Angiogenesis Inhibitor TNP-470 During Bone Marrow Transplant and in Minimal Residual Disease

High-dose therapy with stem cell rescue is a treatment option for patients with advanced solid tumors. Although this approach has promise for some pediatric cancers, especially neuroblastoma, it is limited by the risk of relapse post transplant, as well as concern about possible reinfused tumor cells in autologous stem cell products. Anti-angiogenic agents given during and after recovery from highdose therapy with stem cell rescue may decrease the risk of relapse. Additionally, such agents may have their greatest therapeutic effect when administered at a point of minimal residual disease, rather than to treat bulky tumor. TNP-470 is an anti-angiogenic agent now in clinical trials. We have tested TNP-470 in the treatment of neuroblastoma in a mouse xenograft model, and demonstrate that it is most effective when given at lowest disease burden. Additionally, and to assess the feasibility of using anti-angiogenic agents during the period of posttransplant hematopoietic recovery, we have developed a model of stem cell transplant in mice. Mice were treated with TNP-470 and assessed for survival and engraftment. Both treated and control mice demonstrated reliable multilineage engraftment as well as normal lymphoid maturation with no excess mortality in the treated group. This indicates that inhibitors of angiogenesis do not adversely impact engraftment after stem cell transplantation and suggests a clinical study design in which such agents might best be employed in the immediate after stem cell transplant.