Immunization With Mutant<i>p53</i>- and<i>K-ras</i>–Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome

Carbone, David P.; Ciernik, I. Frank; Kelley, Michael J.; Smith, M. Charles; Nadaf, Sorena; Kavanaugh, Denise; Maher, Virginia Ellen; Stipanov, Michael; Contois, David; Johnson, Bruce E.; Pendleton, C. David; Seifert, Burkhardt; Carter, Charley; Read, Elizabeth J.; Greenblatt, Jay J.; Top, Lois E.; Kelsey, Morris I.; Minna, John D.; Berzofsky, Jay A.

doi:10.1200/jco.2005.03.158

Cited by 164 publications

(92 citation statements)

References 39 publications

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“…Previous studies have shown that CD4 + T-cell immunity to position 12 mutated Ras (muRas) can be detected in the majority of patients with pancreatic cancer (3,5). The proof of this T-cell response and the early presence of muRas in the tumoral process have prompted the implementation of clinical trials aimed at inducing CTL responses against defined muRas antigens (9)(10)(11). In these studies, immunizations with peptides of 13 to 17 amino acids in length were able to induce CD4 + and CD8 + T lymphocytes specific for muRas.…”

mentioning

confidence: 99%

Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.

Kubuschok

Neumann

Breit

et al. 2006

Clinical Cancer Research

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Mutated p21 ras proteins (muRas) are present in f90% of pancreatic adenocarcinomas and express mutants which can function as cancer-specific antigens. To evaluate the frequency and magnitude of the natural T-cell response against muRas in 19 HLA-A2-positive patients with muRas-positive pancreatic carcinomas, antigen-experienced T lymphocytes in fresh peripheral blood mononuclear cells were shown by IFN-g enzyme-linked immunospot using muRas peptides (5-21) that encompass both HLA class I (HLA-A2)^and class II^restricted (HLA-DRB1) epitopes. Six of 19 patients (32%) were found to have a specific T-cell response against individual mutation-specific ras 5-21 but not against other ras mutations or wild-type ras. In contrast, none of 19 healthy subjects had T cells specifically secreting IFN-g (P = 0.004). The T-cell response consisted of both CD8 + and CD4 + T cells but was dominated by CD8 T cells in three of four patients. MuRas 5-14 and muRas 6-14 were shown to specifically induce CD8 + T-cell mediated cytotoxicity against HLA-A2-positive, muRas-bearing pancreatic carcinoma cells. The T-cell response was not correlated with prognostic or clinical variables such as tumor-node-metastasis status, stage, or survival. In conclusion, a natural T-cell response against muRas proteins that could be exploited for immunostimulatory therapeutic approaches has been shown in a significant proportion of patients with pancreatic cancer.The ras proto-oncogenes (H-ras, K-ras, and N-ras) encode 21-kDa proteins with intrinsic GTPase activity that are involved in cell proliferation and differentiation. Point mutations in the ras proto-oncogenes have been identified in a wide range of human solid tumors, in particular carcinomas of the pancreas, colon, lung, and thyroid as well as myeloid malignancies. The majority of point mutations of the ras gene reside at codons 12, 13, and 61 (1). These mutations result in the production of aberrant proteins, which are structurally and functionally distinct from normal endogenous ras and, due to their strict tumor specificity, can function as targets for cellular and humoral immune responses in cancer patients (1-5) and healthy donors (6-8).In pancreatic adenocarcinomas where ras point mutations occur in 80% to 90% of cases, it is the K-ras gene at codon 12 that is found frequently mutated. Replacement of the normal glycine (Gly) residue by an aspartatic acid (Asp), valine (Val), cysteine (Cys), or arginine (Arg) residue accounts for f98% of all ras mutations in pancreatic carcinomas, rendering pancreatic cancer an ideal model for the investigations of T-cell responses against ras mutations at position 12. Previous studies have shown that CD4 + T-cell immunity to position 12 mutated Ras (muRas) can be detected in the majority of patients with pancreatic cancer (3, 5). The proof of this T-cell response and the early presence of muRas in the tumoral process have prompted the implementation of clinical trials aimed at inducing CTL responses against defined muRas antigens (9-11). In these st...

