Abstract 1752: Transient exposure of trilaciclib, a CDK4/6 inhibitor, modulates gene expression in tumor immune infiltrates to promote a pro-inflammatory tumor microenvironment
Authors: Lai Anne Y. , Sorrentino Jessica A. , Strum Jay C. , Roberts Patrick J. 
Published: August 2018

Abstract
While immune checkpoint inhibitors (ICIs) are efficacious and lead to durable responses in patients with various cancers, only a minority of patients respond. An approach to increase the response rate of ICIs is to combine them with chemotherapy to induce immunogenic cell death, leading to an enhanced antitumor response. However, chemotherapy can cause damage to cell types of the immune system, potentially diminishing the activity of the chemotherapy/ICI combination. Therefore, a targeted approach to preserve immune system function during chemotherapy could allow optimal efficacy of chemotherapy alone and chemotherapy/ICI combinations. Trilaciclib, a short-acting intravenous CDK4/6 inhibitor, preserves hematopoietic stem and progenitor cells and enhances immune system function during chemotherapy. While combining chemotherapeutic agents such as oxaliplatin or 5-FU with an ICI against PD-1 or PD-L1 delayed tumor growth in MC38 and CT26 mouse tumor models, the addition of intermittent dosing of trilaciclib to chemotherapy/ICI regimens led to further tumor regression and significantly enhanced the durability of response to chemotherapy/ICI. These preclinical results support the hypothesis that intermittent dosing of trilaciclib with chemotherapy/ICI can preserve and/or enhance an antitumor response. To gain insight into the effect of transient exposure of trilaciclib on the tumor microenvironment, we examined the proliferation status, cellular composition, and gene expression of tumor immune infiltrates from MC38 tumor-bearing mice post-treatment. All major intratumor immune cell types (T, NK, and MDSC subsets) are highly proliferative and sensitive to CDK4/6 inhibition. Cell proliferation was reduced by more than 75% after trilaciclib exposure, but was fully restored 48 hours post-treatment. While this brief proliferation arrest did not affect the frequency of each immune population, the overall expression of 59 genes functionally enriched for lymphocyte activation and upregulation of the pro-inflammatory cytokine interferon-γ was significantly enhanced. In parallel, several genes involved in immunosuppressive reactive oxygen species metabolic processes were downregulated. These findings suggest that transient cell-cycle arrest in tumor immune infiltrates can lead to modulation of gene expression, resulting in a pro-inflammatory tumor microenvironment that is favorable for increasing ICI activity. Additional roles of trilaciclib in preserving and enhancing antitumor response in combination with chemotherapy/ICIs are currently being investigated. A phase 2 study to assess the safety and efficacy of trilaciclib or placebo with carboplatin, etoposide, and atezolizumab in first-line extensive stage SCLC patients is ongoing (NCT03041311).
Citation Format: Anne Y. Lai, Jessica A. Sorrentino, Jay C. Strum, Patrick J. Roberts. Transient exposure of trilaciclib, a CDK4/6 inhibitor, modulates gene expression in tumor immune infiltrates to promote a pro-inflammatory tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1752.