Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy.

Immunotherapy is an emerging paradigm for the treatment of cancer, but the potential efficacy of many drugs cannot be sufficiently tested in the mouse. We sought to develop a rational combination of motolimod-a novel Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses in humans but diminished responses in mice-with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. We followed an integrative pharmacologic approach including healthy human volunteers, non-human primates, NSG-HIS ("humanized immune system") mice reconstituted with human CD34 cells, and patients with cancer to test the effects of motolimod and to assess the combination of motolimod with PLD for the treatment of ovarian cancer.

Umbilical cord blood xenografts in immunodeficient mice reveal that T cells enhance hematopoietic engraftment beyond overcoming immune barriers by stimulating stem cell differentiation.

Clinical experience and animal models have shown that donor T cell depletion (TCD) adversely affects engraftment of hematopoietic stem cells (HSCs). Although it is known that donor T cells are acting to overcome residual host immune barriers, they may also exert effects independent of host resistance via direct or indirect interactions with donor stem cells, their microenvironment, or key differentiation events. To more precisely define the effect of T cells on engraftment, we have performed human umbilical cord blood (UCB) transplantation into immunodeficient mice under limiting dilution conditions.

Immunosurveillance and survivin-specific T-cell immunity in children with high-risk neuroblastoma.

Purpose: Tumor immunosurveillance influences oncogenesis and tumor growth, but it remains controversial whether clinical failure of immunosurveillance is a result of lymphocyte dysfunction or tumor escape. In this study, our goal was to characterize the physiology of tumor immunosurveillance in children with high-risk neuroblastoma (HR-NBL).

Patients And Methods: Immunohistopathologic studies were carried out on 26 tumor samples from a cohort of HR-NBL patients diagnosed at Children's Hospital of Philadelphia for the 2-year period from May 2003 to May 2005.

Telomerase vaccination has no detectable effect on SCID-repopulating and colony-forming activities in the bone marrow of cancer patients.

Objectives: The telomerase reverse transcriptase hTERT is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes (CTL). We have previously shown that vaccination of cancer patients against hTERT induces functional anti-tumor CTL in vivo, but it is not known whether hTERT vaccination harms normal cells expressing the enzyme, especially hematopoietic stem cells and progenitors.

Patients And Methods: We employed colony-forming cell (CFC) assays, long-term in vitro cultures, and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulation studies to evaluate the effects of hTERT vaccination on hematopoietic progenitors and stem cells in cancer patients following treatment.

Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia.

Human hematopoietic stem cells (HSCs) are generally regarded as being devoid of the markers expressed by differentiated blood cells, the lineage-specific antigens. However, recent work suggests that genes associated with the myeloid lineage are transcribed in mouse HSCs. Here, we explore whether myeloid genes are actually translated in human HSCs.