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Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

Vierboom MP, Nijman HW, Offringa R, van der Voort EI, van Hall T, van den Broek L, Fleuren GJ, Kenemans P, Kast WM, Melief CJ - J. Exp. Med. (1997)

Bottom Line: The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies.The p53 protein is therefore an attractive target for immunotherapy.Importantly, this occurred in the absence of any demonstrable damage to normal tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunohematology and Blood Bank, University Hospital Leiden, 2300 RC Leiden, the Netherlands.

ABSTRACT
The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 -/-) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

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Recovery of wt p53-specific CTL activity after adoptive  transfer of CTLs into immunocompetent mice. wt p53-specific CTL  clone 1H11 was recovered from the spleens of C57BL/6 p53 +/+ immunocompetent mice 14 d after the CTLs were administered intavenously (A), as tested in a Eu3+ release assay. A nontreated C57BL/6  p53 +/+ immunocompetent mouse (B) was taken along as a negative  control. Spleen cells were restimulated in vitro with 4J and tested for their  peptide specificity on p53 −/− Koko cells (open circles), Koko cells pulsed  with the p53 peptide AIYKKSQHM (filled circles), and recognition of 4J  cells (filled squares) after 7 d of culture.
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Figure 7: Recovery of wt p53-specific CTL activity after adoptive transfer of CTLs into immunocompetent mice. wt p53-specific CTL clone 1H11 was recovered from the spleens of C57BL/6 p53 +/+ immunocompetent mice 14 d after the CTLs were administered intavenously (A), as tested in a Eu3+ release assay. A nontreated C57BL/6 p53 +/+ immunocompetent mouse (B) was taken along as a negative control. Spleen cells were restimulated in vitro with 4J and tested for their peptide specificity on p53 −/− Koko cells (open circles), Koko cells pulsed with the p53 peptide AIYKKSQHM (filled circles), and recognition of 4J cells (filled squares) after 7 d of culture.

Mentions: To investigate whether the wt p53-specific CTLs would also persist in immunocompetent p53 +/+ C57BL/6 mice or would be deleted in the presence of a T cell compartment absent in C57BL/6 nude mice, p53-specific CTLs were transferred into p53 +/+ C57BL/6 immunocompetent mice and the spleens of these mice were assayed for p53-specific activity after 14 d. wt p53-specific CTLs, recognizing the peptide and 4J tumor cells, could be retrieved from spleens of C57BL/6 p53 +/+ immunocompetent mice at day 14 (Fig. 7 A) and up to at least 7 wk after adoptive transfer of these CTLs (data not shown). We also evaluated the ability of these wt p53-specific CTLs to prevent the outgrowth of the more aggressive tumor, 5D, transformed by mutant p53 and N-ras, in a Winn assay (Table 2). The 5D tumor, in contrast to the 4J tumor, is tumorigenic in immunocompetent syngeneic B6 mice. In the group of mice challenged intraperitoneally with 5D and simultaneously treated with control CTL clone 9.5, recognizing an HPV16 E7-derived epitope, 12 out of 12 animals developed a progressively growing tumor and died within 3 wk. In the group of mice challenged intraperitoneally with 5D and treated with the wt p53-specific CTL clone 1H11, only 1 out of 12 developed a progressively growing tumor, thus demonstrating in vivo activity against the tumor without demonstrable autoimmune pathology.


Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

Vierboom MP, Nijman HW, Offringa R, van der Voort EI, van Hall T, van den Broek L, Fleuren GJ, Kenemans P, Kast WM, Melief CJ - J. Exp. Med. (1997)

Recovery of wt p53-specific CTL activity after adoptive  transfer of CTLs into immunocompetent mice. wt p53-specific CTL  clone 1H11 was recovered from the spleens of C57BL/6 p53 +/+ immunocompetent mice 14 d after the CTLs were administered intavenously (A), as tested in a Eu3+ release assay. A nontreated C57BL/6  p53 +/+ immunocompetent mouse (B) was taken along as a negative  control. Spleen cells were restimulated in vitro with 4J and tested for their  peptide specificity on p53 −/− Koko cells (open circles), Koko cells pulsed  with the p53 peptide AIYKKSQHM (filled circles), and recognition of 4J  cells (filled squares) after 7 d of culture.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199025&req=5

Figure 7: Recovery of wt p53-specific CTL activity after adoptive transfer of CTLs into immunocompetent mice. wt p53-specific CTL clone 1H11 was recovered from the spleens of C57BL/6 p53 +/+ immunocompetent mice 14 d after the CTLs were administered intavenously (A), as tested in a Eu3+ release assay. A nontreated C57BL/6 p53 +/+ immunocompetent mouse (B) was taken along as a negative control. Spleen cells were restimulated in vitro with 4J and tested for their peptide specificity on p53 −/− Koko cells (open circles), Koko cells pulsed with the p53 peptide AIYKKSQHM (filled circles), and recognition of 4J cells (filled squares) after 7 d of culture.
Mentions: To investigate whether the wt p53-specific CTLs would also persist in immunocompetent p53 +/+ C57BL/6 mice or would be deleted in the presence of a T cell compartment absent in C57BL/6 nude mice, p53-specific CTLs were transferred into p53 +/+ C57BL/6 immunocompetent mice and the spleens of these mice were assayed for p53-specific activity after 14 d. wt p53-specific CTLs, recognizing the peptide and 4J tumor cells, could be retrieved from spleens of C57BL/6 p53 +/+ immunocompetent mice at day 14 (Fig. 7 A) and up to at least 7 wk after adoptive transfer of these CTLs (data not shown). We also evaluated the ability of these wt p53-specific CTLs to prevent the outgrowth of the more aggressive tumor, 5D, transformed by mutant p53 and N-ras, in a Winn assay (Table 2). The 5D tumor, in contrast to the 4J tumor, is tumorigenic in immunocompetent syngeneic B6 mice. In the group of mice challenged intraperitoneally with 5D and simultaneously treated with control CTL clone 9.5, recognizing an HPV16 E7-derived epitope, 12 out of 12 animals developed a progressively growing tumor and died within 3 wk. In the group of mice challenged intraperitoneally with 5D and treated with the wt p53-specific CTL clone 1H11, only 1 out of 12 developed a progressively growing tumor, thus demonstrating in vivo activity against the tumor without demonstrable autoimmune pathology.

Bottom Line: The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies.The p53 protein is therefore an attractive target for immunotherapy.Importantly, this occurred in the absence of any demonstrable damage to normal tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunohematology and Blood Bank, University Hospital Leiden, 2300 RC Leiden, the Netherlands.

ABSTRACT
The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 -/-) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

Show MeSH
Related in: MedlinePlus