TAMI-78. STEM CELL IMMUNOTHERAPY MODULATES IMMUNOREGULATORY PATHWAYS IN THE TUMOR MICROENVIRONMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi214-vi215
Author(s):  
Tyler Wildes ◽  
Bayli DiVita Dean ◽  
Joseph Dean ◽  
Laura Falceto Font ◽  
Catherine Flores
Keyword(s):  
T Cells ◽  
Adoptive Immunotherapy ◽  
Immune Activation ◽  
Cellular Therapy ◽  
High Grade ◽  
Adoptive Cellular Therapy ◽  
Hematopoietic Stem ◽  
Regulatory Pathways ◽  
High Grade Gliomas

Abstract INTRODUCTION A major obstacle in efficacious therapeutics against high-grade gliomas has been an inability to overcome powerful regulatory mechanisms within the TME that hamper immune activation. Fortunately, immunotherapy has enabled the enhancement of immune activation within the TME through adoptive immunotherapy and checkpoint inhibition. We found that co-transfer of hematopoietic stem cells (HSCs) with either adoptive immunotherapy or PD-1 blockade significantly improves therapeutic outcomes by manipulating the cellular components that make up the TME in high-grade gliomas. HSC co-transfer with immunotherapy leads to increased in situ downregulation of multiple immune regulatory pathways, activation of tumor-reactive T cells, and significant reduction in the frequency of MDCs and TAMs within the TME. METHODS C57BL/6 mice with orthotopic KR158B-gliomas received either adoptive immunotherapy using activated tumor-reactive T cells or αPD-1, either with or without HSC co-transfer. After treatment of late-stage tumors, brains were sectioned and digital spatial profiling (NanoString GeoMx) of the TME was conducted in situ. Briefly, tumor-bearing brain sections were stained for nuclei, CD3, CD45, and GFP (HSC-derived cells); regions of interest (ROIs) containing 200 nuclei were selected and processed for whole genome sequencing. Areas rich in immune cells within the TME were chosen as ROIs and compared between groups. Results were corroborated with flowcytometry and PCR. RESULTS Mice that received HSCs with either adoptive cellular therapy or αPD-1 had reductions in expression of multiple regulatory markers in the TME including iNOS, TGFβ, and PD-L1. This was accompanied by reductions in the frequencies of MDSCs and TAMs. An increased relative abundance of activated CD8+ T cells within the TME was also observed. Interestingly, we found that HSC-derived cells provided rich amounts of dendritic cells at the TME when co-transferred with immunotherapy. Host-derived myeloid cells were significantly displaced from the TME in mice receiving HSC plus adoptive cellular therapy or αPD-1.

scholarly journals Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 143-151 ◽  
Author(s):  
Renier J. Brentjens ◽  
Kevin J. Curran
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cellular Therapy ◽  
Hematologic Malignancies ◽  
Lymphoproliferative Disease ◽  
Myelogenous Leukemia ◽  
Cellular Immunotherapy ◽  
Adoptive Cellular Therapy ◽  
Hematopoietic Stem ◽  
Lymphoid Malignancies

Abstract The ability of immune-competent donor T cells to mediate a beneficial graft-versus-leukemia (GVL) effect was first identified in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies. Unfortunately, with the exception of chronic myelogenous leukemia and EBV-induced lymphoproliferative disease, allo-HSCT GVL lacks the potency to significantly affect disease progression or recurrence in most other hematologic malignancies. The inadequacy of a GVL effect using past approaches is particularly evident in patients with lymphoid malignancies. However, with the advent of improved gene transfer technology, genetically modified tumor-specific immune effectors have extended cellular immunotherapy to lymphoid malignancies. One promising strategy entails the introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs), which redirect the specificity and function of immune effectors. CAR-modified T cells targeted to the B cell–specific CD19 antigen have demonstrated promising results in multiple early clinical trials, supporting further investigation in patients with B-cell cancers. However, disparities in clinical trial design and CAR structure have complicated the discovery of the optimal application of this technology. Recent preclinical studies support additional genetic modifications of CAR-modified T cells to achieve optimal clinical efficacy using this novel adoptive cellular therapy.

