplantation ,Leukemia ,Immunology ,Cell- and Tissue-Based Therapy ,Hematopoietic Stem Cell Transplantation ,Transplants ,Graft vs Host Disease ,Cell Biology ,Hematology ,Biochemistry ,Tissue Donors ,Recurrence ,Chronic Disease ,Humans ,Transplantation, Homologous ,Child - Abstract
Hematopoietic stem cell transplant (HSCT) is a curative option for patients with high-risk acute lymphoblastic leukemia (ALL), but relapse remains a major cause of treatment failure. To prevent disease relapse, we prepared and infused donor-derived multiple leukemia antigen–specific T cells (mLSTs) targeting PRAME, WT1, and survivin, which are leukemia-associated antigens frequently expressed in B- and T-ALL. Our goal was to maximize the graft-versus-leukemia effect while minimizing the risk of graft-versus-host disease (GVHD). We administered mLSTs (dose range, 0.5 × 107 to 2 × 107 cells per square meter) to 11 patients with ALL (8 pediatric, 3 adult), and observed no dose-limiting toxicity, acute GVHD or cytokine release syndrome. Six of 8 evaluable patients remained in long-term complete remission (median: 46.5 months; range, 9-51). In these individuals we detected an increased frequency of tumor-reactive T cells shortly after infusion, with activity against both targeted and nontargeted, known tumor-associated antigens, indicative of in vivo antigen spreading. By contrast, this in vivo amplification was absent in the 2 patients who experienced relapse. In summary, infusion of donor-derived mLSTs after allogeneic HSCT is feasible and safe and may contribute to disease control, as evidenced by in vivo tumor-directed T-cell expansion. Thus, this approach represents a promising strategy for preventing relapse in patients with ALL.
- Published
- 2021
20. Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States
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Cohen, Jeffrey I., Jaffe, Elaine S., Dale, Janet K., Pittaluga, Stefania, Heslop, Helen E., Rooney, Cliona M., Gottschalk, Stephen, Bollard, Catherine M., Rao, V. Koneti, Marques, Adriana, Burbelo, Peter D., Turk, Siu-Ping, Fulton, Rachael, Wayne, Alan S., Little, Richard F., Cairo, Mitchell S., El-Mallawany, Nader K., Fowler, Daniel, Sportes, Claude, Bishop, Michael R., Wilson, Wyndham, and Straus, Stephen E.
- Published
- 2011
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21. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies
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Shaffer, Donald R., Savoldo, Barbara, Yi, Zhongzhen, Chow, Kevin K.H., Kakarla, Sunitha, Spencer, David M., Dotti, Gianpietro, Wu, Meng-Fen, Liu, Hao, Kenney, Shannon, and Gottschalk, Stephen
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- 2011
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22. CD45RA-Depleted Haploidentical Transplantation Combined with NK Cell Addback Results in Promising Long-Term Outcomes in Pediatric Patients with High-Risk Hematologic Malignancies
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Naik, Swati, primary, Talleur, Aimee C, additional, Li, Ying, additional, Madden, Renee M., additional, Mamcarz, Ewelina, additional, Qudeimat, Amr, additional, Sharma, Akshay, additional, Srinivasan, Ashok, additional, Suliman, Ali Y, additional, Epperly, Rebecca, additional, Obeng, Esther A., additional, Velasquez, Mireya Paulina, additional, Hijano, Diego, additional, Maron, Gabriela, additional, Gottschalk, Stephen, additional, and Triplett, Brandon M, additional
- Published
- 2021
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23. CD45RO+ T-Cell Add Back and Prophylactic Blinatumomab Administration Post Tcrαβ/CD19-Depleted Haploidentical Transplantation in Pediatric Patients with High Risk Acute Leukemia
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Naik, Swati, primary, Madden, Renee M., additional, Mamcarz, Ewelina, additional, Srinivasan, Ashok, additional, Sharma, Akshay, additional, Talleur, Aimee C, additional, Epperly, Rebecca, additional, Qudeimat, Amr, additional, Suliman, Ali Y, additional, Obeng, Esther A., additional, Velasquez, Mireya Paulina, additional, Hijano, Diego, additional, Maron, Gabriela, additional, Li, Ying, additional, Gottschalk, Stephen, additional, and Triplett, Brandon M, additional
- Published
- 2021
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24. Donor-Derived Adoptive T-Cell Therapy Targeting Multiple Tumor Associated Antigens to Prevent Post-Transplant Relapse in Patients with ALL
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Naik, Swati, primary, Vasileiou, Spyridoula, additional, Tzannou, Ifigeneia, additional, Kuvalekar, Manik, additional, Watanabe, Ayumi, additional, Robertson, Catherine, additional, Gee, Adrian P., additional, Grilley, Bambi J., additional, Carrum, George, additional, Kamble, Rammurti, additional, Hill, LaQuisa C., additional, Krance, Robert A., additional, Martinez, Caridad A., additional, Omer, Bilal, additional, Gottschalk, Stephen, additional, Heslop, Helen E., additional, Rooney, Cliona M., additional, Vera, Juan, additional, Leen, Ann, additional, and Lulla, Premal D., additional
- Published
- 2021
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25. CD19-CAR T Cells Develop Exhaustion Epigenetic Programs during a Clinical Response
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Zebley, Caitlin C., primary, Brown, Charmaine, additional, Mi, Tian, additional, Fan, Yiping, additional, Alli, Shanta, additional, Boi, Shannon, additional, Galletti, Giovanni, additional, Lugli, Enrico, additional, Langfitt, Deanna, additional, Metais, Jean-Yves, additional, Lockey, Timothy, additional, Meagher, Michael M, additional, Triplett, Brandon M, additional, Talleur, Aimee C, additional, Gottschalk, Stephen, additional, and Youngblood, Benjamin, additional
- Published
- 2021
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26. Expect the unexpected: piggyBac and lymphoma
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Wilson, Matthew H., primary and Gottschalk, Stephen, additional
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- 2021
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27. Expect the unexpected: piggyBac and lymphoma
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Matthew H. Wilson and Stephen Gottschalk
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,MEDLINE ,Cell Biology ,Hematology ,medicine.disease ,business ,Biochemistry ,Lymphoma - Published
- 2021
28. Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients
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Louis, Chrystal U., Straathof, Karin, Bollard, Catherine M., Gerken, Claudia, Huls, M. Helen, Gresik, M. Victoria, Wu, Meng-Fen, Weiss, Heidi L., Gee, Adrian P., Brenner, Malcolm K., Rooney, Cliona M., Heslop, Helen E., and Gottschalk, Stephen
- Published
- 2009
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29. Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant
