Advertisement

Cancer Immunology, Immunotherapy

, Volume 61, Issue 3, pp 373–384 | Cite as

A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients

  • Osama E. Rahma
  • Ed Ashtar
  • Malgorzata Czystowska
  • Marta E. Szajnik
  • Eva Wieckowski
  • Sarah Bernstein
  • Vincent E. Herrin
  • Mortada A. Shams
  • Seth M. Steinberg
  • Maria Merino
  • William Gooding
  • Carmen Visus
  • Albert B. DeLeo
  • Judith K. Wolf
  • Jeffrey G. Bell
  • Jay A. Berzofsky
  • Theresa L. Whiteside
  • Samir N. Khleif
Original article

Abstract

Purpose

Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine.

Experimental design

Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles.

Results

Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively.

Conclusion

We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials.

Keywords

p53 IL-2 Ovarian cancer Cancer vaccine 

Notes

Acknowledgments

Supported in part by the intramural research program of the National Institute of Health (NIH), National Cancer Institute, Center for Cancer Research and by of the NCI/NIH grants P01 CA109688 (TLW) and R01 DE13918 (TLW) as well as National Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469) and the Gynecologic Oncology Group Statistical Office (CA37517). Dr. M. Szajnik is a postdoctoral fellow supported by the NHLBI contract HB-37-165 (TLW). The following member institutions participated in this study: Tacoma General Hospital; MD Anderson Cancer Center; Columbus Cancer Council and the Cleveland Clinic Foundation.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2011_1100_MOESM1_ESM.pdf (137 kb)
Immune Response Measured in the Peripheral Blood Obtained from Patient# 10A. The immune response of patient #10A using IFN-γ ELISPOT; reciprocal frequencies of wt p53 tetramer+ T cells; differentiation status of tetramer+ CD8+ T cells; percentage of activated CD4+ T cells and Treg in the peripheral circulation; percentage of Tr1 cells (CD132+TGF-β1+) in the peripheral circulation; and percentage of IL-10+ T cells measured ± stimulation signal. The samples were taken after each vaccine as indicated on the X axis with an arrow pointing to the IL-2 cycle. (PDF 137 kb)
262_2011_1100_MOESM2_ESM.pdf (58 kb)
Immune Response Measured in the Peripheral Blood Obtained from Patient# 6B. The immune response of patients #6B using IFN-γ ELISPOT; reciprocal frequencies of wt p53 tetramer+ T cells; differentiation status of tetramer+ CD8+ T cells; percentage of activated CD4+ T cells and Treg in the peripheral circulation; percentage of Tr1 cells (CD132+TGF-β1+) in the peripheral circulation; and percentage of IL-10+ T cells measured ± stimulation signal. The samples were taken after each vaccine as indicated on the X axis with an arrow pointing to the IL-2 cycle. (PDF 58 kb)
262_2011_1100_MOESM3_ESM.pdf (6 kb)
Levels of CA125 in Patients’ Sera Prior to and After Vaccination on Each Arm. The post-vaccination CA125 values are taken after the last vaccine that each patient received. CA125 levels are shown in U/mL. (PDF 5 kb)