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mentioning

confidence: 99%

Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.

Kubuschok

Neumann

Breit

et al. 2006

Clinical Cancer Research

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“…25 The study was done independently of the subjects' HLA Class I and Class II haplotypes. The tumor of 1 of the subjects expressed the p53 Y220C mutation.…”

Section: Discussionmentioning

confidence: 99%

Immunological characterization of missense mutations occurring within cytotoxic T cell‐defined p53 epitopes in HLA‐A*0201⁺ squamous cell carcinomas of the head and neck

Ito

Visús

Hoffmann³

et al. 2007

Intl Journal of Cancer

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Previous analyses of p53 in 40 HLA-A*0201(HLA-A2) 1 squamous cell carcinomas of the head and neck (SCCHN) indicated that 6/13 p53 missense mutations that were detected, S149C, T150R, V157F, Y220C, Y220H and E271K, occurred within HLA-A2-restricted cytotoxic T lymphocyte (CTL)-defined p53 epitopes. Of the 6, the p53 S149C, Y220C and Y220H peptides were immunogenic. Anti-p53 mutant S149C and Y220H effector cells crossreacted against the parental wild type sequence (wt) p53 peptides, whereas anti-p53 Y220C effector cells were specific for the mutant peptide, p53 Y220C cDNA-transfected HLA-A2 1 SaOS cells, and an HLA-A2 1 SCCHN cell line naturally expressing the mutation. These results indicate that the p53 Y220C mutation can be processed and presented for CD8 1 T cell recognition. Furthermore, using an autologous PBMC/tumor system, anti-p53 Y220C peptide-effector cells recognizing the autologous tumor could also be generated. Our analysis of p53 in 10 additional HLA-A2 1 SCCHN tumors detected the p53 Y220C in 2/10 tumors raising the overall frequency of the p53 Y220C mutation to 6/50 (12%) HLA-A2 1 SCCHN tumors. In contrast, independent of their HLA class I genotypes, the p53 Y220C mutation frequency for all human tumors analyzed to date is 1.5%. This unexpectedly high frequency of the p53 Y220C mutation in HLA-A2 1 SCCHN suggests that vaccines targeting this mutation would not only be expected to induce robust anti-tumor immune responses in HLA-A2 1 subjects, but also be more widely applicable than previously envisioned for any given p53 missense mutation. ' 2007 Wiley-Liss, Inc.

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“…Vaccination of cancer patients requires a target which would be present exclusively in cancer cells. Carbone et al [33] demonstrated prolonged survival of cancer patients (including lung cancer), which were immunized with cellular vaccine containing mutant p53 and KRASderived peptides.…”

Section: Kirsten-rous Avian Sarcoma (Kras)mentioning

confidence: 99%

The role of genetic and other biomarkers in NSCLC prognosis

et al. 2014

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AbstractThe development of non-small-cell lung cancer (NSCLC) is a multistep process, which is triggered and maintained by various factors. Many steps of non-small-cell lung carcinogenesis, risk factors and biomarkers have been identified; however no consistent model has been established of personalized medicine for these patients. Distinct various gene expression, products of mutated genes and other markers such as circulating nucleic acids or tumor cells has been proven to be potential biomarkers of non-small cell lung cancer as well as potential targets for new treatment strategies. This article will highlight promising biomarkers in non-small cell lung cancer prognosis.

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Immunization With Mutantp53- andK-ras–Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome

Cited by 164 publications

References 39 publications

Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.

Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.

Immunological characterization of missense mutations occurring within cytotoxic T cell‐defined p53 epitopes in HLA‐A*0201⁺ squamous cell carcinomas of the head and neck

The role of genetic and other biomarkers in NSCLC prognosis

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Immunization With Mutantp53- andK-ras–Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome

Cited by 164 publications

References 39 publications

Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.

Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer.

Immunological characterization of missense mutations occurring within cytotoxic T cell‐defined p53 epitopes in HLA‐A*0201+ squamous cell carcinomas of the head and neck

The role of genetic and other biomarkers in NSCLC prognosis

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Immunological characterization of missense mutations occurring within cytotoxic T cell‐defined p53 epitopes in HLA‐A*0201⁺ squamous cell carcinomas of the head and neck