Under the first aim of this project work has been divided into 2 areas. The first explored modulation of cancer T cell receptor directed immunotherapy by the allogeneic environment and identified that selective inhibition of STAT1 in donor plasmacytoid dendritic cells could reduce the severity of GVHD with preservation of anti-tumor T cell responses. This work has just recently been accepted for publication Blood (Capitini et al). The second part of the project studied compartment-specific effects of alloantigen expression on inhibition of antitumor immune responses following alloHSCT and utilized a precursor B cell leukemia line derived from mice with transgenic expression of E2aPBX1, a recurring translocation present in approximately 5% of pediatric ALL (Bijl et al, Genes and Development, 2005) and developed in our laboratory into a transplantable model. This work was published in Biology of Blood and Marrow Transplantation (Shand et al). In ongoing work using this transplantable ALL we have demonstrated that ALL can be effectively targeted by a T cell response in vivo but that this response requires vaccination of the donor T cell inocula. Second, allogeneic antigens contribute to the cure following T cell infusion but results in GVHD. Finally, sorted populations of T cells from primed donors can mediate selective graft versus leukemia responses. Using this model we have begun studying the early progression of the leukemia in bone marrow and the impact of this progression on T cells. We have identified that a surprisingly large percentage of T cells in leukemia-infiltrated compartments express high levels of the negative regulator of T cell function, programmed death 1 (PD-1) receptor. Addition studies have shown that the percentage of PD-1+ T cells correlates with the extent of leukemic involvement and that PD-1+ T cells also express other markers of a senescent phenotype such as T cell immunoglobulin and mucin domain 3 (Tim-3). Interestingly, careful assessment T cells during early leukemia progression have shown that the induction of PD1 occurs early (by day 5 after injection of leukemia) whereas acquisition of other T cells senescent markers such as Tim-3 and Lymphocyte Activation Gene 3 (LAG3) occur later suggesting that these markers may be more functionally relevant in terms of antileukemic potential. Indeed, T cells from irradiated tumor cell primed mice also express PD1 but not Tim-3 or LAG3 and mediate an antileukemic effect. Finally, preliminary a data from human bone marrow samples leukemia samples from patients with ALL (obtained from our Hematologic Malignancy Biology Study) have shown expression of PD1, Tim-3 and LAG3 on a subset of T cells. In summary, this data provides insights into how immunosuppressive effects of ALL in the bone marrow microenvironment may be reversed as an adjuvant to ALL-targeted immunotherapy.
Under Aim2 of this project we have obtained a murine CD19-targeted chimeric antigen receptor (CAR) from Dr. James Kochenderfer analogous to those used in the clinical setting to induce remission in 50-70% of patients with chemotherapy-refractory or recurrent ALL in ongoing clinical trials. These hybrid receptors (Immunoglobulin antigen binding domain and T cell receptor signaling components) are the primary focus of project ZIA BC 011565 being conducted in the Fry laboratory. Using the CD19 and the allogeneic transplant models described in Aim 1 we have study the immunobiology associated with CAR therapy after alloHSCT. Preliminary data ahs demonstrated that CAR expressing T cells can cause GVHD mediated by the endogenous alloreactive TCR but that this occurs only when there CAR antigen present and that this is exacerbated by CAR T cell production of cytokines (mainly IL-6, a cytokine implicated in major toxicity observed after CD19 CAR therapy in the clinic). Under the third Aim of this project and utilizing tools developed under Aim where the effect of ALL on the bone marrow microenvironment (T cell expression of exhaustion markers) we have begun studying the role of bone marrow niche factors on the progression and therapeutic resistance of ALL. We have started with a candidate approach based on the results of genomic screening where it was found that a subset of pre B cell ALL overexpresses the thymic stromal stromal receptor (TSLPR) and that overexpression of this receptor is associated with a higher risk of relapse. Importantly, the TSLP cytokine binds to a heterodimeric receptor comprised of TSLPR and the IL-7 receptor alpha chain. The Fry laboratory has past expertise in the immunobiology of IL-7. Using our transplantable ALL model we have demonstrated that overexpression of TSLPR by transduction results in accelerated early progression of leukemia and resistance to chemotherapeutic agents. We have also shown that TSLP is produced by bone marrow stromal cells suggesting that the biologic effect of TSLPR overexpression in ALL is ligand-dependent. We are currently exploring whether neutralization of TSLP can reverse the impact of TSLPR overexpression which has potential therapeutic implications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011295-05
Application #
8938043
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Shalabi, Haneen; Wolters, Pamela L; Martin, Staci et al. (2018) Systematic Evaluation of Neurotoxicity in Children and Young Adults Undergoing CD22 Chimeric Antigen Receptor T-Cell Therapy. J Immunother 41:350-358
Fry, Terry J; Shah, Nirali N; Orentas, Rimas J et al. (2018) CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24:20-28
Shalabi, Haneen; Kraft, Ira L; Wang, Hao-Wei et al. (2018) Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma. Haematologica 103:e215-e218
Jacobsohn, David A; Loken, Michael R; Fei, Mingwei et al. (2018) Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression. Biol Blood Marrow Transplant 24:2040-2046
Yang, Yinmeng; Kohler, M Eric; Chien, Christopher D et al. (2017) TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci Transl Med 9:
Chung, Yang Jo; Fry, Terry J; Aplan, Peter D (2017) Myeloablative hematopoietic stem cell transplantation improves survival but is not curative in a pre-clinical model of myelodysplastic syndrome. PLoS One 12:e0185219
Shah, Nirali N; Watson, Theresa M; Yates, Bonnie et al. (2017) Procalcitonin and cytokine profiles in engraftment syndrome in pediatric stem cell transplantation. Pediatr Blood Cancer 64:
Walker, Alec J; Majzner, Robbie G; Zhang, Ling et al. (2017) Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase. Mol Ther :
Allen, Elizabeth S; Stroncek, David F; Ren, Jiaqiang et al. (2017) Autologous lymphapheresis for the production of chimeric antigen receptor T cells. Transfusion 57:1133-1141
Shah, Nirali N; Fry, Terry J (2017) Anti-CD19 resistance can ""stem"" from progenitors. Blood 130:1961-1963

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