NF-kB p50 Gene Edited, Activated Immature Myeloid Cells as a Novel Cancer Immunotherapy

Location
Johns Hopkins University School of Medicine, Baltimore, Maryland
Salary
Per NIH pay scale (currently $48,432 for new PhD, $51,324 with 3 yrs PDF experience, etc) + benefits
Posted
October 08 2018
Position Type
Full Time
Organization Type
Academia

    The p50 subunit of NF-kB contains a Rel Homology Domain that mediates dimerization and DNA-binding but lacks a trans-activation domain. Under basal conditions p50:p50 dimers bind and repress NF-kB target genes, and myeloid cells lacking p50 have an increased pro-inflammatory state. Multiple solid tumors grow more slowly in p50-/- mice, associated with conversion of tumor myeloid cells from the immune-suppressive M2 to the activated M1 state, which in turns favors activation of anti-tumor T cell immunity, as we have shown for glioblastoma (Barberi et al 2018).

    Realizing that targeting the p50 protein in myeloid cells would be difficulty, we are investigating the translational utility of infusing p50-/- myeloid progenitors, expanded from the marrow of p50-/- mice, and find efficacy against several syngeneic murine cancers, including glioblastoma, prostate cancer, and pancreatic cancer (Suresh et al, 2018). We utilize immature cells with both monocyte/macrophage and dendritic cell potential, as mature cells do not reach tumors efficiently.  We provide 5-FU prior to cell infusions, to reduce marrow production of myeloid cells that might compete with the adoptively transferred cells.  Current efforts include optimizing the cytokines used to generate p50-IMC (e.g. M-CSF versus GM-CSF/FL to favor monocyte vs dendritic cell formation), optimizing the chemotherapy given prior to p50-IMC (e.g. providing Cytoxan instead of 5-FU to also target Tregs), and evaluation of synergy between p50-IMC and checkpoint inhibitors (e.g. anti-PD-1) or epigenetic modifiers (e.g. azacytidine, HDAC inhibitors).

    The new post-doctoral fellow will focus on gene editing of the p50 gene in murine and human myeloid progenitors, using either lentiviral transduction or non-viral methods such as Cas9 protein:sgRNA complex nucleofection, followed by assessment of activity against syngeneic murine tumors or human tumor xenografts in immune-deficient mice. Developing an effective means to inactivate the p50 alleles via gene editing (or alternatively to knockdown p50 mRNA) is an essential step towards clinical translation of this novel myeloid immunotherapy, which we anticipate will be effective against a broad range of solid tumors.  This position is fully funded by a new grant just received by Dr. Friedman. 

    Alan D. Friedman has spent the last 30 years investigating the transcriptional regulation of normal myeloid cell development, myeloid transformation, and myeloid tumor immunology.  He is a past Searle Scholar and Leukemia and Lymphoma Society Scholar and a recipient of multiple NIH and non-governmental grants.  He has mentored more than 30 post-doctoral fellows and graduate students. His laboratory currently consists of a Research Associate and two Post-doctoral Fellows. Dr. Friedman continues to work extensively at the bench and fosters a supportive and collaborative laboratory environment.     

Barberi T, Martin A, Suresh R, Barakat DJ, Harris-Bookman S, Drake CG, Lim M, Friedman AD. Absence of host NF-kB induces murine glioblastoma tumor regression, increases survival, and decreases T cell induction of tumor-associated macrophage M2 polarization. Cancer Immunol. Immunoth., 2018; 67:1491-1503.

Suresh R, Barberi T, Barakat DJ, Pienta KJ, Friedman AD. NF-κB p50 deficient immature myeloid cell (p50-IMC) adoptive cell transfer activates the tumor microenvironment to slow tumor growth. Abstract accepted for presentation at the 2018 meeting of the Society for Immunotherapy of Cancer, November, 2018.

A Ph.D. with strong molecular biology expertise is desired.  Please send CV and names and contact information (phone, emails) for three references to Alan D. Friedman, afriedm2@jhmi.edu

Johns Hopkins University is an equal opportunity employer and does not discriminate on the basis of race, color, gender, religion, age, sexual orientation, national or ethnic origin, disability, marital status, veteran status, or any other occupationally irrelevant criteria.

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