While immune checkpoint inhibitors (ICI) are efficacious and lead to durable responses in patients with various cancers, only a minority of patients respond. An approach to increase the efficacy of ICI 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 ICI combination. Using trilaciclib, a short-acting IV CDK4/6 inhibitor that preserves hematopoietic stem cells and enhances immune system function during chemotherapy, we have developed a novel approach to preserve immune system function during chemotherapy to allow optimal activity of ICI.
To evaluate the efficacy of trilaciclib added to chemotherapy/ICI combinations, tumor-bearing immunocompetent mice (MC38 or CT26) were treated with trilaciclib, chemotherapy (oxaliplatin or 5-FU), or ICIs (anti-PD-L1 or anti-PD-1) alone or in combination, and tumor size was measured for up to 100 days. To gain insight into the effect of transient exposure of trilaciclib on the tumor microenvironment, we are examining the cellular composition, proliferation status and gene expression of tumor immune infiltrates from MC38 tumor-bearing mice post-treatment.
The addition of trilaciclib to chemotherapy/ICI significantly improved anti-tumor activity and prolonged overall survival. Potential mechanisms by which transient trilaciclib exposure enhances anti-tumor activity include: reduction of Treg populations, preservation of T lymphocyte function, and changes in gene expression leading to enhanced lymphocyte activation and a pro-inflammatory tumor microenvironment.
These findings suggest that transient trilaciclib-induced G1 cell-cycle arrest in tumor immune infiltrates prior to chemotherapy/ICI combination treatment creates a favorable tumor microenvironment resulting in increased antitumor activity. Based on these findings, 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).
G1 Therapeutics
G1 Therapeutics
P.J. Roberts, A.Y. Lai, J.A. Sorrentino, R.K. Malik: All authors are employees of G1 Therapeutics.