Expert Examines Clues to Deploying Immunotherapy in Breast Cancer

Author(s):

Immunotherapy will be most effective as a treatment for breast cancer when it is used to alter the tumor microenvironment, according to a careful examination of studies exploring the immune response presented by Nora Disis, MD.

Mary "Nora" L. Disis, MD

Although breast cancer tumors are immunogenic, recent studies have discovered that this immunogenicity varies according to the molecular subtype, with most subtypes being dominated by a type II immune microenvironment that dampens the generation and proliferation of cytotoxic T cells (CTL) necessary for tumor eradication.

“Clinically effective antitumor activity involves type I adaptive immunity that is characterized by CD4 cytokine secretion and activation of CD8 cell lytic activity plus high densities of Th1 memory cells, but few regulatory T-cells,” explained Disis, professor of medicine and Associate Dean for Translational Science at the University of Washington.

“However, the majority of antigens expressed in most breast cancer subtypes are aberrantly expressed proteins that elicit a self-signal and trigger a type II immune response,” she continued. “In breast cancer, we see a Th2 response with minimal tumor-specific Th1 activity.”

Tumor infiltrating cells (TILs) are present in the tumor environment to varying degrees across all subtypes of breast cancer and are the harbinger of a favorable outcome, according to Disis.

“Triple negative breast cancer [TNBC] appears to be the breast cancer subtype most readily modulated by immune checkpoint inhibitors,” she commented, noting that anti—PD-L1 activity was demonstrated in the KEYNOTE-012 phase Ib trial of pembrolizumab in TNBC patients who were positive for PD-L1 with an overall response rate of 18.5%.¹

This response consisted mainly of stable disease which may represent immunologic equilibrium, wherein the immune response is controlling the tumor but not yet able to eradicate it, Disis explained.

“The clinical strategy here is to augment type 1 immunity by active immunization to expand CTLs or by treating with agents to suppress immune cells like T-regs that can limit the expansion of CTLs in order to maintain this immune response and to control or even to eradicate the tumor.”

To this end, atezolizumab, an anti—PD-L1 antibody, is being tested in combination with nab-paclitaxel in patients with TNBC in the phase III IMpassion 130 trial.²

In HER2 breast cancer, Disis said, “exploratory studies conducted in the adjuvant and neoadjuvant setting have shown an association between the level of peripheral, type 1, HER2-specific T-cells in the blood with favorable clinical outcomes. These data suggest that there may be an immune biomarker for clinical response in this breast cancer subtype.”

Disis also outlined how estrogen plays a fundamental role in the regulation of immune cell function by binding the estrogen receptor alpha expressed on T-regs to enhance the immunosuppressive function of these cells, and also to stimulate TGF-beta production, which acts to further suppress immunity: “Clinical approaches must generate and maintain type I immunity while simultaneously controlling these immunosuppressive elements.”

She suggested that alternate immune checkpoints for HR-postive tumors that trigger T-cell activation be explored, adding that some agents are already available, including BTK inhibitors, such as ibrutinib that inhibit inducible T-cell kinase, which, she said, is required for Th2 activation.

“I have a lot of hope for the use of immunotherapy in breast cancer, but as more of a platform for generating the Th1 immune response and an immunogenic tumor environment,” Disis concluded.

References

Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460-2467.
Emens LA, Adams S, Loi S, et al. IMpassion130: a phase III randomized trial of atezolizumab with nab-paclitaxel for first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016; 34(suppl; abstr TPS1104).
Ladoire E, Arnould L, Mignot G, et al. T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival. B J Cancer. 2011;105(3):366-371.

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The strategy in HER2 breast cancer is to increase densities of effector T-cells in the tumor microenvironment, she continued. Trastuzumab has recently been shown to induce the development of T-bet, the transcription factor that directs the Th1 lineage of cells and of TILs by 50%. The presence of high TIL density in the tumor microenvironment following trastuzumab was demonstrated to be an independent predictor of improved relapse-free survival.³