- Author
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Lulla, Premal D., primary, Naik, Swati, additional, Vasileiou, Spyridoula, additional, Tzannou, Ifigeneia, additional, Watanabe, Ayumi, additional, Kuvalekar, Manik, additional, Lulla, Suhasini, additional, Carrum, George, additional, Ramos, Carlos A., additional, Kamble, Rammurti, additional, Hill, LaQuisa, additional, Randhawa, Jasleen, additional, Gottschalk, Stephen, additional, Krance, Robert, additional, Wang, Tao, additional, Wu, Mengfen, additional, Robertson, Catherine, additional, Gee, Adrian P., additional, Chung, Betty, additional, Grilley, Bambi, additional, Brenner, Malcolm K., additional, Heslop, Helen E., additional, Vera, Juan F., additional, and Leen, Ann M., additional
- Published
- 2021
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30. Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia
- Author
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Gottschalk Højfeldt, Sofie, primary, Grell, Kathrine, additional, Abrahamsson, Jonas, additional, Lund, Bendik, additional, Vettenranta, Kim, additional, Jónsson, Ólafur G., additional, Frandsen, Thomas L., additional, Wolthers, Benjamin O., additional, Marquart, Hanne Vibeke, additional, Vaitkeviciene, Goda, additional, Lepik, Kristi, additional, Heyman, Mats, additional, Schmiegelow, Kjeld, additional, and Albertsen, Birgitte Klug, additional
- Published
- 2021
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31. Engineering naturally occurring CD7−T cells for the immunotherapy of hematological malignancies
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Freiwan, Abdullah, Zoine, Jaquelyn T., Crawford, Jeremy Chase, Vaidya, Abishek, Schattgen, Stefan A., Myers, Jacquelyn A., Patil, Sagar L., Khanlari, Mahsa, Inaba, Hiroto, Klco, Jeffery M., Mullighan, Charles G., Krenciute, Giedre, Chockley, Peter J., Naik, Swati, Langfitt, Deanna M., Mamonkin, Maksim, Obeng, Esther A., Thomas, Paul G., Gottschalk, Stephen, and Velasquez, M. Paulina
- Abstract
•Naturally occurring CD7 negative T cells are functional effector T cells that can be used for chimeric antigen receptor therapy.•CD7 negative T cells expressing a CD7-CAR have robust antitumor activity and bypass fratricide.
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- 2022
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32. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity
- Author
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Sauer, Tim, primary, Parikh, Kathan, additional, Sharma, Sandhya, additional, Omer, Bilal, additional, Sedloev, David, additional, Chen, Qian, additional, Angenendt, Linus, additional, Schliemann, Christoph, additional, Schmitt, Michael, additional, Müller-Tidow, Carsten, additional, Gottschalk, Stephen, additional, and Rooney, Cliona M., additional
- Published
- 2021
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33. Molecular monitoring during dose reduction predicts recurrence after TKI cessation in CML
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Ingmar Glauche, Silvia Cicconi, Richard E. Clark, Ingo Roeder, and Andrea Gottschalk
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Oncology ,Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Immunology ,Biochemistry ,Myelogenous ,Remission induction ,Recurrence ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Progression-free survival ,Protein Kinase Inhibitors ,media_common ,Clinical Trials as Topic ,Withholding Treatment ,Dose-Response Relationship, Drug ,business.industry ,Remission Induction ,Cell Biology ,Hematology ,medicine.disease ,Prognosis ,Progression-Free Survival ,Leukemia ,Dose–response relationship ,Molecular Diagnostic Techniques ,Dose reduction ,Drug Monitoring ,business - Published
- 2020
34. Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer
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Bollard, Catherine M., Gottschalk, Stephen, Leen, Ann M., Weiss, Heidi, Straathof, Karin C., Carrum, George, Khalil, Mariam, Wu, Meng-fen, Huls, M. Helen, Chang, Chung-Che, Gresik, M. Victoria, Gee, Adrian P., Brenner, Malcolm K., Rooney, Cliona M., and Heslop, Helen E.
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- 2007
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35. CD45RA-Depleted Haploidentical Transplantation Combined with NK Cell Addback Results in Promising Long-Term Outcomes in Pediatric Patients with High-Risk Hematologic Malignancies
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Renee Madden, Ying Li, Ali Y Suliman, Brandon M. Triplett, Rebecca Epperly, Ashok Srinivasan, Swati Naik, Ewelina Mamcarz, Gabriela Maron, Esther A. Obeng, Akshay Sharma, Aimee C Talleur, Stephen Gottschalk, Diego R. Hijano, Amr Qudeimat, and Mireya Paulina Velasquez
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Oncology ,medicine.medical_specialty ,Haploidentical transplantation ,business.industry ,Immunology ,Cell ,Cell Biology ,Hematology ,Biochemistry ,medicine.anatomical_structure ,Internal medicine ,medicine ,Long term outcomes ,business - Abstract
Novel graft engineering strategies that allow selective T-cell depletion have made haploidentical donor (haplo) hematopoietic cell transplantation (HCT) feasible for patients lacking a matched donor. We hypothesized that selective CD45RA+ cell depletion can limit graft-versus-host disease (GVHD) through removal of naive T cells but allow for rapid immune reconstitution through adoptive transfer of memory T cells, minimizing risk of graft failure, infections and relapse. We performed a prospective clinical trial utilizing CD45RA+ depleted haplo HCT followed by donor NK cell addback to maximize the graft-versus-leukemia effect in children with high-risk hematological malignancies (NCT01807611), and present here an interim analysis. Between 2013 to 2019, 72 patients (42 males, 30 females) were enrolled. The median age was 8.1 years (range 0.6-20.8). Twenty-nine patients had acute lymphoblastic leukemia (ALL), 39 had myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), 3 had biphenotypic leukemia and 1 had Non-Hodgkin's Lymphoma. At time of HCT, 25 patients were in CR1, 24 in CR2, 4 in CR3/> and 19 had active disease. Of the 53 patients in CR, 22 had evidence of minimal residual/detectable disease (MRD) at HCT. Donors used were mothers (n=30), fathers (n=35), or sibling/other (n=6) with majority (n=62) being KIR-ligand mismatched to the recipient. All patients received serotherapy-free, reduced intensity conditioning with fludarabine, melphalan, cyclophosphamide and Total Lymphoid Irradiation. GCSF mobilized peripheral blood grafts were infused on i) Day 0 CD34 + selected graft (median CD34+: 9.85 x10 6cells/kg, range 1.96-44.64) and ii) Day +1 CD45 RA+ depleted graft (median: CD34+: 5.82 x10 6cells/kg, range 0.58-39.43); providing a large number of CD45RO+ T-cells (median CD3+ : 60.1 x10 6cells/kg, range 16.08-528.43) after depletion of CD45RA+ cells (CD3+CD45RA+ median 0, range 0-0.2 x10 6cells/kg). NK cells (median: 11.7 x10 6cells/kg; range: 1.65-99.2), isolated from a non-mobilized apheresis by CD3 depletion/CD56 selection, were infused on day +6. GVHD prophylaxis included MMF (n=61) and/or Sirolimus (n= 8) until day +42 post-HCT. The median time for neutrophil and platelet engraftment was 11 (range 9-13) and 17 days (range 10-100) respectively. One patient had primary graft failure and was successfully re-transplanted. Immune reconstitution was rapid and robust and recapitulated CD45RA depleted graft content with mean CD3, CD4 and CD8 T-cell count at day +30 of 1080, 640 and 230 cells/ul respectively. TCR Vbeta spectratyping revealed a broad repertoire by day +100 prior to the emergence of naïve T cells. The incidence of Cytomegalovirus and Adenovirus viremia was 38% (28/72) and 13% (10/72) respectively. The cumulative incidence of aGVHD was 36.1% (25.1-47.2%), aGVHD grade III-IV was 29.2% (19.1-39.9%) and chronic GVHD was 20.8% (CI: 12.3-30.9%). With a median follow-up of 3.1 years (range 0.04-8.0 years) the 3-year leukemia free survival (LFS) was 88% (CI: 76.1-100%) for patients in CR1, 70.8% (CI: 54.8-91.6%) for patients in CR2, 50% (CI: 18.8-100%) for patients in CR3/> and 21.1% (CI: 8.81-50.3) for patients with active disease (p = In conclusion, selective CD45RA+ depletion allowed for adoptive transfer of abundant memory T cells that along with NK cell addback was associated with rapid, functional immune reconstitution, resulting in low rates of graft failure, viral reactivation and relapse. Despite a higher incidence of aGVHD compared to other T-cell depleted grafts, our approach translated into promising long-term outcomes in this high-risk patient population. Disclosures Sharma: Vindico Medical Education: Honoraria; CRISPR Therapeutics: Other, Research Funding; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy. Gottschalk: Novartis: Consultancy; Catamaran Bio: Consultancy; Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Immatics: Membership on an entity's Board of Directors or advisory committees; Tidal: Consultancy; Tessa Therapeutics: Consultancy. Triplett: Miltenyi: Other: Travel, meeting registration.
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- 2021
36. CD19-CAR T Cells Develop Exhaustion Epigenetic Programs during a Clinical Response
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Benjamin Youngblood, Michael M Meagher, Jean-Yves Metais, Shannon K. Boi, Timothy D. Lockey, Tian Mi, Caitlin C. Zebley, Enrico Lugli, Giovanni Galletti, Aimee C Talleur, Charmaine Brown, Shanta Alli, Deanna Langfitt, Yiping Fan, Stephen Gottschalk, and Brandon M. Triplett
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Immunology ,biology.protein ,Cancer research ,Immunology and Allergy ,Cell Biology ,Hematology ,Epigenetics ,Car t cells ,Biology ,Biochemistry ,CD19 - Abstract
Background: CD19-CAR T-cell therapy has emerged as a curative approach for patients with relapsed/refractory B-cell malignancies, including lymphoma and acute lymphoblastic leukemia (ALL). However, many patients develop recurrent disease after initial responses. Therapeutic failure is most likely due to T cell extrinsic and intrinsic mechanisms. While CD19-negative relapse has emerged as a major extrinsic mechanism, T cell intrinsic mechanisms remain elusive. T-cell exhaustion is driven by epigenetic programs, however epigenetic changes in CAR T cells pre and post infusion have not been determined longitudinally. Thus, the goal of this study was to determine the epigenetic landscape of CD19-CAR T cells pre and post infusion as an initial step to elucidate intrinsic mechanisms that limit CAR T-cell effector functions in humans. Methods/Results: A longitudinal analysis of CD8+ CD19-CAR T cell epigenetic changes was performed by whole-genome DNA methylation profiling of CAR T cells during manufacturing and from peripheral blood mononuclear cells (PBMCs) of infused patients. DNA methylation profiling was performed on samples from 15 patients enrolled on our institutional, autologous CD19-CAR T cell therapy study (NCT03573700). CAR T cell expansion and persistence was determined by measuring vector copy numbers in the PBMCs of treated patients. B cell aplasia was tracked by monitoring B cell reconstitution as an additional measure of CD19-CAR T cell function. We had previously established novel exhaustion DNA methylation datasets that delineate between progenitor and fully exhausted T cells. These datasets served as a guide for stratifying our post-infusion CAR T cells along the exhaustion developmental trajectory. Lastly, publicly available single-cell transcriptional profiles of CD19-CAR T cells from patients were mined to validate expression of the transitory exhaustion signature. Our data show that CD19-CAR T cells lose repressive DNA methylation at effector loci (e.g. PRF1, TBET) while gaining methylation at genes (e.g. LEF1, TCF7) associated with memory potential. We confirmed that these epigenetic changes are coupled to endogenous human T cell effector and memory differentiation by cross-referencing our epigenetic data with publicly available transcriptional profiles for antigen-specific effector and long-lived memory CD8 T cells from individuals vaccinated for yellow fever. Furthermore, we show that CAR T cells were unable to mount an in vivo recall response after recovery of antigen-positive B cells or disease relapse. This observation, coupled to the fact that these patients' CAR T cells developed exhaustion-associated DNA methylation programs, further supports the broader conclusion that CAR T cells acquire stable epigenetic exhaustion programs that limit their protective capacity. Conclusion: Our data demonstrate for the first time that CAR T cell expansion during a clinical response is coupled to progressive restriction of gene regulatory programs that control T cell fate potential. Furthermore, we show that CD19-CAR T cells undergo exhaustion epigenetic programs that are coupled to an inability to mount a recall response in the presence of antigen-positive normal and malignant B cells. This work lays the foundation for future efforts aimed at improving the efficacy of cellular therapy by reversing epigenetic programs that are coupled to CAR T-cell exhaustion. Disclosures Triplett: Miltenyi: Other: Travel, meeting registration. Gottschalk: Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Catamaran Bio: Consultancy; Novartis: Consultancy; Tidal: Consultancy; Immatics: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Consultancy. Youngblood: ElevateBio: Consultancy; ElevateBio: Honoraria; AstraZeneca: Honoraria; Cell Signaling: Honoraria; Merck: Research Funding; other: Other: patents and patent applications in the field of cancer cell and gene therapy .
