55P - Immune checkpoint vaccines and radiation combination strategy (55P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Cancer Immunology and Immunotherapy
Head and Neck Cancers
Presenter Keng-Hsueh Lan
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors K. Lan1, S. Kuo1, A. Cheng1, K. Lan2
  • 1Department Of Oncology, National Taiwan University Hospital, 100 - Taipei/TW
  • 2Department Of Oncology, Taipei Veterans General Hospital, 11217 - Taipei/TW

Abstract

Background

We intend to develop DNA- and protein-based vaccines targeting immune checkpoints in order to augment the anti-tumor immune responses of radiation therapy.

Methods

Murine CTLA-4 and PD-L1 DNA sequences were PCR amplified from a mouse cDNA library. The PCR products were fused with a transmembrane domain of placental alkaline phosphatase into an expression plasmid, pVAC-1, forming CTLA-4-PD-L1 DNA vaccine (DNA vaccine). CTLA-4 and PD-L1 fusion protein vaccine (protein vaccine) was acquired using E. coli expression system. Mouse tumor models were established by inoculating CT26 colorectal cells on Balb/c mice, and LLC Lewis lung cancer cells on c57BL/6 mice, respectively (on day 0). The mice of each tumor model were divided into 3 groups, each with 5 mice. Group 1 was treated with radiation therapy (RT) alone, group 2 with RT plus DNA vaccine (coupled with liposome), and group 3 with RT plus protein vaccine. Vaccination was done via subcutaneous injections on day 1, 8 and 15. RT was given on day 14 and 21 with 10 Gy each. Sera from the mice was subjected to ELISA assay for the titers of antibodies against CTLA-4 and PD-L1. The sizes of tumors were recorded. After the mice were sacrificed, the tumor samples were subjected to IHC staining for immune profiles, and the splenocytes to cytotoxicity and ELISpot assays.

Results

In the CT26 model, combination treatment with either RT plus DNA vaccine or RT plus protein vaccine (group 2 or 3, respectively) showed better tumor suppression than RT alone (group 1). This superior tumor control in combination treatment groups paralleled the enhanced cytotoxicity of their splenocytes when co-cultured with CT26 cells. Also, the splenocytes from the combination treatment groups showed activated T cell responses as indicated by increased interferon-γ production. The immunohistochemistry staining demonstrated less PD-L1-positive cells in the tumor samples from the combination groups. In the LLC model, however, only the treatment with RT plus CTLA4-PDL1 DNA vaccine showed better tumor suppression than with RT alone.

Conclusions

We have developed potent DNA and protein vaccines targeting CTLA-4 and PD1 immune checkpoints, enhancing the tumor control effects of radiation in the colorectal and lung cancer animal models. This combination treatment strategy show the potential to enhance tumor-specific immune responses and hence could confer systemic anti-tumor ability on radiation therapy, namely, abscopal effect.

Clinical trial identification

Legal entity responsible for the study

Keng-Hsueh Lan

Funding

Ministry of Science and Technology, R.O.C.

Disclosure

All authors have declared no conflicts of interest.