Targeting vasculogenesis to prevent progression in multiple myeloma.

The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.

Phase 2 trial of intravenously administered plerixafor for stem cell mobilization in patients with multiple myeloma following lenalidomide-based initial therapy.

Initial therapy of multiple myeloma with lenalidomide-based regimens can compromise stem cell collection, which can be overcome with the addition of plerixafor. Plerixafor is typically given subcutaneously (SQ), with collection ∼11 h later for maximum yield. Intravenous administration may allow more rapid and predictable mobilization. This trial was designed to assess the efficacy and feasibility of IV plerixafor in patients receiving initial therapy with a lenalidomide-based regimen. Patients received G-CSF at 10 µg/kg/day for 4 days followed by IV plerixafor at 0.24 mg/kg/dose starting on day 5; plerixafor was administered early in the morning with apheresis 4-5 h later. Thirty-eight (97%) patients collected at least 3 × 10(6) CD34+ cells/kg within 2 days of apheresis. The median CD34+ cells/kg after 1 day of collection was 3.9 × 10(6) (range: 0.7-9.2) and after 2 days of collection was 6.99 × 10(6) (range: 1.1-16.5). There were no grade 3 or 4 non-hematological adverse events, and one patient experienced grade 4 thrombocytopenia. The most common adverse events were nausea, diarrhea and abdominal bloating. IV plerixafor is an effective strategy for mobilization with low failure rate and is well tolerated. It offers flexibility with a schedule of early-morning infusion followed by apheresis later in the day.

Expression of an antigen homologous to the human CO17-1A/GA733 colon cancer antigen in animal tissues.

The CO17-1A/GA733 antigen is associated with human carcinomas and some normal epithelial tissues. This antigen has shown promise as a target in approaches to passive and active immunotherapy of colorectal cancer. The relevance of animal models for studies of immunotherapy targeting this antigen in patients is dependent on the expression of the antigen on normal animal tissues. Immunohistoperoxidase staining with polyclonal rabbit antibodies to the human antigen revealed the human homologue on normal small intestine, colon and liver of mice, rats and non-human primates, whereas mouse monoclonal antibodies to the CO17-1A or GA733 epitopes on the human antigen did not detect the antigen. Polyclonal rabbit antibodies, elicited by the murine antigen homologue derived from recombinant baculovirus-infected insect cells, immunoprecipitated the antigen from mouse small intestine, colon, stomach, kidney and lung. The isolated recombinant murine protein bound polyclonal, but not monoclonal, antibodies to the human CO17-1A/GA733 antigen, and recombinant human antigen bound polyclonal antibodies elicited by the murine antigen homologue. Thus, the antigen homologue expressed by animal tissues is similar, but not identical, to the human antigen. These results have important implications for experimental active and passive immunotherapy targeting the CO17-1A/GA733 antigen.