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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Di Fronzo, Nancy L
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Sloan-Kettering Institute for Cancer Research
New York
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Ferrando-Martínez, Sara; Ruiz-Mateos, Ezequiel; Dudakov, Jarrod A et al. (2015) WNT signaling suppression in the senescent human thymus. J Gerontol A Biol Sci Med Sci 70:273-81
Kinnebrew, Melissa A; Lee, Yeon Joo; Jenq, Robert R et al. (2014) Early Clostridium difficile infection during allogeneic hematopoietic stem cell transplantation. PLoS One 9:e90158
Tuckett, Andrea Z; Thornton, Raymond H; Shono, Yusuke et al. (2014) Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy. Blood 123:2797-805
Geiger, Theresa L; Abt, Michael C; Gasteiger, Georg et al. (2014) Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med 211:1723-31
Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91
Shono, Yusuke; Tuckett, Andrea Z; Ouk, Samedy et al. (2014) A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discov 4:578-91
Palomba, M Lia; Piersanti, Kelly; Ziegler, Carly G K et al. (2014) Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells. PLoS One 9:e79987
Ghosh, Arnab; Holland, Amanda M; van den Brink, Marcel R M (2014) Genetically engineered donor T cells to optimize graft-versus-tumor effects across MHC barriers. Immunol Rev 257:226-36
Velardi, Enrico; Dudakov, Jarrod A; van den Brink, Marcel R M (2013) Clinical strategies to enhance thymic recovery after allogeneic hematopoietic stem cell transplantation. Immunol Lett 155:31-5
van Heijst, Jeroen W J; Ceberio, Izaskun; Lipuma, Lauren B et al. (2013) Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med 19:372-7

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