Abstract 5628: Trilaciclib (G1T28), a CDK4/6 inhibitor, enhances the efficacy of combination chemotherapy and immune checkpoint inhibitor treatment in preclinical models
Authors: Jessica A. Sorrentino, Anne Y. Lai, Jay C. Strum, Patrick J. Roberts
Journal: Cancer Research (2017)

Abstract While immune checkpoint inhibitors 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 immune checkpoint inhibitors is to combine them with chemotherapy in order to enhance immunogenic cell death and “prime” the immune system. However, chemotherapy itself can cause damage to various cell types of the immune system, potentially diminishing the activity of the chemotherapy/checkpoint inhibitor combination. Therefore, a targeted approach to preserve immune system function during chemotherapy would allow optimal activity of the checkpoint inhibitor therapy. Trilaciclib (G1T28), a potent and selective IV CDK4/6 inhibitor, preserves hematopoietic stem cells and enhances immune system function during chemotherapy. We and others have previously shown T lymphocytes are extremely sensitive to CDK4/6 inhibition causing a transient arrest of proliferation and protection from damage by chemotherapy. Post treatment with trilaciclib and chemotherapy, T lymphocytes are released from the transient arrest in the presence of chemotherapy-induced immunogenic cell death allowing better priming of an anti-tumor immune response. To evaluate the effect of trilaciclib combination treatments, MC38 tumor bearing mice were treated with trilaciclib, oxaliplatin, or anti-PD-L1 alone or in combination, and tumor size was measured during and post treatment for 100 days. Our results demonstrate that the addition of trilaciclib to an oxaliplatin/anti-PD-L1 combination (TOP) treatment significantly improves anti-tumor activity. Specifically, twice as many mice treated with TOP for 15 days had a complete response (CRs) when compared to oxaliplatin/anti-PD-L1 (OP); 6/10 CRs vs 3/10 CRs, respectively. In addition, the CRs were durable and without any evidence of recurrence at 100 days. Furthermore, TOP treatment caused a 60% increase in overall survival (OS) compared to mice treated with OP; median OS for TOP was 98 days compared to 61 days (HR, 0.53) for the OP treatment group. Assessment of ex-vivo stimulation of cytokine release from harvested splenocytes to measure T-cell activation, and evaluation of immune infiltrates and T-cell receptor repertoire within the tumors are ongoing. Taken together, we demonstrate that the short-acting IV CDK4/6 inhibitor, trilaciclib, which has been shown to preserve immune function during chemotherapy, enhances the anti-tumor activity of chemotherapy/anti-PD-L1 combination therapy. Citation Format: Jessica A. Sorrentino, Anne Y. Lai, Jay C. Strum, Patrick J. Roberts. Trilaciclib (G1T28), a CDK4/6 inhibitor, enhances the efficacy of combination chemotherapy and immune checkpoint inhibitor treatment in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5628. doi:10.1158/1538-7445.AM2017-5628