Combining CD34+ stem cell selection with prophylactic pathogen and leukemia directed T‐cell immunotherapy to simultaneously reduce graft versus host disease, infection, and leukemia recurrence after allogeneic stem cell transplant

• Published in: American journal of hematology 2023-01, Vol.98 (1), p.159-165
• Main Authors: Gottlieb, David J., Sutrave, Gaurav, Jiang, Wei, Avdic, Selmir, Street, Janine A., Simms, Renee, Clancy, Leighton E., Antonenas, Vicki, Gloss, Brian S., Bateman, Caroline, Bishop, David C., Micklethwaite, Kenneth P., Blyth, Emily
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Adoptive immunotherapy; Antigens; CD19 antigen; CD34 antigen; CD4 antigen; CD8 antigen; Chimeric antigen receptors; Cyclophosphamide; Cytomegalovirus; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - therapy; Globulins; Graft versus host disease; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; Graft-versus-host reaction; Hematology; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Histocompatibility antigen HLA; Humans; Immune reconstitution; Immunotherapy; Infections; Leukemia; Leukocytes (neutrophilic); Lymphatic leukemia; Malignancy; Pathogens; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Radiation; Stem Cell Transplantation; Stem cells; T-Lymphocytes; Transplantation, Homologous; Transplants & implants; Treatment Outcome; Tumors
• ISSN: 0361-8609; 1096-8652
• DOI: 10.1002/ajh.26594

We designed a trial to simultaneously address the problems of graft versus host disease (GVHD), infection, and recurrence of malignancy after allogeneic stem cell transplantation. CD34+ stem cell isolation was used to minimize the development of acute and chronic GVHD. Two prophylactic infusions, one combining donor‐derived cytomegalovirus, Epstein–Barr virus, and Aspergillus fumigatus specific T‐cells and the other comprising donor‐derived CD19 directed chimeric antigen receptor (CAR) bearing T‐cells, were given 21–28 days after transplant. Two patients were transplanted for acute lymphoblastic leukemia from HLA identical siblings using standard doses of cyclophosphamide and total body irradiation without antilymphocyte globulin. Patients received no post‐transplant immune suppression and were given no pre‐CAR T‐cell lymphodepletion. Neutrophil and platelet engraftment was prompt. Following adoptive T‐cell infusions, there was rapid appearance of antigen‐experienced CD8+ and to a lesser extent CD4+ T‐cells. Tetramer‐positive T‐cells targeting CMV and EBV appeared rapidly after T‐cell infusion and persisted for at least 1 year. CAR T‐cell expansion occurred and persisted for up to 3 months. T‐cell receptor tracking confirmed the presence of product‐derived T‐cell clones in blood targeting all three pathogens. Both patients are alive over 3 years post‐transplant without evidence of GVHD or disease recurrence. Combining robust donor T‐cell depletion with directed T‐cell adoptive immunotherapy targeting infectious and malignant antigens permits independent modulation of GVHD, infection, and disease recurrence. The combination may separate GVHD from the graft versus tumor effect, accelerate immune reconstitution, and improve transplant tolerability. Donor stem cell product undergoes CD34 stem cell selection. CD34 positive stem cells are used for transplantation. Pathogen‐ and leukemia‐specific T‐cells are manufactured from CD34 negative fraction and infused prophylactically 21 days after transplant.