K-RAS mutations are frequently found in adenocarcinomas of the pancreas, and induction of immunity against mutant ras can therefore be of possible clinical benefit in patients with pancreatic cancer. We present data from a clinical phase I/II trial involving patients with adenocarcinoma of the pancreas vaccinated by i.d. injection of synthetic mutant ras peptides in combination with granulocyte-macrophage colony-stimulating factor. Forty-eight patients (10 surgically resected and 38 with advanced disease) were treated on an outpatient basis. Peptide-specific immunity was induced in 25 of 43 (58%) evaluable patients, indicating that the protocol used is very potent and capable of eliciting immune responses even in patients with end-stage disease. Patients followed-up for longer periods showed evidence of induction of long-lived immunological memory against the ras mutations. CD4 ؉ T cells reactive with an Arg12 mutation also present in the tumor could be isolated from a tumor biopsy, demonstrating that activated, ras-specific T cells were able to selectively accumulate in the tumor. Vaccination was well tolerated in all patients. Patients with advanced cancer demonstrating an immune response to the peptide vaccine showed prolonged survival from the start of treatment compared to non-responders (median survival 148 days vs. 61 days, respectively; p ‫؍‬ 0.0002). Although a limited number of patients were included in our study, the association between prolonged survival and an immune response against the vaccine suggests that a clinical benefit of ras peptide vaccination may be obtained for this group of patients. © 2001 Wiley-Liss, Inc. Key words: peptide vaccination; pancreatic cancer; mutant ras; granulocyte-macrophage colony-stimulating factor; adenocarcinomaMost patients with pancreatic adenocarcinoma are inoperable at the time of diagnosis. There is currently no effective non-surgical treatment option, and median survival time remains short (3 to 4 months). The small subgroup of operable cases (approx. 10%) has a median survival time of approximately 18 months. 1 Advances in treatment options for patients with pancreatic cancer are urgently needed.Mutations in the proto-oncogenes of the RAS family are frequent in human malignancies, and K-RAS mutations are found in most adenocarcinomas of the pancreas. 2 In addition, the fact that most RAS mutations are confined to codons 12, 13 and 61 3 makes the protein an attractive target for induction of tumor-specific T cells. Previous studies have shown that immune responses to mutated ras peptides and proteins can occur spontaneously in patients with malignancy or can be elicited in normal individuals. 4 -10 Peptide-specific T-cell responsiveness against mutant ras can also be induced in vivo in cancer patients by vaccination with antigen-presenting cells (APCs) loaded ex vivo with ras peptides or ras peptides emulsified in adjuvant. 11,12 These peptides, which are 13 to 17 amino acids in length, represent natural ras epitopes [13][14][15] and are designed primarily to...

The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch-repair machinery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of potential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGF␤RII and BAX. These tumors therefore represent an interesting human system for studying TIL and characterizing tumor-specific T cells. We here describe T cell reactivity against several T helper cell epitopes, representing a common frameshift mutation in TGF␤RII, in TIL and peripheral blood lymphocytes from patients with MSI ؉ tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI ؉ colon cancers and from all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes provide attractive targets for cancer vaccines, including a prophylactic vaccine for individuals carrying a genetic disposition for developing HNPCC.

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