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- 2021
37. Donor-Derived Adoptive T-Cell Therapy Targeting Multiple Tumor Associated Antigens to Prevent Post-Transplant Relapse in Patients with ALL
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Bilal Omer, Catherine Robertson, Spyridoula Vasileiou, LaQuisa Hill, Juan F. Vera, Adrian P. Gee, Caridad Martinez, Ifigeneia Tzannou, George Carrum, Cliona M. Rooney, Helen E. Heslop, Bambi Grilley, Swati Naik, Stephen Gottschalk, Robert A. Krance, Rammurti T. Kamble, Ann M. Leen, Ayumi Watanabe, Premal Lulla, and Manik Kuvalekar
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business.industry ,T cell ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Post transplant ,medicine.anatomical_structure ,Antigen ,Cancer research ,Medicine ,In patient ,Donor derived ,Multiple tumors ,business - Abstract
Background: Hematopoietic stem cell transplant (HSCT) is a curative option for patients with high-risk Acute Lymphoblastic Leukemia (HR-ALL), but relapse remains a major cause of treatment failure. Strategies to enhance the graft-versus-leukemia (GVL) effect have been employed to prevent relapse, including modulating immune suppression post-HSCT to hasten immune reconstitution or with the use of donor lymphocyte infusions (DLIs). However, DLIs carry a significant risk of graft-versus-host disease (GVHD) due to the concurrent transfer of alloreactive T cells. To enhance the GVL effect while minimizing GVHD, we developed a protocol for the generation of ex vivo expanded, donor-derived T-cell lines targeting PRAME, WT1 and Survivin - tumor associated antigens that are frequently expressed in both B- and T-cell ALL. These multi-antigen-targeted T cells (multiTAAs) were adoptively transferred to pediatric and adult patients with HR-ALL who had undergone an allogeneic HSCT. Methods: Donor-derived multiTAA-specific T cells were generated by co-culturing PBMCs with autologous DCs loaded with pepmixes (15 mer peptides overlapping by 11 amino acids) spanning all 3 target antigens in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail. Following 2-4 rounds of stimulation these multiTAA-specific T cells were infused to patients with ALL who had undergone an HSCT but remained at a high risk for disease relapse. Results: We have generated 15 clinical grade multiTAA-specific T cell lines comprising CD3+ T cells (mean 95.1±1.9%) with a mixture of CD4+ (mean 22.8±6.3%) and CD8+ (mean 52.5±5.3%) cells, which expressed central [CD45RO+/CD62L+: 13.5±2.8%] and effector memory markers [CD45RO+/CD62L-: 56.4±3.8%]. The expanded lines recognized the targeted antigens PRAME (range 0-370 SFC/2x10 5), WT1 (0-363 SFC/2x10 5), and Survivin (0-65 SFC/2x10 5) in an IFNg ELIspot. None of the lines reacted against non-malignant patient-derived cells (3.7±0.8% specific lysis; E: T 20:1) - a study release criterion indicating lack of alloreactivity. We have infused 11 HR-ALL patients (8 pediatric and 3 adult) with donor-derived multiTAA-specific T cells to prevent disease relapse (Table 1). Patients were administered with up to 4 infusions of cells at 3 escalating dose levels, ranging from 0.5 - 2x10 7 cells/m 2. Infusions were well tolerated with no dose-limiting toxicity, GVHD, cytokine release syndrome or other adverse events. Three patients were not evaluable per study criteria as they received >0.5mg/kg of steroids (2 patients received stress doses for septic shock and 1 for elevated liver enzymes presumed to be GVHD that was later ruled out) within 4 weeks of infusion and were replaced. Six of the 8 remaining patients infused remain in CR on long-term follow up at a median of 46.5 months post-infusion (range 9-51 months). In patients who remained in long term CR we detected an expansion of tumor-reactive T cells in their peripheral blood post-infusion against both targeted (WT1, Survivin, PRAME) and non-targeted antigens (SSX2, MAGE-A4, -A1, -A2B, -C1, MART1, AFP and NYESO1) reflecting epitope and antigen spreading, which correlated temporally (within 4 weeks) with multiTAA infusions. By contrast in the two patients who relapsed we saw no evidence of in vivo T cell amplification within the first 4 weeks after infusion. Conclusion: The preparation and infusion of donor-derived multiTAA-specific T cells to patients with B- and T-ALL post allogeneic HSCT is feasible, safe and as evidenced by in vivo tumor-directed T cell expansion and antigen spreading in patients, may contribute to disease control. This strategy may present a promising addition to current immunotherapeutic approaches for prophylaxis for leukemic relapse in HSCT recipients. Figure 1 Figure 1. Disclosures Vasileiou: Allovir: Consultancy. Tzannou: Gileas: Honoraria; Allovir: Current equity holder in publicly-traded company. Kuvalekar: Allovir: Consultancy. Watanabe: Allovir: Consultancy. Grilley: QB Regulatory Consulting: Other: Ownership, project management support, Research Funding; Marker: Consultancy, Other: Regulatory and project management support; Allovir: Current equity holder in publicly-traded company, Other: Leadership. Hill: Incyte: Membership on an entity's Board of Directors or advisory committees. Omer: Allovir: Research Funding. Gottschalk: Tessa Therapeutics: Consultancy; Immatics: Membership on an entity's Board of Directors or advisory committees; Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Tidal: Consultancy; Novartis: Consultancy; Catamaran Bio: Consultancy. Heslop: Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Kuur Therapeutics: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Allovir: Current equity holder in publicly-traded company; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Marker Therapeutics: Current equity holder in publicly-traded company; Fresh Wind Biotherapies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Rooney: Allogene: Patents & Royalties; Bellicum: Patents & Royalties; Bluebird: Current equity holder in publicly-traded company; Allovir: Current equity holder in publicly-traded company; Alimera: Consultancy; Memgen: Consultancy; TScan Therapeutics: Consultancy; Takeda: Patents & Royalties; Marker: Current equity holder in publicly-traded company; Tessa: Consultancy, Other: Leadership, Research Funding. Vera: Allovir: Consultancy, Current equity holder in publicly-traded company, Other: Leadership, travel , accomodations, expenses, Patents & Royalties; Marker: Current Employment, Other: Travel, Accomodations, Expenses, Patents & Royalties, Research Funding. Leen: Allovir: Consultancy, Current equity holder in publicly-traded company; Marker: Current equity holder in publicly-traded company.
