癌症疫苗能够刺激机体产生特异性免疫性应答，尤其是针对肿瘤抗原的特异性CD8＋的细胞毒T细胞。1994年到1995年间生产的最早的癌症疫苗主要应用于非突变抗原患者中，结果显示肿瘤相关抗原具有一定的免疫原性，而且能够诱导少数晚期癌症患者产生临床反应。过去10年来，技术的发展使我们能够研发针对癌症患者特异性突变抗原的疫苗。多种癌症疫苗正在研发中，包括多肽、蛋白质、抗原提呈细胞(APCs)、肿瘤细胞和病毒载体疫苗。目前肿瘤的标准治疗包括外科、消融、化疗、放疗，都能诱导机体产生抗肿瘤免疫，因此我们认为这些治疗也具有一定的癌症疫苗的效应。通过监测肿瘤患者接受标准治疗前后免疫应答能力的变化，我们找到了肿瘤免疫的生物标志物。正在进行临床试验的联合治疗方案有望成为改善患者预后的最佳策略。

Cancer vaccines

Although surgery remains the mainstay for the treatment of most solid tumors, investigators are seeking complementary therapies to eradicate microscopic disease, which causes tumor relapse even after an apparently complete surgical excision. Although adjuvant chemotherapy has achieved some significant results, the control of minimal residual disease is still a challenge for clinicians. Among novel therapeutic approaches, immunotherapy holds promise. This anticancer strategy aims at triggering a highly specific endogenous killing machine against tumor cells. Recent progress in tumor immunology has improved our understanding of host-immune system interactions. In particular, new technologies have fostered the identification of potentially immunogenic tumor antigens that can be used as suitable targets for immune effector cells. After observing immunotherapy-mediated clinical responses in patients with metastatic disease, investigators have started evaluating this anticancer modality in the adjuvant setting. Here, we review the immunological strategies so far explored in humans and report worldwide results following the clinical application of adjuvant immunotherapy for solid tumors.

Adjuvant immunotherapy for solid tumors: From promise to clinical application

The 10-year cumulative experiences of five year survivals of patients entered into a successful phase II specific active tumor-associated antigen (TAA) immunotherapy trial, a successful phase III specific active immunotherapy trial A and of patients from centers with acceptable protocol violation levels of an unsuccessful specific active immunotherapy trial B are evaluated. Here the authors report the efficacy of specific active TAA immunotherapy when the protocol is adhered to strictly, where the induction of cell-mediated immunity to TAA indicated a successful adherence to the protocol rather than the strategic result when centers from the third trial with major violations are included. The authors repeat here a summary of each of the three separate trials, each of the three trials having been reported elsewhere in their entirety, so that these total results may be compared to the present analysis. The survival experiences of a total of 234 lung cancer Stage I and Stage II patients, including all violations, from centers in northern New York, northern New Jersey, western Pennsylvania and eastern Canada show a statistically valid (P = 0.0002) 5-year survival difference between the control groups (receiving adjuvant alone or no treatment) at 49% survival and the specific active immunotherapy groups at 69% survival. The best promise of specific active immunotherapy alone in an adjunctive treatment setting is with early stage lung cancer. In addition to tests which monitor the effect of TAA immunotherapy induction of long-lasting cell-mediated immunity, tests (monoclonal antibody-derived epitope enzyme immunoassays) were developed to monitor specific, early antibody rises in the bloodstream (circulating humoral immunity).

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819870915%2960%3A6%3C1249%3A%3AAID-CNCR2820600616%3E3.0.CO%3B2-I

Adjuvant specific active lung cancer immunotherapy trials. Tumor-associated antigens.

