A significant cause of mortality after unrelated umbilical cord blood transplant (UCBT) is due to recurrence of the underlying malignancy. While infusion of tumor-specific T cells is a conceptually attractive strategy to enhancing graft-versus-leukemia (GVL)-effect and reducing relapse rates for patients undergoing allogeneic transplant with marrow- or peripheral blood-derived hematopoietic progenitor cells, the anonymity of the umbilical cord blood (UCB) donor has so far precluded this application of adoptive immunotherapy after UCBT. To overcome this limitation, we have generated T cells from UCB that are specific for CD19, a molecule commonly expressed on B-lineage leukemias and lymphomas. The specificity for CD19 is derived from a chimeric immunoreceptor expressed on the cell surface of genetically modified T cells that combines antibody-recognition of CD19 with the effector-function of T cells activated through chimeric CD3-?. This grant proposes to enhance the therapeutic potential of these UCB-derived CD19-specific T cells by evaluating three approaches to improving their in vivo persistence, and therefore anti-tumor effect, after adoptive transfer. (1) Ex vivo-expanded genetically manipulated CD8+ T cells are dependent in vivo on T-cell help, which can be provided by exogenous IL-2, to sustain proliferation and survival. Therefore, CD19-specific T cells will be combined with CD10-specific-IL2 immunocytokine (ICK) in order to coordinate delivery of a T-helper (Th) response at sites of CD10-binding in the microenvironment of CD19+CD10+ B-lineage malignancies. (2) Genetically modified CD19-specific CD4+ T cells are a potential source of antigen-specific help. Therefore, UCB-derived CD4+ T cells will be evaluated as a source of Th activity for CD8+ CD19- specific T cells. (3) Fully-competent activation of T cells resulting in their proliferation and survival requires coordinated signaling through both an antigen receptor and secondary co-stimulator molecules. Therefore, the CD19-specific chimeric immunoreceptor will be modified to provide genetically modified CD4+ and CD8+ T cells, with tandem activation and co-stimulation through CD28, upon engagement with B7-CD19+ malignant targets. These data will facilitate the design of clinical protocols using adoptive immunotherapy to enhance the GVL-effect, not just after UCBT, but also after allogeneic hematopoietic stem-cell transplants in general. Lay language: Infusing tumor-specific T cells derived from cord blood may reduce relapse rates after umbilical cord blood transplant. This grant therefore proposes to generate tumor specific T cells from cord blood and evaluate their potential for immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120956-04
Application #
7762175
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2007-02-05
Project End
2011-12-31
Budget Start
2010-02-05
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$292,600
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Hurton, Lenka V; Singh, Harjeet; Najjar, Amer M et al. (2016) Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A 113:E7788-E7797
Kebriaei, Partow; Singh, Harjeet; Huls, M Helen et al. (2016) Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest 126:3363-76
Torikai, Hiroki; Mi, Tiejuan; Gragert, Loren et al. (2016) Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application. Sci Rep 6:21757
Caruso, Hillary G; Torikai, Hiroki; Zhang, Ling et al. (2016) Redirecting T-Cell Specificity to EGFR Using mRNA to Self-limit Expression of Chimeric Antigen Receptor. J Immunother 39:205-17
Najjar, Amer M; Manuri, Pallavi R; Olivares, Simon et al. (2016) Imaging of Sleeping Beauty-Modified CD19-Specific T Cells Expressing HSV1-Thymidine Kinase by Positron Emission Tomography. Mol Imaging Biol 18:838-848
Krishnamurthy, Janani; Rabinovich, Brian A; Mi, Tiejuan et al. (2015) Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma. Clin Cancer Res 21:3241-51
Singh, H; Moyes, J S E; Huls, M H et al. (2015) Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19-specific chimeric antigen receptor. Cancer Gene Ther 22:95-100
Liadi, Ivan; Singh, Harjeet; Romain, Gabrielle et al. (2015) Individual Motile CD4(+) T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor Cells. Cancer Immunol Res 3:473-82
Caruso, Hillary G; Hurton, Lenka V; Najjar, Amer et al. (2015) Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. Cancer Res 75:3505-18
Deniger, Drew C; Yu, Jianqiang; Huls, M Helen et al. (2015) Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations. PLoS One 10:e0128151

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