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- 2021
38. CD45RO+ T-Cell Add Back and Prophylactic Blinatumomab Administration Post Tcrαβ/CD19-Depleted Haploidentical Transplantation in Pediatric Patients with High Risk Acute Leukemia
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Amr Qudeimat, Mireya Paulina Velasquez, Swati Naik, Akshay Sharma, Ali Y Suliman, Ewelina Mamcarz, Stephen Gottschalk, Rebecca Epperly, Brandon M. Triplett, Gabriela Maron, Ying Li, Diego R. Hijano, Esther A. Obeng, Aimee C Talleur, Ashok Srinivasan, and Renee Madden
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Oncology ,medicine.medical_specialty ,Haploidentical transplantation ,biology ,business.industry ,T cell ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,CD19 ,medicine.anatomical_structure ,Internal medicine ,High Risk Acute Leukemia ,medicine ,biology.protein ,Blinatumomab ,business ,medicine.drug - Abstract
For patients receiving haploidentical donor (haplo) hematopoietic cell transplant (HCT), depletion of TCRαβ T cells from the haplo-graft allows for excellent outcomes and low rates of graft-versus-host disease (GVHD), albeit with a significant delay in immune reconstitution (IR). The adoptive transfer of donor T-cells has been used to optimize IR but increases the risk of GVHD. CD45RA-depleted (memory) T-cells are associated with low rates of alloreactivity and thereby GVHD but retain specificity for leukemic and viral antigens. We implemented a prospective trial utilizing escalating doses of CD45RA-depeleted T-cell as addback following TCRαβ/CD19-depleted haploHCT to improve IR. Patients with acute lymphoblastic leukemia (ALL) also received prophylactic Blinatumomab (Blina) following infusion of CD45RA-depeleted T-cell to overcome the risk immune escape secondary to HLA-loss and relapse (NCT03849651). Between 2019 to 2020, 30 pediatric patients (9 males, 21 females) with high-risk acute leukemia were enrolled. Median age at HCT was 8.7 years (range 0.9-18.8). Nineteen patients had ALL, 11 patients had AML. Ten patients were in CR1, 13 in CR2 and 7 in CR3/>. Five patients received prior CD19-CAR T-cell therapy. The donors used were mothers (n=15), fathers (n=13), or sibling/others (n=2). All patients received a reduced intensity preparative regimen consisting of Fludarabine, Melphalan, Cyclophosphamide and Thiotepa. ATG was given on days -5, -4 and -3. Mobilized peripheral blood graft were infused on day 0 with a median number of CD34+ cells, γδ+ T-cells, αβ+ T cells, and B cells of 14.8, 22.7, 0, and 0.09x 10 6/kg, respectively. No GVHD prophylaxis was used post-HCT. Two weeks following engraftment, patients received CD45RA-depleted T-cell addback in 3 escalating doses (DL1: 1x10 5cells/kg, DL2: 1x10 6 cells/kg, DL3:1x10 7 cells/kg). All 30 patients engrafted with a median time for neutrophil and platelet engraftment of 10 (range: 9-11) and 15 (range: 13-20) days, respectively. Infusion of escalating doses of CD45RA-depleted T-cells was well tolerated. One month post infusion, there was a significant increase in the median number of CD3 T-cells, including CD8 and CD45RO+ T-cell subsets (**p In this interim analysis, addback of CD45RA- depleted T-cells following TCRαβ/CD19-depleted haplo HCT was safe and led to enhanced functional immune reconstitution. Prophylactic infusion of Blina is well tolerated and its use post-transplant warrants further investigation. Analyses into the effect of ATG on immune reconstitution are underway. Figure 1 Figure 1. Disclosures Sharma: CRISPR Therapeutics: Other, Research Funding; Novartis: Other: Salary support paid to institution; Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy; Vindico Medical Education: Honoraria. Gottschalk: Catamaran Bio: Consultancy; Immatics: Membership on an entity's Board of Directors or advisory committees; Other: Other: patents and patent applications in the field of cancer cell and gene therapy ; Novartis: Consultancy; Tidal: Consultancy; Tessa Therapeutics: Consultancy. Triplett: Miltenyi: Other: Travel, meeting registration.
