ZIC BC 011029 (ZIC) | |||
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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 | $420,830 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Bone Marrow Transplantation (100.0%) Cancer (100.0%) |
Cervical Cancer (4.0%) Head and Neck (10.0%) Hodgkins disease (20.0%) Larynx (10.0%) Multiple Myeloma (30.0%) Non Hodgkins Lymphoma (30.0%) Penis (2.0%) Vaginal (4.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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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 11-C-0016 (P.I. Daniel Fowler), patients with multiple myeloma have received an autologous hematopoietic stem cell transplant followed by infusion of a distinctive autologous T cell product, 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 following pentostatin induced lymphodepletion. The T1.Rapa cells were generated through expansion of host T cells by CD3/CD28 bead costimulation in the presence of IFN-alpha and rapamycin, to generate a persistent cell product with Th1/Tc1 activity. We provided translational scale-up of the T1.Rapa product developed in Dr. Fowler's laboratory, provided operating protocols and materials documentation in support of the FDA submission, and characterized changes induced by the T1.Rapa culture using microarray, flow cytometry and cytokine production assays. These demonstrated skewing toward Th1/Tc1 central memory cells with elevated expression of both IFN-induced and autophagy-associated genes. In the ongoing clinical trial, we assessed serial changes in effector and regulatory T cell populations in blood and in bone marrow (the main tumor site), and demonstrated concurrent changes in gene expression and T cell phenotype consistent with increased Th1/Tc1 activity following T1.Rapa infusion. Finally, using gDNA-based T cell receptor sequencing (Immunoseq by Adaptive Biotechnologies) we identified novel clonal expansions following infusion and tracked their persistence in patients with prolonged remission. (2) 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. Development of resistance to immune therapies can be linked to the immunogenicity of the infused antibody immunotoxin agent. This year we collaborated with Dr. Pastan's laboratory to investigate regulation of immunogenicity of immunotoxins by HLA-DR/DP/DQ expression (Mazor et al, AAPSJ, 2017) (3) We have supported the implementation by Dr. James Kochenderfer of Chimeric Antigen Receptor (CAR) therapy to treat lymphoma, leukemia and myelomas. In the first trial of the use of donor-derived anti-CD19 Chimeric Antigen Receptor (CAR) T cells in patients with relapsed or persistent lymphoma following allogeneic transplant (Protocol 10-C-0054: P.I. James Kochenderfer (ETIB)), PDCMF staff in Cell Processing Section optimized the CAR transduction and subsequent CAR T cell expansion process, developed the operational protocols and documentation for IND submission and trained the clinical staff in this new procedure. Subsequently PDCMF staff supported the implementation of a new lentiviral human-immunoglobulin-based anti-CD19 CAR vector that Dr. Kochenderfer had designed, which entered into clinical trials this past year (16-C-0054). In the PDCMF laboratory we have sup |