In breast cancer, the relevance of the host immune response to the tumor has long been debated. Unlike melanoma and renal cell carcinoma, breast cancer was thought to be nonimmunogenic. However, a robust body of literature now suggests that breast cancer, particularly the more aggressive subtypes of HER2-positive and triple-negative breast cancer (TNBC), does elicit host antitumor immune responses, and that the robustness of the response correlates with prognosis. Therefore, there is great interest in exploring the potential role of immunotherapy in treating patients with breast cancer.
An argument could be made that the field of breast cancer already has a successful immunotherapeutic agent. Trastuzumab, a monoclonal antibody targeting the extracellular portion of the HER2 protein, is utilized in the treatment of patients with HER2-positive breast cancer. While the benefit of trastuzumab has previously been attributed to its ability to inhibit HER2-mediated signaling, there is an increased appreciation of the agent's immune-mediated mechanisms of action. Trastuzumab is a humanized IgG antibody with a conserved Fc portion, and data show a role for antibody-dependent, cell-mediated cytotoxicity mediated by natural killer cells. In addition, small studies have demonstrated that patients administered trastuzumab generate HER2-specific CD4+ T-cell and endogenous anti-HER2 antibody responses.
The PRESENT (Prevention of Recurrence in Early Stage Node Positive Breast Cancers with Low to Intermediate HER2 Expression with NeuVax™ Treatment) trial is evaluating nelipepimut-S, a human leukocyte antigen (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein. This phase III registration trial follows phase I/II clinical studies evaluating nelipepimut-S combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) as a simple vaccine administered in the adjuvant setting to prevent disease recurrence in patients with high-risk breast cancer.
Multiple other vaccine strategies are being investigated in patients with breast cancer, including several ongoing or recently completed phase II studies. Examples of these include additional HER2-derived peptide vaccines; an allogeneic GM-CSF– secreting vaccine; a HER2 peptide-pulsed, dendritic cell vaccine; and PANVAC, which incorporates vaccinia and fowlpox viruses genetically engineered to express the tumor-associated antigens carcinoembryonic antigen and MUC-1. All of these vaccine strategies have shown potential clinical benefit in specific disease settings in which they are being further investigated.
Data from 2 trials of antibodies targeting the T-cell inhibitory molecule PD-1 or its ligand, programmed cell death receptor 1 ligand (PD-L1), were reported at the 2014 SABCS meeting. One was KEYNOTE-012, a phase Ib study of the anti-PD-1 antibody pembrolizumab in patients with metastatic TNBC with tumors expressing any degree of PD-L1 positivity measured by IHC performed using a proprietary anti-PD-L1 antibody. The second trial was a phase Ia study of the anti-PD-L1 antibody atezolizumab in patients with PD-L1–positive TNBC.
Another avenue of immunotherapy for breast cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system's anti-cancer response. Several trials of adoptive T cell transfer techniques are currently under way for patients with breast cancer, including:
A phase II study of anti-HER2 bi-armed activated T cells after second line chemotherapy in women with HER2-negative metastatic breast cancer (NCT01022138).
A phase I trial of chimeric antigen receptor (CAR) T cells targeting cMet—which is abnormally activated in cancer and correlates with poor prognosis—is being tested in metastatic breast cancer refractory to at least one standard therapy or newly diagnosed patients with operable triple negative breast cancer (NCT01837602).
A phase I trial of T cells that are genetically engineered to target carcinoembryonic antigen (CEA), which is prominently expressed on breast cancer and other tumors, in metastatic breast cancer (NCT00673829).
In recent years, a lot of progresses of immunotherapy for breast cancer have been made. And many others are on the way.
Mittendorf E A et al. Breast Cancer Immunotherapy: Is It Ready for Prime Time?[J]. American Journal of Hematology/Oncology®, 2015, 11(9).
Ernst B et al. Immunotherapy for the treatment of breast cancer[J]. Current oncology reports, 2015, 17(2): 1-10.