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- 2021
39. Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience
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Talleur, Aimee C, primary, Madden, Renee M., additional, Qudeimat, Amr, additional, Mamcarz, Ewelina, additional, Sharma, Akshay, additional, Srinivasan, Ashok, additional, Suliman, Ali Y, additional, Velasquez, Mireya Paulina, additional, Lockey, Timothy, additional, Gaboriault, Alisha, additional, Karol, Seth E., additional, Inaba, Hiroto, additional, Li, Ying, additional, Young, Pam, additional, Kang, Guolian, additional, Cheng, Cheng, additional, Zheng, Wenting, additional, Zhou, Sheng, additional, Akel, Salem M., additional, Geiger, Terrence L, additional, Meagher, Michael M, additional, Pui, Ching-Hon, additional, Triplett, Brandon M, additional, and Gottschalk, Stephen, additional
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- 2020
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40. GRP78 Is Expressed on the Cell Surface of Pediatric AML Blasts and Can be Targeted with GRP78-CAR T Cells without Toxicity to Hematopoietic Progenitor Cells
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Hebbar, Nikhil, primary, Epperly, Rebecca, additional, Vaidya, Abishek, additional, Huang, Sujuan, additional, Cheng, Cheng, additional, Gottschalk, Stephen, additional, and Velasquez, Mireya Paulina, additional
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- 2020
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41. Multi-Omic Based Antigen Discovery for the Immunotherapy of Pediatric Acute T Cell Lymphoblastic Leukemia
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Hebbar, Nikhil, primary, Qu, Chunxu, additional, Wang, Hong, additional, Shao, Ying, additional, Nguyen, Phuong, additional, Freiwan, Abdullah, additional, Epperly, Rebecca, additional, Li, Yuxin, additional, Cho, Ji-Hoon, additional, Shaw, Timothy, additional, Peng, Junmin, additional, Easton, John, additional, Gottschalk, Stephen, additional, Mullighan, Charles G, additional, and Velasquez, Mireya Paulina, additional
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- 2020
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42. The Association between Asparaginase Enzyme Activity Levels and Toxicities in Childhood Acute Lymphoblastic Leukaemia in the NOPHO ALL2008 Protocol
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Lynggaard, Line Stensig, primary, Moeller, Lisbeth, additional, Rank, Cecilie Utke, additional, Gottschalk Højfeldt, Sofie, additional, Henriksen, Louise Tram, additional, Jarvis, Kirsten Brunsvig, additional, Ranta, Susanna, additional, Niinimäki, Riitta, additional, Harila-Saari, Arja, additional, Wolthers, Benjamin Ole, additional, Heyman, Mats, additional, Frandsen, Thomas Leth, additional, Schmiegelow, Kjeld, additional, and Albertsen, Birgitte Klug, additional
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- 2020
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43. Venetoclax Enhances Anti-Leukemia Activity of CD123-Specific BiTE-Secreting T-Cells in AML
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Mu-Mosley, Hong, primary, Ostermann, Lauren B, additional, Zhao, Ran, additional, Bonifant, Challice L., additional, Gottschalk, Stephen, additional, Velasquez, Mireya Paulina, additional, and Andreeff, Michael, additional
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- 2020
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44. NOR-GRASPALL2016 (NCT03267030): Asparaginase Encapsulated in Erythrocytes (eryaspase) - a Promising Alternative to Peg-Asparaginase in Case of Hypersensitivity
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Lynggaard, Line Stensig, primary, Gottschalk Højfeldt, Sofie, additional, Moeller, Lisbeth, additional, Vaitkeviciene, Goda Elizabeta, additional, Langenskiöld, Cecilia, additional, Lehmann, Anne Kristine, additional, Lepik, Kristi, additional, Lähteenmäki, Päivi Maria, additional, Schmiegelow, Kjeld, additional, and Albertsen, Birgitte Klug, additional
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- 2020
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45. Multi-Omic Based Antigen Discovery for the Immunotherapy of Pediatric Acute T Cell Lymphoblastic Leukemia
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John Easton, Nikhil Hebbar, Timothy I. Shaw, Yuxin Li, Junmin Peng, Abdullah Freiwan, Stephen Gottschalk, Charles G. Mullighan, Ji-Hoon Cho, Hong Wang, Mireya Paulina Velasquez, Phuong Nguyen, Ying Shao, Rebecca Epperly, and Chunxu Qu
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Myeloid ,medicine.diagnostic_test ,medicine.drug_class ,medicine.medical_treatment ,Genetic enhancement ,Immunology ,Cell Biology ,Hematology ,Immunotherapy ,Biology ,Monoclonal antibody ,Biochemistry ,Chimeric antigen receptor ,Flow cytometry ,medicine.anatomical_structure ,Antigen ,Proteome ,medicine ,Cancer research - Abstract
Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk disease due to treatment related complications and poor prognosis of patients with relapsed disease. Immunotherapy with monoclonal antibodies (MAbs) and/or chimeric antigen receptor (CAR) T-cells for T-ALL is limited by identification of tumor specific target antigens. Differential expression is necessary to prevent on-target/off-tumor toxicities and fratricide of activated T-cells. Targeting multiple antigens can bypass immune escape and result in improved T-cell effector function, since antigen density correlates with T-cell activation. Here we designed a pipeline (Figure 1) to identify unique surface antigens expressed in T-ALL using proteomic and transcriptomic analyses followed by flow cytometry validation, and functional studies with CAR T cells targeting the identified antigens. We generated an Illumina total stranded RNAseq library from healthy donor myeloid and lymphoid cells of bone marrow, peripheral blood and cord blood (N= 116). We compared data to 265 St. Jude pediatric T-ALL samples and against 53 normal tissue expression data from the GTEx (Genotype-Tissue Expression) project. To analyze the T-cell surface proteome, we isolated plasma membrane fractions from 11 samples including healthy T-cells and T-ALL cell lines using a differential centrifugation-based method. The purity of the plasma membrane fraction was confirmed by western blot. Na+/K+ ATPase and GAPDH were used as controls for the plasma membrane and cytosolic fractions respectively. Following plasma membrane enrichment, the membrane proteins were applied for proteomic analysis using an advanced TMT-L/LC-MS/MS pipeline, and the acquired proteomic data were further processed via the JUMP software suite. 997 unique proteins were quantified from the membrane fractions. Integrated analysis the transcriptomic and proteomic datasets showed significant correlation and yielded a list of candidate genes, which were validated by flow cytometry on a panel of T-ALL cell lines (CCRF, RPMI8402, and MOLT3) and resting and activated T-cells from healthy donors. We identified GRP78 as one of the differentially expressed cell surface antigens and further confirmed its expression on additional T-ALL cell lines (KE37, PF382, PEER, CEMC7) and 3 PDX samples. Finally, we generated GRP78-CAR T cells and demonstrate that GRP78-CAR T cells recognize and kill GRP78+ T-ALL cells and have potent antitumor activity in xenograft and PDX models. We have established an unbiased pipeline to identify differentially expressed antigens on the cell surface of T-ALL blasts and created a healthy tissue RNAseq library. The results from our analyses are encouraging and interrogation of our pipeline has yielded differentially expressed immunotherapy targets for the treatment of relapsed refractory T-ALL. Our results highlight the importance of integrated surface proteomics and transcriptomics analysis. Figure 1: Outline of strategy for target selection: Figure Disclosures Hebbar: St. Jude: Patents & Royalties. Epperly:St. Jude: Patents & Royalties. Gottschalk:Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; TESSA Therapeutics: Other: research collaboration; Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; Merck and ViraCyte: Consultancy. Mullighan:AbbVie, Inc.: Research Funding; Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Velasquez:Rally! Foundation: Membership on an entity's Board of Directors or advisory committees; St. Jude: Patents & Royalties.