scholarly journals Cross-talk between T Cells and Hematopoietic Stem Cells during Adoptive Cellular Therapy for Malignant Glioma

2018 ◽  
Vol 24 (16) ◽  
pp. 3955-3966 ◽  
Author(s):  
Tyler J. Wildes ◽  
Adam Grippin ◽  
Kyle A. Dyson ◽  
Brandon M. Wummer ◽  
David J. Damiani ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Malignant Glioma ◽  
Cross Talk ◽  
Cellular Therapy ◽  
Adoptive Cellular Therapy ◽  
Hematopoietic Stem

IMMU-23. NEOANTIGEN-DIRECTED CELLULAR THERAPY IN A PRECLINICAL MOUSE MODEL OF MALIGNANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi96-vi97
Author(s):  
Max Schaettler ◽  
Gavin Dunn
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Cd8 T Cells ◽  
Cellular Therapy ◽  
Immunological Tolerance ◽  
Dependent Manner ◽  
Adoptive Cellular Therapy ◽  
Specific Expression ◽  
Cervical Lymph Nodes

Abstract Adoptive cellular therapy in the form of CAR T cells or TCR engineered T cells has emerged as a novel approach in the treatment of both solid and hematologic malignancies. Neoantigens generated by tumor somatic mutations represent potentially attractive therapeutic targets in this context owing to their tumor-specific expression and circumvention of immunological tolerance. However, existing cell therapy systems generally target self-proteins or virally overexpressed antigens that fail to recapitulate the features of endogenous tumor neoantigens. Thus, there exists a need for a model in which tumor-specific neoantigens can be targeted via adoptive cellular therapy. Prior work from our lab identified the Imp3D81N mutation (mImp3) within GL261 as a neoantigen recognized by CD8 T cells in both intracranial tumors and draining cervical lymph nodes. To generate a system for targeting this neoantigen, we isolated and cloned mImp3-specific TCRs through a single-cell sort followed by a nested multiplexed PCR reaction. The specificity and functionality of these isolated TCRs was determined through introduction into a T cell hybridoma, identifying a top candidate based upon a high degree of cytokine production and specificity for the mutant epitope. A TCR transgenic mouse was then generated in which more than 90% of all T cells were CD8 T cells bearing this mImp3-specific TCR. T cells isolated from this mouse display specificity for the mImp3 peptide and display in vitro reactivity to GL261 and other cell lines in a mImp3-dependent manner. Therefore, this model represents the first TCR transgenic targeting a brain tumor neoantigen, opening the door for further investigation into cell therapy against this class of antigens.

Abstract 530: Circulating γδ T cells are activated and depleted during progression of high-grade gliomas: Implications for γδ T cells therapy of GBM

2012 ◽  
Author(s):  
Benjamin Beck ◽  
G Yancey Gillespie ◽  
Richard D. Lopez ◽  
Gretchen A. Cloud ◽  
Cathy Langford ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
High Grade ◽  
High Grade Gliomas

scholarly journals Adoptive cellular therapy enhances the helper T cell response and reduces the number of regulatory T cells

2011 ◽  
Vol 2 (4) ◽  
pp. 737-743 ◽  
Author(s):  
TAKESHI ISHIKAWA ◽  
SATOSHI KOKURA ◽  
NAOYUKI SAKAMOTO ◽  
TSUGUHIRO MATSUMOTO ◽  
JUN FUNAKI ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Response ◽  
Cellular Therapy ◽  
T Cell Response ◽  
Helper T Cell ◽  
Adoptive Cellular Therapy

scholarly journals Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2643-2652 ◽  
Author(s):  
Lisa Marie Serrano ◽  
Timothy Pfeiffer ◽  
Simon Olivares ◽  
Tontanai Numbenjapon ◽  
Jennifer Bennitt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Adoptive Immunotherapy ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
Hematopoietic Stem ◽  
B Lineage

AbstractDisease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)–derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.

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