Abstract 540: Adjuvant effect of anti-PD-L1 in boosting HER2-targeted T cell adoptive immunotherapy
Authors: Xia Yang , Hu Yangyang , Wang Yi , Bao Yangyi , Dai Fu , Huang Shiang , Hurt Elaine , Hollingsworth Robert E. , Thakur Archana , Lum Lawrence , Chang Alfred E. , Wicha Max S. , Li Qiao 
Published: July 2016

In a phase I clinical trial, we used anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) armed T cells. Utilizing HER2-directed T cells benefitted both HER2+ patients and patients with 1 or 2+ HER2 expression, ones that would be considered “HER2-negative” by classical criteria. We have also shown that the level of cancer stem cell (CSC) marker ALDH in HER2+ breast cancer cells (ALDHhighHER2+) is much higher than that in HER2- breast cancer cells (ALDHlowHER2-), and that in luminal breast cancers that are considered HER2-, HER2 is actually selectively expressed in the ALDHhigh CSC population. These observations might account for the surprising result that HER2Bi-armed T cells, while intended to target HER2, seemed to benefit HER2- patients after adoptive transfer. In this study, we found that the HER2Bi-armed T cells used in the clinical trial killed ALDHhigh human breast CSCs isolated from MCF7 (HER2-) tumor significantly more than ALDHlow MCF7 cells in vitro, while the same HER2Bi-armed T cells killed ALDHhigh human breast CSCs (ALDHhighHER2+) isolated from BT474 (HER2+) tumor equally to ALDHlow BT474 cells (ALDHlowHER2+). We then tested the “mouse HER2” (neu) expression on ALDHhigh vs. ALDHlow 4T1 cells (mouse TNBC), and found that mHER2 was selectively expressed in the ALDHhigh 4T1 CSC population. These results replicated our findings in human breast cancers that HER2 is selectively expressed on CSCs, even in HER2- murine tumors, such as 4T1. For mHER2 targeting in animal models, we generated anti-mouse HER2-CD3 bispecific (mHER2Bi) that binds to mouse HER2 and mouse CD3. In vitro, the mHER2Bi-armed T cells killed ALDHhigh 4T1 CSCs significantly more than ALDHlow 4T1 cells. In vivo, adoptive transfer of mHER2Bi-armed T cells for HER2 targeted therapy showed antitumor effect in mHER2- 4T1-bearing host. To boost the therapeutic efficacy of mHER2-targeted T cells, we administrated anti-mouse PD-L1 during mHER2Bi-armed T cell adoptive transfer. This combination decreased metastases significantly more than the use of either strategy alone. Collectively, these studies have generated evidence providing proofs of principle that due to the selective expression of HER2 on CSCs, HER2-targeted T cell therapy could benefit HER2- host as well as HER2+ hosts via immune destruction of HER2+ CSCs, and use of anti-PD-L1 as an adjuvant could significantly boost the efficacy of HER2-targeted T cell therapy.

Citation Format: Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Archana Thakur, Lawrence Lum, Alfred E. Chang, Max S. Wicha, Qiao Li. Adjuvant effect of anti-PD-L1 in boosting HER2-targeted T cell adoptive immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 540.