Adoptive immunotherapy for pancreatic cancer: Cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1

Abstract

MUC1 is a tumor-associated antigen that is overexpressed in invasive ductal carcinomas of the pancreas (PC). MUC1-specific cytotoxic T lymphocytes (CTLs) recognize MUC1 molecules in a HLA-unrestricted manner. In this study, we performed adoptive immunotherapy (AIT) in patients with PC with CTLs stimulated by the MUC1expressing human PC cell line YPK-1. To induce CTLs, peripheral blood mononuclear cells (PBMCs) were cultured for 3 days with inactivated YPK-1 cells and then stimulated with interleukin (IL)-2 for 7 days. The cytotoxicity of these cells against human cancer cell lines was analyzed, and a variety of antibodies were evaluated for their ability to inhibit cytotoxicity. We treated 8 patients with unresectable PC and 20 patients with resectable PC postsurgically. CTLs were induced as described above, suspended in 100 ml saline and injected intravenously. Induced CTLs were cytotoxic against 5 MUC1-expressing PC cell lines and a breast cancer cell line, regardless of the HLA phenotype. Low cytotoxicity was observed in 7 MUC1-negative cancer cell lines. Anti-CD3 monoclonal antibody (mAb) or anti-CD8 mAb strongly inhibited cytotoxicity against YPK-1, whereas anti-class I mAb showed no inhibition. YPK-1 cells incubated with anti-MUC1 mAb also showed low cytotoxicity. Clinically, the median survival time was 5.0 months for patients with unresectable PC treated with AIT. None of the 5 patients without liver metastasis showed hepatic recurrence. The median survival time was 17.8 months for 18 out of 20 patients with resectable PC who underwent curative surgery, and the 1-, 2-and 3-year survival rates after surgery were 83.3, 32.4, and 19.4%, respectively. Liver metastasis was found in only one patient and no side effects of AIT were observed. CTLs stimulated by a MUC1-expressing human pancreatic cancer cell line showed a strong tumor cytotoxic activity in a MUC1-specific and MHC-unrestricted manner. AIT with stimulated CTLs significantly suppressed the postsurgical hepatic recurrence of PC. Adjuvant immunotherapy with CTLs may be useful in the postsurgical treatment of PC.

MUC1 Expression in Colorectal Cancer is Associated with Malignant Clinicopathological Factors

“…We recently decided to investigate MUC1 expression in colorectal cancer because it is a marker for poor prognosis 4 , its expression may affect the selection of chemotherapeutic agents and use of MUC1-cytotoxic T-lymphocyte CTL immunotherapy 5 , and little is reported about MUC1 expression in colorectal cancer tissues to date 6 7 .…”

Induction of antigen-specific CTL and antibody responses in mice by a novel recombinant tandem repeat DNA vaccine targeting at mucin 1 of pancreatic cancer

“…Although MUC1-specific antibodies and/or CTLs were detected in host and protected the host from attacking by tumor cells that express MUC1 (Johnen et al 2001), they were not adequate to generate effective anti-tumor immunity to totally inhibit the growth of tumor (Brossart et al 2000;Snyder et al 2006). Moreover, clinical trials with MUC1 showed that MUC1 is a relatively poor immunogen in human beings (Kawaoka et al 2008;Sugiura et al 2008) and that the induction of clinically effective anti-tumor immune responses had not been achieved. Consequently, it is necessary to develop new vaccination protocols to induce strong anti-tumor immune responses that are applicable for the treatment of pancreatic cancer.…”

“…Treatment strategies targeting at the residual cancer cells, which are responsible for local recurrence and metastasis, are therefore necessary. Immunotherapy is expected to improve the prognosis of pancreatic cancer because it can act specifically against the tumor (Kawaoka et al 2008). Adoptive immunotherapy for pancreatic cancer has included the use of peptide vaccine, dendritic cell (DC) vaccine and DNA vaccine.…”

Pancreatic Cancer Fostered Immunosuppression Privileges Tumor Growth and Progression

“…Rather than being isolated from the tumor, lymphocytes are obtained from the peripheral blood, after which they are exposed to retroviral vectors encoding for specific genetically modified TCR designed to target specific tumor antigens. In the PDAC setting, Muc1-specific autologous T cells isolated from patients'PBMCs were expanded by incubation with a Muc1-presenting cell line prior to administration to eight patients with unresectable and 20 patients with resectable PDAC postsurgically [193]. This treatment reduced postsurgical hepatic recurrence and improve survival with respect to surgery alone, although the overall benefit was minimal (median survival: 17.8 vs. 14.0 months).…”