Posted October 13, 2017

Sandra McAllister, Ph.D., Brigham and Women's Hospital, Inc.

Clinical trials conducted by numerous researchers using the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib and palbociclib have shown promise in breast cancer patients. CDK4/6 are key cell cycle regulator proteins found to be fundamental drivers of breast tumor initiation and progression. Mechanistic analyses from these CDK4/6 trials suggest that CDK4/6 inhibitors promote cell cycle arrest in tumor cells. In studying the efficacy of CDK4/6 inhibitors in preventing malignant conversion in otherwise indolent tumors, Dr. Sandra McAllister and colleagues discovered a novel mechanism of action for these inhibitors - they induce antitumor immunity. With support from a Fiscal Year 2013 Breast Cancer Research Program Era of Hope Scholar Award, Dr. McAllister aimed to elucidate the novel mechanism by which CDK4/6 inhibitors can induce antitumor immunity.

Using a mouse model of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, Dr. McAllister and colleagues observed a 40% reduction in tumor volume in mice treated with abemaciclib. Tumor volume reduction was due to suppressed tumor cell proliferation in response to abemaciclib, as expected. Gene expression analysis of the resultant tumors showed that mice administered abemaciclib did indeed downregulate genes related to cell cycle and mitosis, while, unexpectedly, genes responsible for promoting antitumor immunity were found to be upregulated. These results were validated in three cell line models representative of triple negative, luminal A and luminal B subtypes of breast cancer, as well as a patient-derived xenograft (PDX) tumor model from a HER2+ treatment-refractory breast cancer patient. Delving deeper into the effects of abemaciclib on tumor immunity, Dr. McAllister examined levels of regulatory T cells (T_reg), immune cells that are known to suppress the activity and proliferation of the cytotoxic T-cells that kill tumor cells. Her team found significant reductions in intratumoral and circulating T_regs. Additionally, the ratio of T_regs to cytotoxic T-cells was found to be significantly decreased in the tumors treated with abemaciclib.

Collaborators
Left to right: Jean Zhao, Sandra McAllister, Molly DeCristo, Shom Goel

Lab Group
Back row L to R: Jessalyn Ubellacker, Molly DeCristo, Tyler Laszewski, Jessica Olive,
Melissa Petit, Zafira Casta�o
Front row L to R: Bennett King, Anna Molineaux, Sandra McAllister, Qiuchen Guo

Immunotherapy has proven to be very effective in recent years with the increased use of immune checkpoint inhibitors, which function by blocking proteins (i.e., PD-L1) that downregulate the immune system thus helping to restore the normal balance. To determine whether the antitumor T-cell response could be enhanced, Dr. McAllister treated mice with an anti-PD-L1 antibody in combination with abemaciclib. Tumors treated with abemaciclib in combination with the anti-PD-L1 antibody showed a 70% reduction in tumor volume. Remarkably, by day 35 the tumors treated with the combination therapy had not resumed growth whereas tumors of mice treated with abemaciclib alone resumed growth by day 21.

To demonstrate clinical translatability, Dr. McAllister obtained patient samples from the ongoing Washington University School of Medicine sponsored NeoPalAna trial. The NeoPalAna trial is a single arm phase II clinical trial assessing antiproliferative activity of neoadjuvant palbociclib in ER+ breast cancer patients. Genome-wide expression analyses revealed that patients who received palbociclib had a significant downregulation of genes related to cell cycle as well as an upregulation in genes related to antitumor immunity.

Dr. McAllister's research findings, published this year in Nature, show for the first time that abemaciclib and palbociclib not only modulate tumor cell cycle arrest, but they are also able to tip the immune balance to promote antitumor immune responses. Moreover, CDK4/6 inhibitors were also found to render tumors more responsive to immune checkpoint inhibitors. Thus, results from Dr. McAllister's Era of Hope Scholar Award provide a foundation for future preclinical and clinical studies that assess the combination of CDK4/6 inhibitors with immunotherapies.

CDK4/6 inhibitors shift the balance within breast cancer tissue in favor anti-cancer immunity

Publication:

Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim H-J, McAllister SS, and Zhao JJ. 2017. CDK4/6 inhibition triggers anti-tumor immunity. Nature 548(7668):471-475

Link:

Public and Technical Abstracts: New Diagnostic and Therapeutic Approaches to Eradicating Recurrent Breast Cancer

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