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- 2020
46. NOR-GRASPALL2016 (NCT03267030): Asparaginase Encapsulated in Erythrocytes (eryaspase) - a Promising Alternative to Peg-Asparaginase in Case of Hypersensitivity
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Kjeld Schmiegelow, Sofie Gottschalk Højfeldt, Anne Kristine Lehmann, Line Stensig Lynggaard, Goda Vaitkeviciene, Cecilia Langenskiöld, Päivi M. Lähteenmäki, Kristi Lepik, Lisbeth Moeller, and Birgitte Klug Albertsen
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Asparaginase ,medicine.medical_specialty ,Allergy ,business.industry ,Incidence (epidemiology) ,Immunology ,technology, industry, and agriculture ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Rash ,Gastroenterology ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Toxicity ,Cohort ,medicine ,medicine.symptom ,Adverse effect ,business - Abstract
Introduction: Asparaginase is an essential part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity occurred in 16.8% (clinical allergy (13.8%) or silent inactivation (3.0%)) of patients treated with pegylated asparaginase (PEG-asp) in the NOPHO ALL2008 cohort (Hoejfeldt et al 2018). Hypersensitivity (clinical allergy or silent inactivation) is the most common cause of truncated asparaginase therapy, and truncated treatment has been associated with decreased event-free survival (Silverman et al 2001). Asparaginase encapsulated in erythrocytes (eryaspase) is an alternative formulation of asparaginase aiming to prolong the half-life of asparaginase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane prevents activation of the immune system and protects asparaginase against elimination. A phase 2 study has demonstrated prolonged asparaginase enzyme activity (AEA) and significantly reduced incidence of hypersensitivity in patients with ALL, who had a prior exposure to other asparaginase preparations (NCT01518517). The aim of the NOR-GRASPALL 2016 study is to evaluate the safety and efficacy of eryaspase in combination with multiagent chemotherapy according to the NOPHO ALL2008 protocol and the ALLTogether Pilot study. Antileukemic treatment in these protocols include 4-8 doses of PEG-asp as first line treatment. Methods: NOR-GRASPALL 2016 is a phase 2 multinational multicentre trial conducted in the Nordic/Baltic countries. It is a single-arm study for non-high-risk patients with ALL and hypersensitivity to PEG-asp. Eryaspase (150 U/kg) is scheduled to complete the intended course of asparaginase (1-7 doses). AEA-measurements are used as biomarkers for treatment efficacy. Results: Since August 2017, 36 children and two adults were included in the study. Median age was 6.0 years (IQR: 3.3;8.7). 37 patients (97.4%) had clinical allergy to PEG-asp of whom 59.5% (n=22) had a severe allergic reaction. One patient (3.3%) was included due to silent inactivation. AEA-measurements were available in all patients but one (n=37), and in none of these patients AEA was detectable following PEG-asp treatment. In total, 171 doses of eryaspase were administered. A total of 34 of the 36 patients (94.7%) had AEA >100 U/L and 27 patients (71.1%) had AEA-levels >400 U/L 14 days after first eryaspase administration (expected nadir). The median AEA-level was 798 U/L [IQR: 387;864]. In total 90.7% of all samples collected 14 days after eryaspase administration had AEA >100 U/L and 69.3% had AEA >400 U/L. The median AEA-level was 621U/L [IQR: 331;962]. Adverse events with relation to eryaspase were reported in 8 of 36 patients (22%). Six patients experienced a possible allergic reaction to eryaspase; one patient had a severe allergic reaction, three patients developed a rash and two patients had "drug fever", deemed related to eryaspase. Three of these six patients (50%) had low AEA-levels after developing allergic symptoms, the remaining patients (50%) had AEA-levels comparable with all other patients in the study. Four patients experienced adverse events related to eryaspase; two patients with mild hyperlipidaemia and two with hepatoxicity. No other severe adverse events with relation to eryaspase have been reported. Final study results will be provided at the meeting. Conclusion: Eryaspase consistently demonstrated prolonged AEA in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated. We conclude that eryaspase is a promising alternative to PEG-asp in case of hypersensitivity. Disclosures Schmiegelow: Jazz Pharmaceuticals: Other: Speaker and/or Advisory Board Honoraria ; Amgen: Other: Speaker fee; Medscape: Other: Speaker fee; Servier: Other: Educational grant. Speaker and/or Advisory Board Honoraria . Albertsen:Erytech Pharma: Other: Sponsor of the investigator initiated study: NOR-GRASPALL 2016. No financial benefits..
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- 2020
47. Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience
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Alisha Gaboriault, Akshay Sharma, Sheng Zhou, Cheng Cheng, Wenting Zheng, Ashok Srinivasan, Salem M. Akel, Pam Young, Stephen Gottschalk, Ewelina Mamcarz, Amr Qudeimat, Renee Madden, Mireya Paulina Velasquez, Ali Y Suliman, Timothy D. Lockey, Guolian Kang, Seth E. Karol, Michael M Meagher, Brandon M. Triplett, Terrence L. Geiger, Ching-Hon Pui, Hiroto Inaba, Aimee C Talleur, and Ying Li
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Single Center ,Biochemistry ,Minimal residual disease ,Fludarabine ,Transplantation ,Leukemia ,Cytokine release syndrome ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
CD19-CAR T-cell therapy has shown remarkable efficacy in pediatric patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (r/r ALL). Despite high short-term remission rates, many responses are not durable and the best management of patients who achieve a complete response (CR) post-CAR T-cell therapy remains controversial. In particular, it is unclear if these patients should be observed or proceed to consolidative allogeneic hematopoietic cell transplantation (HCT). To address this question, we reviewed the clinical course of all patients (n=22) who received either an investigational CAR T-cell product (Phase I study: SJCAR19 [NCT03573700]; n=12) or tisagenlecleucel (n=10) at our institution. The investigational CD19-CAR T cells were generated by a standard cGMP-compliant procedure using a lentiviral vector encoding a 2nd generation CD19-CAR with a FMC63-based CD19 binding domain, CD8a stalk and transmembrane domain, and 41BB.ζ signaling domain. Patients received therapy between 8/2018 and 3/2020. All products met manufacturing release specifications. Within the entire cohort, median age at time of infusion was 12.3 years old (range: 1.8-23.5) and median pre-infusion marrow burden using flow-cytometry minimal residual disease (MRD) testing was 6.8% (range: 0.003-100%; 1 patient detectable by next-generation sequencing [NGS] only). All patients received lymphodepleting chemotherapy (fludarabine, 25mg/m2 daily x3, and cyclophosphamide, 900mg/m2 daily x1), followed by a single infusion of CAR T-cells. Phase I product dosing included 1x106 CAR+ T-cells/kg (n=6) or 3x106 CAR+ T-cells/kg (n=6). Therapy was well tolerated, with a low incidence of cytokine release syndrome (any grade: n=10; Grade 3-4: n=4) and neurotoxicity (any grade: n=8; Grade 3-4: n=3). At 4-weeks post-infusion, 15/22 (68.2%) patients achieved a CR in the marrow, of which 13 were MRDneg (MRDneg defined as no detectable leukemia by flow-cytometry, RT-PCR and/or NGS, when available). Among the 2 MRDpos patients, 1 (detectable by NGS only) relapsed 50 days after CAR T-cell infusion and 1 died secondary to invasive fungal infection 35 days after infusion. Within the MRDneg cohort, 6/13 patients proceeded to allogeneic HCT while in MRDneg/CR (time to HCT, range: 1.8-2.9 months post-CAR T-cell infusion). All 6 HCT recipients remain in remission with a median length of follow-up post-HCT of 238.5 days (range 19-441). In contrast, only 1 (14.3%) patient out of 7 MRDneg/CR patients who did not receive allogeneic HCT, remains in remission with a follow up of greater 1 year post-CAR T-cell infusion (HCT vs. no HCT: p In conclusion, infusion of investigational and FDA-approved autologous CD19-CAR T cells induced high CR rates in pediatric patients with r/r ALL. However, our current experience shows that sustained remission without consolidative allogeneic HCT is not seen in most patients. Our single center experience highlights not only the need to explore maintenance therapies other than HCT for MRDneg/CR patients, but also the need to improve the in vivo persistence of currently available CD19-CAR T-cell products. Disclosures Sharma: Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Velasquez:St. Jude: Patents & Royalties; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; TESSA Therapeutics: Other: research collaboration; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy.
