Details

Autor(en) / Beteiligte

• Kamp, William M.
• Park, Hong-Jai
• Slovak, Ryan J.
• Ludwig, Johannes M.
• Kang, Insoo
• Kim, Hyun S.

Titel

Quantification of immune response after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer

Ist Teil von

• Journal of clinical oncology, 2020-02, Vol.38 (4_suppl), p.160-160

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract only 160 Background: Checkpoint inhibitors have demonstrated significant clinical impact in colorectal cancer with deficient mismatch repair (MMR) and high microsatellite instability. However, most patients have disease with stable microsatellites and typically respond poorly to most immunotherapies. The purpose of this study was to quantify the immune responses induced by mono versus dual immune checkpoint blockade (DICB) in a MMR proficient model of colorectal cancer. Methods: A MMR proficient model of colorectal cancer was established in 30 BALB/c mice via bilateral subcutaneous flank injections of 0.5x10 6 CT26.WT murine colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Mice were assigned to receive either sham antibodies (InVivoMAb IgG controls), monotherapy with anti-PD-1 antibodies (Clone J43; BioXcell, West Lebanon, NH, USA), or DICB with anti-PD-1 and anti-CTLA-1 antibodies (Clone 9D9; BioXcell). Tumor growth was monitored over time and mice were sacrificed at either 7 or 14 days post-treatment. Single cell suspensions of harvested tumors and spleens were analyzed using FACS. The number of CD8 + and CD4 + T cells as well as the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3 was quantified in each sample. Results: DICB was associated with a reduction in tumor volume as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor DICB significantly affected tumor infiltration by lymphocytes. Tumor infiltrating CD8 + T cells in the DICB treatment group demonstrated less expression of PD-1 and LAG3 compared to the control and monotherapy groups (PD-1: 1723±90.5 [Mean fluorescence intensity ± SEM] vs 2489±119.9 & 2404±117.9; p < 0.05) (LAG3: 453.8±21.58 vs 664.1±53.21 & 719.7±14.25; p < 0.05). The DICB group also showed increased expression of TIM3 (11,779±1271 vs 2832±380.9 & 4081±426.6; p < 0.05). Conclusions: These results suggest dual therapy with anti-CTLA and anti-PD-1 antibodies inhibits the growth of stable microsatellite colorectal cancer by suppressing key immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism that could be a target for future combination immunotherapies.