8P - Modulating tumor microenvironment using a VEGF active immunotherapeutic approach in gastrointestinal tumors: Beyond angiogenesis modulation

Background

Targeting of the vascular endothelial growth factor (VEGF) is known for going beyond mere modification of angiogenesis, and extends to the systemic and intratumoral regulation of immune cells activation state. In this study, we aim to explore the effect of a VEGF active immunotherapy based on a recombinant antigen named CIGB-247, in the systemic and tumor compartments in preclinical settings for mice, and in a subset of 22 patients with advanced gastrointestinal cancer (GIC) from phase I clinical trials (RPCEC00000102 and RPCEC00000155).

Methods

BALB/c mice were immunized with CIGB-247, and challenged with CT26 colon carcinoma cells subcutaneously. A week after the last immunization mice were euthanized and the tumor and the systemic compartment, were analyzed by ELISA, flow cytometry, and RT-QPCR assays. GIC patients’ serum and leukocyte samples were evaluated for cytokines, specific VEGF antibody titers, and VEGFR2 neutralization using ELISA, while the cellular response was assessed by ELISPOT.

Results

The vaccine significantly boosted the infiltration of activated CD3+ cells and caused a decrease in the number of MDSCs and Tregs in analyzed compartments. The levels of VEGF, PLGF, and CXCL1 were significantly reduced in the tumor lysates, while the concentration of CD8 activation-related molecules like IFN-γ, and GRZ-B were induced. Finally, we analyzed GIC cases within the two phase I clinical trials after stratification between responders and non-responders. The evaluations indicate a significant increase in the VEGF-specific humoral and cellular response parallel to a reduction in VEGF that relates significantly to increased survival. Within this small cohort, reduction or stabilization of other proangiogenic factors was also detected.

Conclusions

CIGB-247 antigen-based vaccine increased tumor-infiltrating lymphocytes and reversed the immunosuppressive effect of the tumor microenvironment in the CT26 mouse model. Such results were corroborated in a GIC patient cohort indicating that the strategy might be a successful treatment option for such patients by modifying systemic and tumor microenvironment beyond angiogenesis modulation.

Clinical trial identification

RPCEC00000102, RPCEC00000155.

Editorial acknowledgement

Legal entity responsible for the study

Center for Genetic Engineering and Biotechnology.

Funding

HEBERBiotec.

Disclosure

All authors have declared no conflicts of interest.