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- 2020
48. Venetoclax Enhances Anti-Leukemia Activity of CD123-Specific BiTE-Secreting T-Cells in AML
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Hong Mu-Mosley, Stephen Gottschalk, Mireya Paulina Velasquez, Ran Zhao, Michael Andreeff, Lauren B Ostermann, and Challice L. Bonifant
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biology ,business.industry ,Venetoclax ,CD3 ,Genetic enhancement ,Immunology ,Myeloid leukemia ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,chemistry.chemical_compound ,chemistry ,medicine ,Cancer research ,biology.protein ,Interleukin-3 receptor ,Stem cell ,business - Abstract
Background: CD123 is frequently expressed in hematologic malignancies including AML. CD123 has been a potential immunotherapeutic target in AML due to its association with leukemic stem cells that play an essential role in disease progression and relapse. Our previous study using T-cells secreting CD123/CD3-bispecific T-cell engagers (BiTEs) (CD123-ENG T-cells) has shown activity in preclinical studies, recognizing and killing acute myeloid leukemia (AML) blasts in vitro and in vivo. CD123-ENG T-cells secrete bispecific molecules that recognize CD3 (T-cells) and CD123 (AML blasts), and are able to direct transduced T-cells and recruit bystander T-cells to kill CD123-positive blasts. Venetoclax is a BCL-2 inhibitor that can restore functional apoptosis signaling in AML cells, and has been FDA approved for the treatment of AML patients in combination with hypomethylating agents. To improve the efficacy of CD123-ENG T-cells we explored efficacy in AML by combining targeted immunotherapy (CD123-ENG T cells) with targeted inhibition of anti-apoptotic BCL-2 (venetoclax) in vitro and in vivo models of AML. Methods : CD123-ENG T-cells were generated by retroviral transduction and in vitro expansion. Non-transduced (NT) T-cells served as control. In vitro, GFP+ MOLM-13 AML cells were pretreated with venetoclax (0, 10µM, and 20µM) for 24 hours prior to co-culture with CD123-ENG or NT T-cells at an effector/target ratio of 1:10. After 16 hours, MOLM-13 AML cells were analyzed by flow cytometry and quantitated using counting beads; cytotoxicity was calculated relative to untreated MOLM-13 control. The anti-AML activity of the combination was further evaluated in a MOLM-13-luciferase xenograft AML mouse model. Leukemia progression was assessed by bioluminescence imaging. The frequency of MOLM13 AML and human T cells in periphera blod (PB) was determined by flow cytometry. Results: In vitro, we demonstrated that pretreatment of Molm13 AML cells with venetoclax enhanced the cytolytic activity of CD123-ENG T-cells compared to NT- or no T-cell controls. Interestingly, venetoclax sensitized Molm13 to CD123-ENG T-cell killing in a dose-dependent manner (Fig.1; 50%/31% killing by CD123-ENG T-cells versus 27%/14% of killing by NT T cells post pretreatment with 10µM or 20µM ventoclax, p Conclusion: Our data support a concept of combining pro-apoptotic targeted and immune therapy using venetoclax and CD123-ENG T-cells in AML. While it has been reported that venetoclax does not impair T-cell functionality, more in-depth analysis of the effect of Bcl-2 inhibition on T-cell function and survival appears warranted, as it could diminish survival not only of AML blasts but also of immune cells. Disclosures Bonifant: Patents filed in the field of engineered cellular therapies: Patents & Royalties: Patents filed in the field of engineered cellular therapies. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy; TESSA Therapeutics: Other: research collaboration. Velasquez:Rally! Foundation: Membership on an entity's Board of Directors or advisory committees; St. Jude: Patents & Royalties. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees.
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- 2020
49. Molecular monitoring during dose reduction predicts recurrence after TKI cessation in CML
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Gottschalk, Andrea, primary, Glauche, Ingmar, primary, Cicconi, Silvia, primary, Clark, Richard E., primary, and Roeder, Ingo, primary
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- 2020
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50. Enhanced Transduction Lentivector Gene Therapy for Treatment of Older Patients with X-Linked Severe Combined Immunodeficiency
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De Ravin, Suk See, primary, Anaya O'Brien, Sandra, primary, Kwatemaa, Nana, primary, Theobald, Narda, primary, Liu, Siyuan, primary, Lee, Janet, primary, Kardava, Lela, primary, Liu, Taylor, primary, Goldman, Frederick, primary, Moir, Susan, primary, Bleesing, Jack, primary, Neven, Benedicte, primary, Puck, Jennifer, primary, Cowan, Morton J, primary, Mamcarz, Ewelina, primary, Gottschalk, Stephen, primary, Meagher, Michael M, primary, Notarangelo, Luigi, primary, Kang, Elizabeth, primary, Wu, Xiaolin, primary, and Malech, Harry L., primary
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- 2019
- Full Text
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