Delayed immune reconstitution, and in particular T cell deficiency, is an important contributor to morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, leading to infections and malignant relapse. Strategies to enhance post-transplant T cell reconstitution can significantly improve the overall outcome of allo-HSCT. However, at the present time such strategies are not readily available. In the first funding period we have performed preclinical studies regarding administration of interleukin-7 (IL-7) or keratinocyte growth factor (KGF), as well as inhibition of sex steroids (chemical or surgical) resulting in three clinical trials at our center. In the current (second) funding period we have performed studies in mouse HSCT models demonstrating the feasibility and efficacy of adoptive cell therapy with ex vivo generated precursor T cells (preT) to enhance post-transplant T cell reconstitution. We found that adoptively transferred preT can be used as an """"""""off-the-shelf"""""""" cell therapy and administered across MHC barriers to enhance thymic regeneration and T cell immunity. We are currently preparing a phase I clinical trial to study the adoptive transfer of third party cord blood-derived preT transduced with an anti-CD19 chimeric antigen receptor for allo-HSCT recipients with high risk ALL. Our proposal for the next funding period aims to further explore the potential benefits of adoptive transfer of preT, as well as modify our preT cell culture method to develop an artificial implantable hematopoietic niche that can support T cell development. We hypothesize that (a) preT rapidly reconstitutes T cell immunity in allo-HSCT recipients via both thymic and extrathymic developmental pathways, (b) preT can be engineered to enhance anti-tumor activity and the regeneration of thymic and extrathymic niches and (c) the preT culture system can be modified to develop an artificial hematopoietic niche for T cell development. We propose to study in Aim 1 the contribution of extrathymic sites to preT-derived T cell reconstitution, the crosstalk of preT and thymic stroma resulting in long-term thymic regeneration, and strategies to enhance preT transfer.
In Aim 2 we propose to study genetic engineering of preT to enhance their anti-tumor or (extra)thymic regenerative potential. We also plan to engineer an artificial hematopoietic niche for T cell development that can be implanted to enhance T cell development.
Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy with curative potential for a variety of malignant and non-malignant diseases. The recovery of T cell immunity is severely delayed after a HSCT and this is an important cause of infections and relapse of the malignancy. In this application we propose to administer precursor T cells, which we have generated in tissue culture systems, to the stem cell graft to enhance the recovery of post-transplant T cell recovery. We plan to study 1) the sites within or outside the thymus where these cells engraft, 2) assess their effects on the regeneration of the thymus, 3) develop strategies to enhance engraftment of these cells, 4) genetically engineer the precursor T cells to enhance their anti-tumor and regenerative potential, and 5) develop an artificial thymus-like organoid that can be implanted to improve T cell recovery.
|Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4|
|Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246|
|Matsuzawa-Ishimoto, Yu; Shono, Yusuke; Gomez, Luis E et al. (2017) Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J Exp Med 214:3687-3705|
|Dudakov, Jarrod A; Mertelsmann, Anna M; O'Connor, Margaret H et al. (2017) Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood 130:933-942|
|Staffas, Anna; Burgos da Silva, Marina; van den Brink, Marcel R M (2017) The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood 129:927-933|
|Chaudhry, Mohammed S; Velardi, Enrico; Malard, Florent et al. (2017) Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation: Time To T Up the Thymus. J Immunol 198:40-46|
|Peled, Jonathan U; Devlin, Sean M; Staffas, Anna et al. (2017) Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J Clin Oncol 35:1650-1659|
|Ghosh, Arnab; Smith, Melody; James, Scott E et al. (2017) Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med 23:242-249|
|Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel et al. (2017) RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci Transl Med 9:|
|Weber, Daniela; Jenq, Robert R; Peled, Jonathan U et al. (2017) Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 23:845-852|
Showing the most recent 10 out of 90 publications