Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas

Peptide vaccines enhance the response of T cells toward tumor antigens and represent a strategy to augment antigen-independent immunotherapies of cancer. However, peptide vaccines that include native tumor antigens rarely prevent tumor growth. We have assembled a set of peptide variants for a mouse-colon tumor model to determine how to improve T-cell responses. These peptides have similar affinity for MHC molecules, but differ in the affinity of the peptide-MHC/T-cell receptor interaction with a tumor-specific T-cell clone. We systematically demonstrated that effective antitumor responses are generated after vaccination with variant peptides that stimulate the largest proportion of endogenous T cells specific for the native tumor antigen. Importantly, we found some variant peptides that strongly stimulated a specific T-cell clone in vitro, but elicited fewer tumor-specific T cells in vivo, and were not protective. The T cells expanded by the effective vaccines responded to the wild-type antigen by making cytokines and killing target cells, whereas most of the T cells expanded by the ineffective vaccines only responded to the peptide variants. We conclude that peptide-variant vaccines are most effective when the peptides react with a large responsive part of the tumor-specific T-cell repertoire.

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“…Sf9 and High Five insect cells (15) (Invitrogen), CT26 tumor cells (43), and CT-T-cell clone cells (11) were cultured as described.…”

Section: Methodsmentioning

confidence: 99%

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Jordan

McMahan

Kemmler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…For tumor protection assays, mice were primed (day -17) and boosted (day -10) intraperitoneally with LANAC alone or LANAC and peptide. On day 0, mice were injected subcutaneously in the left back flank with 5 × 10 4 CT26 tumor cells (34). Tumor-free survival was assessed by palpation at the site of injection.…”

Section: Ifn-g Elisa and Proliferation Assays Stimulation Of The T Cmentioning

confidence: 99%

“…We refer to affinity as the strength of binding of the pMHC to a single TCR molecule and functional avidity as the responsiveness of T cells to peptide antigen (33). The TCR used in this study recognizes the immunodominant H-2L d -restricted antigen from the transplantable colon tumor, CT26, syngeneic to BALB/c mice (34). This epitope is derived from the endogenous retroviral protein gp70, amino acids 423-431, and is referred to as the AH1 peptide (35).…”

Section: Introductionmentioning

confidence: 99%

Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines

McMahan

McWilliams²,

Jordan³

et al. 2006

Journal of Clinical Investigation

172

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One approach to enhancing the T cell response to tumors is vaccination with mimotopes, mimics of tumor epitopes. While mimotopes can stimulate proliferation of T cells that recognize tumor-associated antigens (TAAs), this expansion does not always correlate with control of tumor growth. We hypothesized that vaccination with mimotopes of optimal affinity in this interaction will improve antitumor immunity. Using a combinatorial peptide library and a cytotoxic T lymphocyte clone that recognizes a TAA, we identified a panel of mimotopes that, when complexed with MHC, bound the TAA-specific TCR with a range of affinities. As expected, in vitro assays showed that the affinity of the TCR-peptide-MHC (TCR-pMHC) interaction correlated with activity of the T cell clone. However, only vaccination with mimotopes in the intermediate-affinity range elicited functional T cells and provided protection against tumor growth in vivo. Vaccination with mimotopes with the highest-affinity TCR-pMHC interactions elicited TAA-specific T cells to the tumor, but did not control tumor growth at any of the peptide concentrations tested. Further analysis of these T cells showed functional defects in response to the TAA. Thus, stimulation of an antitumor response by mimotopes may be optimal with peptides that increase but do not maximize the affinity of the TCR-pMHC interaction.

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“…All cell lines, including Panc02 and its variants, were maintained in plastic flasks as adherent monolayers in RPMI-1640 medium supplemented with 10% fetal bovine serum, sodium pyruvate, nonessential amino acids, l-glutamine, and vitamin solution (Flow Laboratories, Rockville, MD, USA). Panc02 was originally established by Corbett et al (1984) by implanting cottonthread-carrying 3-methylcholanthrene into the pancreas of C57BL/6 mice followed by serial s.c. transplantation.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis

et al. 2003

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In the present study, a model system for studying the role of nitric oxide (NO) in tumor growth and metastasis was reported. Incubation of Panc02 murine pancreatic adenocarcinoma cells in vitro with cytokines and interferon led to heterogeneous expression of NO synthase II (NOS II) protein. Clonal sublines expressing different levels of NOS II were then established using a limited dilution technique. After orthotopical implantation into the pancreas of syngeneic C57BL/6 mice, clones with a low level of NOS II expression produced tumors in pancreas, metastasized to the liver, and formed ascites, whereas those having a high level of NOS II expression did not. Liver-metastasis variants having low to high metastatic ability were also established using in vivo/in vitro passage. Compared with parental Panc02 cells exhibiting a high level of NOS II expression, these variants had a decreased level of NOS II expression. Furthermore, the heterogeneous Panc02 cells were injected intravenously into a large number of syngeneic mice. Variants that metastasized to the liver, lung, skin, peritoneum, ovary, and lymph nodes were established. All of the metastatic variants exhibited a lower level of NOS II expression than the parental Panc02 cell line did. However, the phenotypes of NOS II induction and metastatic ability were unstable. Multiple in vitro/in vivo selection led to stable low NOS II expression and high metastatic potential. Finally, to further confirm the role of NOS II expression derived from tumor cells in metastasis, poorly metastatic Panc02-H0 and highly metastatic Panc02-H7 cells were injected into the pancreas of syngeneic NOS II À/À mice, and groups of mice received i.p. injections of either phosphatebuffered saline or l-N 6 -(1-iminoethyl) lysine. Inhibition of NOS II activity in vivo significantly promoted distant liver metastasis. Collectively, these data show that NOS II expression is highly heterogeneous and dynamically regulated, which can directly influence tumor growth and metastasis.

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Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas

Abstract: No. 5 MOUSE COLON TUMOR MODEL 9 Corbett et al. 2661* Dosage conversion: to convert mg/kg in the mouse to mg/m* in humans, multiply by 3. That is, a dose of 5 mg/kg in the mouse is equal to 15 mg/m' in humans. (c, OI

Cited by 188 publications

References 7 publications

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines

A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis

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