Background
In recent years, immunotherapy has led to significantly improved survival rates in various cancer entities. In particular, T cell-based immunotherapy, including bispecific antibodies (BsAB) like bispecific T cell engager (BiTE) and CART have revolutionized the treatment landscape of hematological malignancies. Currently a number of clinical trials are applying BsAB/CART also in the solid cancer setting. In gastric cancer, Mucin 17 was identified as a suitable target antigen with a high expression level. A novel bispecific antibody directed against Mucin 17 was developed and is currently being tested in an early first in human clinical trial (AMG 199). As current treatment concepts are being applied in advanced disease with either concomitant or prior polychemotherapy treatments, the question of the optimal timing of AMG 199 needs to be defined. We therefore investigated, if prior polychemotherapy treatment impact T cell contexture and function and thereby impact AMG 199 mediated cytotoxicity against gastric cancer.
Materials and Methods
We longitudinally analyzed T cell function of gastric cancer patients during the course of polychemotherapy. This was done by assessing i) the expression profile of T cell subsets at different time points post chemotherapy by MPFC, ii) T cell function by testing BiTE mediated cytotoxicity against GC cell lines, iii) isolating tumor infiltrating lymphocytes (TILs) from gastric cancer tissue and testing the expression profile of surface markers and the BiTE mediated cytotoxicity against GC cell lines.
Results
Polychemotherapy consisting of 5-FU, docetaxel and oxaliplatin led to an increase in CD8+ T cells and a shift towards memory T cells, whereas the proportion of Tregs was stable. Furthermore, we observed an increased expression of PD-1 and TIM-3 four weeks after the start of chemotherapy. Using our coculture system, AMG199 led to concentration- and E:T ratio-dependent T cell activation and specific lysis of GC cell lines. The cytotoxic capacity and proliferation rate of T cells did not alter throughout the course of polychemotherapy and was comparable to HD T cells. TILs isolated from GC tissue showed similar specific lysis of GC cell lines when compared to peripheral HD T cells, while the proliferation rate of TILs was slightly reduced. Furthermore, we observed an increased expression of the activation markers HLA-DR and CD25 and the checkpoint molecules TIM-3, LAG-3 and B7-H3 on TILs compared to HD T cells.
Conclusions
Taken together, our data support the hypothesis that the currently applied polychemotherapy concepts in GC have no negative impact on T cell phenotype and function. Hence, our data encourage the concept of sequencing bispecifics in a short time interval after completion of polychemotherapy. Further immunomonitoring is crucial for validating and advancing this combination approach.
T. Haase: None. A. Grosser: None. L. Rohrbacher: None. L. Weiss: None. K. Dorman: None. D. Zhang: None. C. Gießen-Jung: None. S. Boeck: None. V. Heinemann: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Amgen. M. Subklewe: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Amgen. A. Reischer: None.