472P - Prevention of metastasis formation by combination therapy targeting Her2 and PD-L1 in Her2-expressing tumors based on observed efficacious vaccination against Her2-positive tumors

Background

The overexpression of human epidermal growth factor receptor Her2 is associated with a more aggressive cancer phenotype. We have formulated a Her2 vaccine (HER-Vaxx), comprising B-cell peptide from the trastuzumab binding site, inducing anti-tumor immune responses and immunological memory in pre-clinical and clinical investigations. In the phase 1b evaluation (NCT02795988) of the vaccine, one patient had progressed with a new metastatic lesion with no Her2 expression. The vaccine’s pre-clinical evaluation was shown to significantly reduce Her2 lung metastases size in a murine model, and was associated with Her2 loss and upregulation of tumoral PD-L1 expression. In light of the preclinical observation, the patient’s primary tumor at the pre- and post-treatment time points was evaluated with regard to expression levels of Her2 and PD-L1.

Methods

Biopsies of the patient’s primary tumor from the pre- and post-treatment time points were evaluated by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for Her2, and combined positive score (CPS) for PD-L1 expression. The murine Her2 lung metastases model was employed to further investigate the proteins’ expression association.

Results

The assessment of the patient’s primary tumor biopsies indicated Her2 3+ (IHC), Her2 /CEP17 ratio of 4.98 (FISH) and 0% PD-L1 CPS at the pre-treatment time point. At the post-treatment time point, the primary tumor’s assessment showed a loss of Her2 expression: 0 (IHC) and Her2 /CEP17 ratio of 1.63 (FISH), with 5% PD-L1 (CPS) expression. In the mouse model, vaccination with HER-Vaxx resulted in a significant reduction of Her2 and upregulation of PD-L1 expression 6 weeks or longer after tumor cell implantation, at transcriptional and translational levels in the same tumors of the metastasized lungs of the vaccinated mice.

Conclusions

These results strongly suggest an immune evasive tumor cell response with an upregulation of PD-L1 expression in both, the clinical and preclinical settings. A combination therapy targeting both Her2 and PD-L1 in Her2-overexpressing tumors might efficiently prevent metastasis formation and immune evasion.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Medical University of Vienna; Imugene Limited.

Funding

Has not received any funding.

Disclosure

N. Ede: Financial Interests, Personal, Full or part-time Employment: Imugene Limited. C. Zielinski: Other, Personal, Other, Consultancies and Speaker’s Honoraria: Athenex, MSD, AstraZeneca, Servier, Eli Lilly; Other, Personal, Other, Patents: Imugene Limited; Other, Institutional, Other: BMS, MSD, Pfizer, AstraZeneca, Merck KgA, Servier, Eli Lilly, Takeda, Daiichi Sankyo, Roche, Boehringer Ingelheim, Celgene, Halozyme, Amgen. A. Good: Other, Personal, Other: Imugene Limited. U. Wiedermann: Other, Personal, Other, CSO of Imugene until September 2018: Imugene Limited; Other, Institutional, Other, Funding to the Institute: MSD, Pfizer, Themis. All other authors have declared no conflicts of interest.