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Clinical Trial
. 2014 Jul 3;16(4):R70.
doi: 10.1186/bcr3685.

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

Ryuji Takahashi, Uhi Toh, Nobutaka Iwakuma, Miki Takenaka, Hiroko Otsuka, Mina Furukawa, Teruhiko Fujii, Naoko Seki, Akihiko Kawahara, Masayoshi Kage, Satoko Matsueda, Yoshito Akagi, Akira Yamada, Kyogo Itoh, Tetsuro Sasada
Clinical Trial

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

Ryuji Takahashi et al. Breast Cancer Res. .

Abstract

Introduction: Since 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.

Methods: Seventy-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.

Results: No 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.

Conclusions: PPV could be feasible for mrTNBC patients because of the safety, immune responses, and possible clinical benefits.

Clinical trial registration number: UMIN000001844 (Registration Date: April 5, 2009).

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Figures

Figure 1
Figure 1
Clinical responses to PPV. a, b) Computed tomography findings of a PR case with mrTNBC (case 2 in Table S2) before and after the 12th vaccination. A 63-year-old woman with a recurrent lung mass underwent 12 vaccinations in combination with gemcitabine (1,000 mg/m2/week for three weeks followed by one week intermission). At four months after the first vaccination, the lung mass was remarkably reduced in size (arrow). c, d) Computed tomography findings of a SD case with mrTNBC (case 18 in Table S2) before and after the eighth vaccination. A 34-year-old woman with a recurrent lung mass underwent eight vaccinations in combination with two cycles of eribulin mesylate (1.4 mg/m2/week for two weeks followed by one week intermission). At three months after the first vaccination, the lung mass was slightly decreased in size (arrow). mrTNBC, metastatic recurrent triple negative breast cancer; PPV, personalized peptide vaccination; PR, partial response; SD, stable disease.
Figure 2
Figure 2
Expressions of TAAs and pathological responses to PPV. After completion of eight vaccinations in combination with two cycles of eribulin mesylate (1.4 mg/m2/week for two weeks followed by one week intermission), the lung metastasis of a SD case with mrTNBC (case 18 in Table S2) was resected at three months after the first vaccination. The TAA expression and T cell infiltration in the resected lung tissue were examined by immunohistochemistry. a, b) Among the four TAAs, that is, SART2, PSA, EGF-R and LCK, two TAAs were expressed in the lung tumor. a) EGF-R (X200); b) SART2 (X200). c, d) Peritumoral infiltration of T lymphocytes was confirmed in the lung tumor. c) CD4+ T lymphocytes (X200); d) CD8+ T lymphocytes (X200). EGF-R, epidermal growth factor receptor; LCK, lymphocyte specific protein tyrosine kinase; mrTNBC, metastatic recurrent triple negative breast cancer; PPV, personalized peptide vaccination; PSA, prostate specific antigen; SART2, squamous cell carcinoma antigen recognized by T-cells 2; SD, stable disease; TAA, tumor associated antigens.
Figure 3
Figure 3
Survival curves among the three intrinsic subtypes. a) The median progression-free survival time of mrTNBC patients was 7.5 months, while that of luminal/HER2-negative patients was 12.2 months, and that of HER2-positive patients was 4.5 months. b) The median overall survival time of mrTNBC patients was 11.1 months, while that of luminal/HER2-negative patients was 26.5 months, and that of HER2-positive patients was 14.9 months. HER2, human epidermal growth factor receptor 2; mrTNBC, metastatic recurrent triple negative breast cancer.
Figure 4
Figure 4
Survival curves for patients treated with PPV with or without combination chemotherapies. a-f) There was no significant survival advantage of combined chemotherapies (CC) in each intrinsic subtype, compared with the treatment by PPV alone. a) b) mrTNBC: PFS and OS, P = 0.467 and P = 0.347, respectively. c,d) luminal/HER2-negative type: PFS and OS, P = 0.220 and P = 0.850, respectively. e,f) HER2-positive type: PFS and OS, P = 0.296 and P = 0.957, respectively. HER2, human epidermal growth factor receptor 2; mrTNBC, metastatic recurrent triple negative breast cancer; OS, overall survival; PFS, progression-free survival; PPV, personalized peptide vaccination.
Figure 5
Figure 5
Survival curves for patients with or without increased IgG responses after PPV. a-f) IgG boosting was a significant prognostic factor for OS and PFS in HER2-positive patients, whereas there was no significant difference between increased IgG responses and these prognoses in mrTNBC and luminal/HER2-negative patients. a, b) mrTNBC: PFS and OS, P = 0.274 and P = 0.152, respectively. c, d) luminal/HER2-negative type: PFS and OS, P = 0.732 and P = 0.571, respectively. e, f) HER2-positive type: PFS and OS, P = 0.0001 and P = 0.001, respectively. HER2, human epidermal growth factor receptor 2; IgG, immunoglobulin G; mrTNBC, metastatic recurrent triple negative breast cancer; OS, overall survival; PFS, progression-free survival; PPV, personalized peptide vaccination.
Figure 6
Figure 6
Survival curves for patients with or without increased CTL responses after PPV. a-f) CTL boosting was suggested to be a potential prognostic factor for OS but not for PFS in mrTNBC patients, whereas there was no significant difference between CTL boosting and these prognoses in luminal/HER2-negative and HER2-positive patients. a, b) mrTNBC: PFS and OS, P = 0.345 and P = 0.053, respectively. c, d) luminal/HER2-negative type: PFS and OS, P = 0.272 and P = 0.740, respectively. e, f) HER2-positive type: PFS and OS, P = 0.714 and P = 0.758, respectively. CTL, cytotoxic T lymphocytes; HER2, human epidermal growth factor receptor 2; mrTNBC, metastatic recurrent triple negative breast cancer; OS, overall survival; PFS, progression-free survival; PPV, personalized peptide vaccination.
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