VEGF-Trap (V-T) overcomes defects in dendritic cell (DC) differentiation without improvement in antigen-specific immune responses

Abstract

21087 Background: Induction of antitumor immune responses requires adequate DC function. Well-documented DC defects in cancer mediated through tumor-derived vascular endothelial growth factor (VEGF) may lead to tumor escape and limit efficacy of cancer vaccines. V-T with extracellular domains of VEGFR 1/ 2 coupled to Fc IgG1 binds all VEGF-A isoforms. Methods: To determine if inhibition of VEGF signaling improves immune responses, we evaluated 15 cancer pts treated with V-T (2.0–7.0 mg/kg) IV over 1 hr Q 2 wks on a phase I trial. To evaluate immune parameters, PBMC were collected prior to, days 15, 29, and 57 of V-T treatment. Ligand blockade was achieved in all patients. Mature DCs (myeloid and plasmacytoid subsets), and regulatory T cells (T regs) were characterized by expression pattern of CD11c, CD86, CD40, CCR7, CD83, CD123, CD4, CD25, and GITR. T cell function was assessed by allogeneic mixed leukocyte reaction (MLR) and proliferation to tetanus toxoid, influenza, or PHA. Results: V-T treatment did not affect the presence of the total population of DCs, myeloid or plasmacytoid subsets, or myeloid-derived suppressor cells (MDSC). It significantly increased the proportion of mature DCs expressing CD86, CD40, CD83, and CCR7R (p<0.05) without overall improvement in T cell immunity. At 8 wks, 11 pts had either stable disease (SD) or partial response (PR) to the therapy and 4 pts had progressive disease (PD), both with no significant differences in the proportion of MDSC or total DCs. The proportion of mature DCs was significantly increased in pts with SD and PR (p<0.025), but remained unchanged in PD pts. However, functional tests were similar in both groups. Another subset analysis revealed significant improvement in immune responses in 6 pts who had stable or decrease in the MDSC proportion, but not in 9 pts with increases in MDSC. During V-T treatment, Tregs further increased above baseline in pts (p=0.048). Conclusions: These data demonstrate that inhibition of VEGF signaling improves differentiation of DCs in cancer patients, while alone it was not sufficient to improve immune responses. These data illustrates the multifaceted nature of immune deficiency in cancer pts and points to a need for complex approaches to modulation of immune reactivity. No significant financial relationships to disclose.