Feasibility study of personalized peptide vaccination for metastatic recurrent triple-negative breast cancer patients

Abstract

IntroductionSince treatment modalities for metastatic recurrent triple-negative breast cancer (mrTNBC) are limited, a novel treatment approach including immunotherapy is required. We have developed a novel regimen of personalized peptide vaccination (PPV), in which vaccine antigens are individually selected from a pool of different peptide candidates based on the pre-existing host immunity. Herein we conducted a phase II study of PPV for metastatic recurrent breast cancer patients to investigate the feasibility of PPV for mrTNBC.MethodsSeventy-nine patients with metastatic recurrent breast cancer who had metastases and had failed standard chemotherapy and/or hormonal therapy were enrolled. They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher peptide-specific immunoglobulin G (IgG) responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for the four HLA-IA phenotypes (HLA-A2, -A24, or -A26 types, or HLA-A3 supertypes), and were subcutaneously administered weekly for 6 weeks and bi-weekly thereafter. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses along with other laboratory analyses were conducted before and after vaccination.ResultsNo severe adverse events associated with PPV were observed in any of the enrolled patients. Boosting of CTL and/or IgG responses was observed in most of the patients after vaccination, irrespective of the breast cancer subtypes. There were three complete response cases (1 mrTNBC and 2 luminal/HER2-negative types) and six partial response cases (1 mrTNBC and 5 luminal/HER2-negative types). The median progression-free survival time and median overall survival time of mrTNBC patients were 7.5 and 11.1 months, while those of luminal/HER2-negative patients were 12.2 and 26.5 months, and those of HER2-positive patients were 4.5 and 14.9 months, respectively.ConclusionsPPV could be feasible for mrTNBC patients because of the safety, immune responses, and possible clinical benefits.Clinical Trial Registration NumberUMIN000001844 (Registration Date: April 5, 2009)

Predictive factors of the tumor immunological microenvironment for long‐term follow‐up in early stage breast cancer

“…The research investigating clinical biomarkers related to immunologic factors or TILs involving EBC is still insufficient. Our previous studies showed that the expression of FOXP3 on lymphocytes or tumor cells of EBC was significantly associated with clinical outcome and tumor‐specific immune responses, as well as the observation that clinical benefits in patients with metastatic BC could be augmented by peptide vaccines derived from various tumor‐associated antigens . In this study, we described the tumor environmental interaction between the density of TILs or macrophages and various immunologic molecules, including PD‐L1, PD‐1, and PTEN, by the intrinsic biological subtypes in EBC.…”

“…Breast cancer is traditionally thought of as a kind of low immunogenic carcinoma, but the influence of local immunologic factors on clinical outcome of BC is still under evaluation. It has been indicated that FOXP3 expression on lymphocytes and tumor cells of EBC is significantly associated with clinical outcome and that the peptide vaccines of tumor‐associated antigens could induce and boost tumor‐specific immune response in patients with metastatic BC . Novel investigations have shown that immunologic factors, such as TILs, and immune relevant factors, including PD‐1, PD‐L1, and PTEN, are significantly associated with responses to treatment and clinical outcome .…”

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

“…Early trials in multiple different tumor types have shown a response rate of 9.9% and a disease control rate of 42.9% in a group of 500 patients with advanced cancer [70]. PPV has been evaluated in TNBC and was safe and potentially effective, with a median PFS of 7.5 months and median OS of 11.1 months in metastatic TNBC, with 1 complete response and 1 partial response noted in a cohort of 18 patients [71]. Additional small studies are ongoing in TNBC (NCT02427581).…”

The Clinical Significance of CD169-Positive Lymph Node Macrophage in Patients with Breast Cancer

“…Notably, the immune status of patients can influence its clinical course [3]. For instance, decreased infiltration of CD8 + cytotoxic T-lymphocytes (CTLs) in tumor has been associated with lymph node metastasis and poor response to neoadjuvant chemotherapy [4–6], while the activation of immune responses has been related to improved overall survival in patients with breast cancer [7]. Thus, an anti-cancer immune status is thought to be important for preventing cancer recurrence and metastasis.…”