Abstract 3216: Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4 checkpoint inhibitor treatment leads to different responses in syngeneic tumor models

Abstract

Checkpoint inhibitor treatment has already become a common therapy of various cancer types. Still there is a growing need for well-characterized preclinical mouse models, as clinical data indicate that patients only partially respond to this regiment. We examined the efficacy of anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapy on 4T1, B16.F10, Clone M-3, CT26wt, LL/2, MC38-CEA and RENCA syngeneic tumor models. The outcome demonstrates a large variation in the response to the immune checkpoint therapy among the analyzed tumor models. Poorly immunogenic models like the LL/2 tumor did not respond to any given therapy, whereas highly immunogenic tumor models like CT26wt or MC38-CEA tumors were inhibited by all tested immunotherapies. The CT26wt tumor model was further characterized in a re-challenge experiment. Growth retardation was observed in CT26wt-tumor bearing mice treated with anti-PD-L1 antibody. A fraction of mice responded with a complete regression of the tumor. These mice were repeatedly challenged subcutaneously with a high number of fresh CT26wt tumor cells. No re-growth of CT26 tumors was observed, whereas challenging with fresh 4T1 tumor cells resulted in a rapid 4T1 growth in these mice, demonstrating a specific immune protection against CT26wt tumors. In addition all syngeneic tumor models were analyzed for the distribution of immune cells such as Treg cells, M1/M2 macrophages and M/PMN-MDSCs in tumor tissue based on multi-color flow-cytometric analysis. These data may help to select a suitable model for testing new drug candidates and define a sensitive combination therapy to support the anti-tumor immune defense in addition to checkpoint inhibitor treatment. Citation Format: Peter Jantscheff, Cynthia Schaefer-Obodozie, Sandra Moor, Holger Weber. Anti-PD-1, Anti-PD-L1 and Anti-CTLA-4 checkpoint inhibitor treatment leads to different responses in syngeneic tumor models. [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 3216.

Mouse-Derived Isograft (MDI) In Vivo Tumor Models I. Spontaneous sMDI Models: Characterization and Cancer Therapeutic Approaches

“…In contrast to gemcitabine, JA-0009 was completely insensitive to immune checkpoint inhibitor intervention by PD-1 or CTLA-4 antibodies (Figure 6). Since several syngeneic standard models were also completely insensitive to immune checkpoint inhibitor intervention (Doc.S2, Figure S2) [82], we compared the JA-0009 flow cytometry data with the respective results from our syngeneic standard tumor models (colon carcinoma MC38-CEA, colon carcinoma CT26.WT, lung carcinoma LL-2, melanoma Clone M3, breast carcinoma 4T1, renal carcinoma RENCA, and melanoma B16.F10) to determine possible similarities. As expected, anti-immune checkpoint inhibitor treatment of sensitive syngeneic tumors (Doc.…”

“…Histologically, the JA-0009 tumor showed a different situation with few infiltrates of small lymphocytes and neutrophils, with more neutrophils than small lymphocytes in carcinomatous tissue (Doc.S1 sMDI–page 34 ff). Flow cytometric analyses confirmed the weak infiltration with CD8 + or CD4 + T cells, but showed a massive invasion of M2 macrophages into the JA-0009 tumor (>70% of tumor infiltrating leukocytes) (Figure 5B) [5,82]. Since M2 macrophages can act as anti-inflammatories due to the production of immunosuppressive factors such as IL-10, transforming growth factor β (TGFβ), or prostaglandin E2 (PGE2), and the recruitment of immunosuppressive regulatory T cells [83], immune checkpoint inhibitor treatment only moderately affected the tumor growth of JA-0009.…”

Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors

“…MC38 wt (PD-L1 high ) and CT26 wt (PD-L1 low ) carcinomas are responsive to anti-PD-L1 mAb therapy, whereas B16-F10 wt (PD-L1 high ) and 4T1 wt (PD-L1 low )carcinomas show low-/nonresponsive behavior (Fig. S4A) [29], suggesting that the anti-PD-L1 mAb therapy response is independent of basal PD-L1 expression on cancer cells.…”