Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Abstract

CDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. For example, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. We propose that such effects, both positive and negative, may be mitigated or exacerbated by altering the CDK4/6i dosing regimen. Here, we discuss what the most recent insights mean for clinical trial design, and propose clinical considerations and strategies that may exploit the full immunotherapeutic potential of CDK4/6 inhibitors.

CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors

“…Recent studies describe the restoration of the T cell function by CDK4/6 blockade. 15 , 18 , 37 , 38 , 43 By dissecting the local immune response in detail, we found significantly increased numbers of cytotoxic T cells and DCs within the TIL compartment, especially in Mlh1 −/− mice. Vice versa , numbers of TAMs decreased, accompanied by rising numbers of IRF5 + cells, reduced levels of the myeloid compartment as well as genes related to PI3K/Akt signaling.…”

Standardization of suspension and imaging mass cytometry readouts for clinical decision making

“…Upregulation of CDK6, a direct target of Cyclin D1, is one of the strongest tumor-intrinsic predictors of resistance to immunotherapy (30). The upregulation of CDK6 observed in this patient suggests that this pathway contributed to the lack of response to anti-PD-1.…”

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclinD‐CDK4/6 pathway alterations in the DutchDRUPand AustralianMoSTtrials

“…Within our combined analysis these outcomes could not be reproduced, with only 3 of 15 (20%) soft tissue sarcoma patients demonstrating SD at 16 weeks. While an indolent natural disease trajectory cannot explain the positive results of the TAPUR NSCLC 35 or HNSCC 36 cohorts based on a CBR of 31% and 37%, optimal sequencing of therapies (EGFR, or checkpoint inhibitors) in these cancers, synergizing with the cytostatic, or immune potentiating effects of CDK4/6 inhibition, may be considered 37 . This provides rationale for a combined therapy approach to induce tumor regression, and a MoST trial of palbociclib and avelumab (ACTRN12620000568910) is currently underway.…”