The studies address the problem of relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after umbilical cord blood transplant (UCBT). We hypothesize that the incidence of relapse following allogeneic UCBT can be reduced by targeting post-transplant minimal residual disease (MRD) with adoptively transferred donor-derived leukemia-specific T-cells. As a strategy to reproducibly generate effector cells for adoptive therapy after UCBT, we have designed a new chimeric antigen receptor (CAR), designated CD19RCD28, which re-directs the antigen specificity of T cells to the B-cell lineage-restricted cell-surface molecule CD19. Genetically-modified CD19-CAR* cytotoxic T lymphocytes (CTL's) are activated through chimeric CD28 and CD3, and lyse B-cell malignant target cells in a CAR-regulated manner. T-cell isolation, genetic modification, and expansion Standard Operating Procedures at MDACC will manufacture clinical cell doses in accordance with quality control/assurance standards mandated by the FDA. The studies proposed in Specific Aim #1 will evaluate the feasibility and safety of adoptive therapy using three escalating doses (108/m2-1010/m2) of donor-derived CD19RCD28+HyTK+ CTL-clones versus oligoclonal/polyclonal T-cell lines, after reduced intensity allogeneic UCBT for high-risk CD19* B-ALL. We hypothesize that the lymphodepleting preparative regimen will promote homeostatic proliferation of transferred T-cells, as well as, limit anti-transgene rejection responses. The correlative studies in Specific Aim #2 focus on delineating the magnitude and duration of persistence of transferred clones versus lines at the three prescribed T-cell dose levels using vector-specific Q-PCR and TCR spectratyping analyses on serially acquired PBMC specimens. We will also evaluate the utility of administering recombinant human IL-2 for enhancing the expansion of transferred T-cells in vivo. The correlative studies proposed in Specific Aim 3 will evaluate the bone marrow and lymph node trafficking of transferred clones versus lines, and, the functional status of transferred T-cells in these anatomic sites of B-ALL MRD. In aggregate, the results of the studies proposed will facilitate the evolution of targeting post-UCBT MRD with CD19-specific T-cells for enhanced disease-free survival of patients with B-lineage ALL, and substantiate the rationale to expand this approach to a broader array of CD19+ malignancies treated by HCT. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
Zip Code
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
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
Kumaresan, Pappanaicken; Figliola, Mathew; Moyes, Judy S et al. (2015) Automated Cell Enrichment of Cytomegalovirus-specific T cells for Clinical Applications using the Cytokine-capture System. J Vis Exp :

Showing the most recent 10 out of 53 publications