References

  1. 1.
    Khleif SN, Abrams SI, Hamilton JM et al (1999) A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. J Immunother 22:155–165PubMedCrossRefGoogle Scholar
  2. 2.
    Toubaji A, Achtar M, Provenzano M et al (2008) Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol Immunother 57:1413–1420PubMedCrossRefGoogle Scholar
  3. 3.
    Phan GQ, Touloukian CE, Yang JC et al (2003) Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens. J Immunother 26:349–356PubMedCrossRefGoogle Scholar
  4. 4.
    Gilboa E (2007) DC-based cancer vaccines. J Clin Invest 117:1195–1203PubMedCrossRefGoogle Scholar
  5. 5.
    Bubenik J (2001) Genetically engineered dendritic cell-based cancer vaccines (review). Int J Oncol 18:475–478PubMedGoogle Scholar
  6. 6.
    Schadendorf D, Ugurel S, Schuler-Thurner B et al (2006) Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 17:563–570PubMedCrossRefGoogle Scholar
  7. 7.
    Slingluff CL Jr, Petroni GR, Yamshchikov GV et al (2003) Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026PubMedCrossRefGoogle Scholar
  8. 8.
    Lu W, Arraes LC, Ferreira WT, Andrieu JM (2004) Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 10:1359–1365PubMedCrossRefGoogle Scholar
  9. 9.
    Su Z, Dannull J, Yang BK et al (2005) Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 174:3798–3807PubMedGoogle Scholar
  10. 10.
    Heiser A, Coleman D, Dannull J et al (2002) Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest 109:409–417PubMedGoogle Scholar
  11. 11.
    Su Z, Dannull J, Heiser A et al (2003) Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res 63:2127–2133PubMedGoogle Scholar
  12. 12.
    Dannull J, Su Z, Rizzieri D et al (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633PubMedCrossRefGoogle Scholar
  13. 13.
    Gabrilovich DI, Ciernik IF, Carbone DP (1996) Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 170:101–110PubMedCrossRefGoogle Scholar
  14. 14.
    Gabrilovich DI, Nadaf S, Corak J, Berzofsky JA, Carbone DP (1996) Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. Cell Immunol 170:111–119PubMedCrossRefGoogle Scholar
  15. 15.
    Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP (1997) Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 3:483–490PubMedGoogle Scholar
  16. 16.
    Kichler-Lakomy C, Budinsky AC, Wolfram R et al (2006) Deficiencies in phenotype expression and function of dendritic cells from patients with early breast cancer. Eur J Med Res 11:7–12PubMedGoogle Scholar
  17. 17.
    Schuler G, Schuler-Thurner B, Steinman RM (2003) The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 15:138–147PubMedCrossRefGoogle Scholar
  18. 18.
    Lesterhuis WJ, de Vries IJ, Schuurhuis DH et al (2006) Vaccination of colorectal cancer patients with CEA-loaded dendritic cells: antigen-specific T cell responses in DTH skin tests. Ann Oncol 17:974–980PubMedCrossRefGoogle Scholar
  19. 19.
    Takahashi H, Nakagawa Y, Yokomuro K, Berzofsky JA (1993) Induction of CD8+ cytotoxic T lymphocytes by immunization with syngeneic irradiated HIV-1 envelope derived peptide-pulsed dendritic cells. Int Immunol 5:849–857PubMedCrossRefGoogle Scholar
  20. 20.
    Sakakura K, Chikamatsu K, Furuya N, Appella E, Whiteside TL, Deleo AB (2007) Toward the development of multi-epitope p53 cancer vaccines: an in vitro assessment of CD8(+) T cell responses to HLA class I-restricted wild-type sequence p53 peptides. Clin Immunol 125:43–51PubMedCrossRefGoogle Scholar
  21. 21.
    Svane IM, Pedersen AE, Johnsen HE et al (2004) Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother 53:633–641PubMedCrossRefGoogle Scholar
  22. 22.
    Svane IM, Pedersen AE, Johansen JS et al (2007) Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers. Cancer Immunol Immunother 56:1485–1499PubMedCrossRefGoogle Scholar
  23. 23.
    DeLeo AB, Whiteside TL (2008) Development of multi-epitope vaccines targeting wild-type sequence p53 peptides. Expert Rev Vaccines 7:1031–1040PubMedCrossRefGoogle Scholar
  24. 24.
    Rosenberg SA, Yang JC, Schwartzentruber DJ et al (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327PubMedCrossRefGoogle Scholar
  25. 25.
    Lotem M, Shiloni E, Pappo I et al (2004) Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma. Br J Cancer 90:773–780PubMedCrossRefGoogle Scholar
  26. 26.
    Qian J, Dong Y, Pang YY et al (2006) Combined prophylactic and therapeutic cancer vaccine: enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice. Int J Cancer 118:3022–3029PubMedCrossRefGoogle Scholar
  27. 27.
    Toubaji A, Hill S, Terabe M et al (2007) The combination of GM-CSF and IL-2 as local adjuvant shows synergy in enhancing peptide vaccines and provides long term tumor protection. Vaccine 25:5882–5891PubMedCrossRefGoogle Scholar
  28. 28.
    Weber J, Sondak VK, Scotland R et al (2003) Granulocyte-macrophage-colony-stimulating factor added to a multipeptide vaccine for resected Stage II melanoma. Cancer 97:186–200PubMedCrossRefGoogle Scholar
  29. 29.
    Dranoff G, Jaffee E, Lazenby A et al (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:3539–3543PubMedCrossRefGoogle Scholar
  30. 30.
    Whiteside T (2005) ELISPOT assays. Assessment of cellular immune responses to anti-cancer vaccines. In: Nagorsen D, Marincola FM (eds.) Analyzing T cell responses. Springer, Dordrecht, pp 143–156Google Scholar
  31. 31.
    Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL (2007) The frequency and suppressor function of CD4+ CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13:6301–6311PubMedCrossRefGoogle Scholar
  32. 32.
    Bergmann C, Strauss L, Wang Y et al (2008) T regulatory type 1 cells in squamous cell carcinoma of the head and neck: mechanisms of suppression and expansion in advanced disease. Clin Cancer Res 14:3706–3715PubMedCrossRefGoogle Scholar
  33. 33.
    Markovic SN, Suman VJ, Ingle JN et al (2006) Peptide vaccination of patients with metastatic melanoma: improved clinical outcome in patients demonstrating effective immunization. Am J Clin Oncol 29:352–360PubMedCrossRefGoogle Scholar
  34. 34.
    Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193:233–238PubMedCrossRefGoogle Scholar
  35. 35.
    Lechler R, