ZIC BC 011029 (ZIC) | |||
---|---|---|---|
Title | Preclinical development and clinical monitoring of adoptive immune therapy | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Hakim, Frances | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $441,077 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Hodgkins disease (25.0%) Multiple Myeloma (50.0%) Non Hodgkins Lymphoma (25.0%) |
||
Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
|||
Abstract | |||
SUMMARY: The Preclinical Development and Clinical Monitoring Facility (PDCMF) of the Experimental Transplantation and Immunology Branch supports the development and implementation of new protocols involving adoptive immune cell therapies through preclinical development, translational implementation of clinical products and preservation and analysis of patient blood and tissues during clinical trials. The work of this core is supported by close collaborative relationships with the Cell Processing Service of DTM, for support of microarray analysis and development of clinical products; the ETIB Flow Cytometry Facility, for support of sorting of clinical products for research endpoints; and the laboratory of Ronald Gress, for technical support in RNA and DNA isolation and quantitative assays. Several novel protocols involving adoptive transfer of T cells have been implemented in recent years as a result of this process. (1) In ETIB protocol 04-C-0055 (PI: Daniel Fowler), PDCMF staff working within CPS/DTM, supported clinical production and molecular characterization of an activated donor CD4 T cell product (T.Rapa.12) administered prophylactically to enhance donor engraftment and reduce AGVHD (Fowler et al, Blood, 2013). Subsequently, a second generation product, cultured for 6 days and having a less differentiated phenotype (Castiello et al, Cytotherapy, 2013), but potential for longer persistence after infusion, was assessed for anti-tumor efficacy in lymphoma and in renal cell carcinoma patients (Fowler et al, Clin Cancer Res, 2015). (2) In ETIB protocol 09-C-0224, (P.I.: Nancy Hardy) we used cellular and molecular assays to monitor changes to test whether localized tumor death following targeted irradiation could stimulate a next-day donor lymphocyte infusion (DLI) to initiate a systemic immune response and trigger immune-mediated tumor regression at non-irradiated sites. We determined that circulating T cells in radiation-plus-DLI treated patients were activated, as compared with DLI alone. Furthermore, using a custom panel of multiplex RNA probes (Nanostring), we identified upregulation of inflammasome and TLR genes responding to cell damage, as well as genes induced by IFNa, at both irradiated and non-irradiated (abscopal) sites, consistent with systemic immune response. (3) In ETIB protocol 11-C-0016 (P.I. Claude Sportes/Daniel Fowler), patients with multiple myeloma received an autologous hematopoietic stem cell transplant followed by infusion of T1.Rapa cells in a phase one trial of escalating T1.Rapa cell doses; through expanding the scale of product manufacturing, serial infusions of T1.Rapa cells were then implemented. This protocol expanded autologous T cells in the presence of IFNa and rapamycin, to generate a cell product with Th1/Tc1 activity). We supported clinical translation of the T1.Rapa cells, from production protocol through IND documentation, and characterized gene expression and T cell lineage phenotype in the T1.Rapa infusion product. In the clinical trial, we assessed serial changes in effector and regulatory T cell populations in blood and in bone marrow (the main tumor site), identified the clonal expansion of specific T cells by T cell receptor sequencing and demonstrated changes in gene expression and T cell phenotype consistent with increased Th1/Tc1 activity. (4) In a collaborative study with Dr. Fowler's laboratory we used flow cytometry to characterize the effects of infusions of mesenchymal stem cells, derived from human marrow, on human T helper cells in a murine xenogeneic GVHD model (Amarnath et al, Stem Cells, 2015). (5) In collaboration with Dr. Fowler, we have assessed the effects of use of the pentostatin/cytoxan regimen he developed for lymphodepletion in support of a mesothelioma protocol using a partially humanized anti-mesothelin antibody-immunotoxin developed by Dr. Pastan's laboratory. This year we collaborated with Dr. Pastan's laboratory to investigate regulation of immunogenicit |