Identifying senescence and immune biomarkers predictive of benefit to combined CDK4 and checkpoint blockade inhibition in patients with dedifferentiated liposarcoma - Few viable treatments exist for patients with locally advanced or metastatic well-differentiated or dedifferentiated liposarcoma (WD/DDLS), which are rare and often neglected orphan cancers. There are approximately 1000 patients per year in the US diagnosed with WD/DDLS, and these cancers generally do not respond to chemotherapy. Recent trials of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, motivated by the finding that the CDK4 gene is amplified in >90% of WD/DDLS, show these agents stabilize disease that had been growing prior to treatment and demonstrated clinically meaningful median progression-free survival (PFS) of 66% at 12 weeks but responses were uncommon. To enhance response rates and improve PFS benefit, we propose to combine the CDK4/6 inhibitor palbociclib with an antibody against the immune checkpoint PD1. Checkpoint inhibitors have some activity in DDLS, leading to partial responses in about 8% of patients. CDK4/6 inhibitors have been shown to increase the efficacy of checkpoint inhibitors and to promote antitumor immunity in breast cancer patients and animal models. In responsive tumors, CDK4/6 inhibitors trigger senescence, causing cells to secrete proinflammatory cytokines and growth factors (termed the senescence-associated secretory phenotype, or SASP), suggesting that these agents may enhance antitumor immunity. To identify patients likely to benefit from this combination therapy, we will investigate mechanisms of response and resistance using pre- and on-treatment biopsy specimens from patients on the proposed phase 2 trial of palbociclib combined with the anti-PD1 antibody INCMGA0012. These studies will focus on the cellular markers previously determined to be required for CDK4/6 inhibitor-induced senescence in WD/DDLS (MDM2 turnover, cadherin 18 expression); markers of terminal senescence (Angplt4), antitumor immune responses; and gene expression. Thus, our Specific Aims are to: (1) Assess the safety and efficacy of CDK4 inhibition using palbociclib in combination with PD1 blockade using INCMGA0012 in 30 patients with WD/DDLS (outcomes: overall response rate, PFS, and overall survival); (2) Examine the roles of senescence, terminal senescence and resultant SASP in response to the combination therapy and, their relationship with immune response; and (3) Characterize the immune microenvironment (specifically CD8+ T cells and PDL1+ tumor cells) and tumor gene expression (assessed with immunohistochemistry and both bulk and single-cell RNA sequencing) prior to and during combined treatment of palbociclib and INCMGA0012, and examine their association with clinical response and outcome. Successful completion of this trial may lead to the introduction of a novel combination immunotherapy strategy for WD/DDLS and identify predictive biomarkers for selection of patients most likely to benefit in both sarcoma and other malignancies.
