During allogeneic hematopoietic cell transplantation allo HCT donor T

During allogeneic hematopoietic cell transplantation (allo-HCT), donor T cells mediate beneficial graft-vs.-tumor (GVT) effects. However, donor T cells also attack host normal tissues, resulting in graft-vs.-host disease (GVHD). Intriguingly, antitumor responses and sustained remissions of advanced chemo-refractory hematologic malignancies were also seen in patients who rejected donor grafts after nonmyeloablative allo-HCT (Dey et al., 2005). Mouse studies further demonstrated that administration of RLI to mixed allogeneic chimeras results in loss of donor hematopoietic chimerism and anti-host leukemia responses (Rubio et al., 2003). Although RLI mediates significantly weaker anti-leukemia response than DLI (Saito et al., 2006), RLI does not induce GVHD, presenting a safe approach for patients with a high risk of GVHD. Our data show that the antitumor response of RLI can be significantly potentiated in lymphopenic recipients, indicating that RLI may be a potential treatment option for leukemia patients with lymphopenia, an independent risk factor for GVHD following allo-HCT (Li et al., 2012).

Conflicts of Interest

Author Contributions

The authors thank Dr. John E. Dick for providing MLL-AF9 vector, Dr. David Neville for providing anti-human CD3-immunotoxin, Dr. Kang Liu for critical review of the manuscript, and Siu-hong Ho for help with flow cytometry. This work was supported by grants from MOST of China (2015CB964400), NSFC (81273334) and NIH (P01AI045897 and R01AI064569). Flow cytometric analysis was partially performed in the CCTI Flow Cytometry Core funded in part through an NIH Shared Instrumentation Grant (1S10RR027050). The funders played no role in study design, data collection, data analysis and interpretation, or writing of the report.

Angiogenesis is a key process in cancer providing oxygen and nutrients to the growing tumor mass. Key player is the vascular endothelial growth factor [VEGF], targeted by antimalaria medication or small molecule kinase inhibitors. First such agent was bevacizumab [Avastin], monoclonal antibody against VEGF. Clear activity in clinical trials has led to implementation of such therapies as standard of care. However, effects are usually on progression–free rather than overall survival, and often measured in weeks (Carmeliet and Jain, 2000). Whilst benefit has been shown in some cancers, in breast cancer there has been controversy on the role of antiangiogenic therapy (Rossari et al., 2012). Early studies showed improvement of response in metastatic disease with Taxol (Jain, 2014), whilst neoadjuvant studies showed contrasting results (Jain, 2014; Bear et al., 2012; Earl et al., 2015; Sikov et al., 2015; von Minckwitz et al., 2012).
Lack of consensus between clinical trials has questioned the effectiveness of bevacizumab in breast cancer, and the drug is no longer in use in several countries. However, there is large evidence of heterogeneity of response. Therefore we undertook a study in the situation where bevacizumab was approved to understand mechanisms behind this heterogeneity, and clinical implications. Circulating levels of short VEGFA isoforms, neuropilin-1 and VEGF receptor 1 expression in tumours or plasma, and VEGFA genetic variants have been reported as potential biomarkers of bevacizumab response (Lambrechts et al., 2013; Hegde et al., 2013). Changes in DCE-MRI parameters with therapy have been shown, such as volume transfer constant (Ktrans), complex function of vessel permeability, surface area and tumor blood flow; however, how to use MRI to impact on drug therapy modulation is controversial (O\’Connor and Jayson, 2012); reflecting limited insight into molecular correlates. A small window study of 21 patients combining DCE-MRI monitoring with limited number of molecular markers, showed reduction of perfusion parameters with increase in tumor apoptosis (Wedam et al., 2006). However, studies to date have been hindered by either combination with chemotherapy, or focus on advance cancers where multiple resistance mechanisms are likely to have developed, or else limited pharmacodynamics assessments probing only some aspects of tumor response.