Epithelial cell mucin has been characterized as a tumor-specific antigen in patients with pancreatic and breast cancer. Mucins are high molecular weight glycoproteins consisting of a heavily glycosylated tandemly repeating 20-amino acid sequence. Aberrant glycosylation of mucins on carcinomatous epithelial cells leads to the exposure of novel core epitopes that are recognized by cytotoxic T lymphocytes (CTLs). We previously reported the establishment of mucin-specific CTL clones that recognize mucin expressed on the surface of EBV-immortalized B cells transfected with the mucin cDNA (MUC1). This recognition was characterized as major histocompatibility complex (MHC)-unrestricted, because of the multivalent nature of mucin. The transfectants had to be incubated with an inhibitor of O-linked glycosylation, phenyl-N-acetyl-alpha-galactosaminide (phenyl-GalNAc) in order to unmask the tandem repeat core epitope recognized by CTLs. In the present study, we examined whether mucin molecules with fewer tandem repeats are capable of MHC-unrestricted recognition by mucin-specific CTL clones. A mucin cDNA expression vector expressing a "truncated" mucin molecule that contains only two tandem repeats was constructed. We found that mucin-specific CTL clones recognize the "truncated" mucin on allogeneic target cells, showing that recognition in this case was MHC-unrestricted as well. In addition, CTL clones lysed "truncated" mucin transfectants significantly better than full-length mucin transfectants treated with phenyl-GalNAc, and controls. The "truncated" construct may represent an effective means of immunizing patients with breast and pancreatic cancer, enabling them to mount a strong and efficient immune response against mucin-bearing tumor cells.

Specific and Effective T‐Cell Recognition of Cells Transfected with a Truncated Human Mucin cDNA

Adjuvant immunotherapy for non-small cell lung cancer.

In 1976 Stewart et al. (Annals of the New York Academy of Sciences 277:436-466) reported the effectiveness of adjuvant specific active immunotherapy of lung carcinoma in improving the postoperative survival of stage I lung carcinoma patients in a phase II study using lung carcinoma-associated antigen (TAA) and complete Freund's adjuvant (CFA). A phase III study was then designed by the authors to see the effects of specific active immunotherapy compared to the conventional management (no treatment) and to nonspecific immunotherapy. From 1976 to 1981, 85 patients with resectable (stages I and II) squamous cell lung carcinoma were entered into a randomized study: 1) control group; 2) specific immunotherapy group--three monthly doses of 500 micrograms of TAA emulsified with CFA; 3) nonspecific immunotherapy group--three monthly doses of CFA emulsified in saline. All the patients in the study received skin tests with 100 micrograms of the same TAA used for the immunotherapy. Recently, a 5-year follow-up of all the patients became available: The life table 5-year survival of group 1 was 34%, of group 2 was 75%, and of group 3 was 53%. The median survivals for the three groups were group 1, 38 months; group 2, 106 months; and group 3, 71 months. The difference was significant at P = .007 (Cox-Mantel test).

Adjuvant, specific, active immunotherapy for resectable squamous cell lung carcinoma: a 5-year survival analysis.

From June 1976 to June 1981, 86 patients with resectable (Stage I and II) squamous cell lung carcinoma were entered into a randomized controlled study with three arms: Control Group - no treatment postoperatively. Specific Immunotherapy Group - three monthly doses of 500 micrograms of tumor associated antigen (TAA) emulsified with complete Freund's adjuvant (CFA). Nonspecific Immunotherapy Group - three monthly doses of CFA emulsified in saline. All the patients in the study received skin tests with PPD (5TU) and 100 micrograms of the same TAA used for the immunotherapy at 1, 4, 6, 9, and 12 months postoperatively. Patients in both immunotherapy groups showed a tendency for a better disease-free interval and overall survival compared to those of the control, but these interval and beneficial therapeutic effects were statistically significant only in the Group III patients who had no hilar lymph node metastasis (T1N0 and T2N0). Although Group III was originally designated as a nonspecific immunotherapy group, retrospectively, it should be called a lowdose specific immunotherapy group because these patients actually received a total of 500 micrograms of TAA (as skin tests) and three doses of CFA at separate sites.

Adjuvant specific immunotherapy of resectable squamous cell lung carcinoma. Analysis at the eighth year.

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Adjuvant, specific, active immunotherapy for resectable squamous cell lung carcinoma: a 5-year survival analysis.

Adjuvant specific immunotherapy of resectable squamous cell lung carcinoma. Analysis at the eighth year.