This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GvHD) had essentially precluded this option. We have therefore been depleting donor T cells of alloreactive precursor cells, using a CD25 immunotoxin. Our method appeared effective and as few as 5 x 104/kg allodepleted haploidentical donor cells substantially accelerated anti-viral immune recovery in the recipient, without increasing GvHD (Blood Plenary Paper[1]). Administration of higher doses of cells will be necessary to obtain an antileukemic effect, and it is almost inevitable that in some patients, these doses of cells will be sufficient to trigger GvHD even after allodepletion. We therefore propose to increase the safety of our approach by incorporating a suicide gene, inducible caspase 9 (iCasp9), in the allodepleted T cells, permitting their destruction should administration have adverse effects. iCasp9 consists of a pro-apoptotic molecule, human caspase 9, joined to a drug-binding domain derived from human FK506-binding protein;addition of a small molecule synthetic drug leads to homodimerization of caspase 9, activation of the caspase pathway and apoptosis of the transduced cells within 24 hours. The dimerizer, AP1903, has successfully completed safety-testing in human volunteers. We have generated a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19) to enable enrichment of transduced cells to 90% purity. We plan to infuse escalating doses of iCasp9-expressing allodepleted cells, starting at doses that are safe even for unmodified allodepleted cells. Our hypothesis is that any GVHD that develops at higher dose levels will respond to administration of AP1903 because of destruction of the gene-modified allodepleted cells If our hypothesis is correct, this approach will enable safe administration of larger and more effective doses of donor cells for optimal anti-tumor and anti-viral immune reconstitution in the majority, while ensuring that the minority who develop GVHD can be effectively treated. I. HYPOTHESIS Transduction of T cells with a suicide gene, inducible caspase 9 (iCasp9), will allow us to achieve a minimization of GVHD. II.
SPECIFIC AIMS Primary objectives i. To determine the maximum number of suicide gene-modified allodepleted donor lymphocytes up to a total of 1 x 107/kg that can be given to recipients of haploidentical stem cell transplants that will result in a rate of Grade III/IV GVHD of 25%. ii. To evaluate the biological effects of administration of AP1903, a dimerizer used to activate the suicide gene mechanism by measuring disappearance of transgene positive cells from the peripheral blood iii. To evaluate the clinical effects of the agents on patients who develop Grade I GVHD and describe the outcome in patients with Grade II GvHD . Secondary objectives iv. To analyze the contribution of the gene-modified cells to immune reconstitution in these patients by measuring their survival, persistence and expansion. v. To measure the overall and disease free survival, at 100 days and at 1 year post transplant.

National Institute of Health (NIH)
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General Clinical Research Centers Program (M01)
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Baylor College of Medicine
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Hunsaker, Sanita L; Garland, Beth H; Rofey, Dana et al. (2018) A Multisite 2-Year Follow Up of Psychopathology Prevalence, Predictors, and Correlates Among Adolescents Who Did or Did Not Undergo Weight Loss Surgery. J Adolesc Health 63:142-150
Lanzieri, Tatiana M; Chung, Winnie; Leung, Jessica et al. (2018) Hearing Trajectory in Children with Congenital Cytomegalovirus Infection. Otolaryngol Head Neck Surg 158:736-744
Bollard, Catherine M; Tripic, Tamara; Cruz, Conrad Russell et al. (2018) Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma. J Clin Oncol 36:1128-1139
Michalsky, Marc P; Inge, Thomas H; Jenkins, Todd M et al. (2018) Cardiovascular Risk Factors After Adolescent Bariatric Surgery. Pediatrics 141:
Lau, Chantal (2018) Breastfeeding Challenges and the Preterm Mother-Infant Dyad: A Conceptual Model. Breastfeed Med 13:8-17
Gururangan, Sridharan; Reap, Elizabeth; Schmittling, Robert et al. (2017) Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11). Cancer Immunol Immunother 66:1589-1595
Lanzieri, T M; Leung, J; Caviness, A C et al. (2017) Long-term outcomes of children with symptomatic congenital cytomegalovirus disease. J Perinatol 37:875-880
El-Hattab, Ayman W; Zarante, Ana Maria; Almannai, Mohammed et al. (2017) Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab 122:1-9
Jin, Haoxing Douglas; Demmler-Harrison, Gail J; Coats, David K et al. (2017) Long-term Visual and Ocular Sequelae in Patients With Congenital Cytomegalovirus Infection. Pediatr Infect Dis J 36:877-882
Oh, Sam S; Du, Randal; Zeiger, Andrew M et al. (2017) Breastfeeding associated with higher lung function in African American youths with asthma. J Asthma 54:856-865

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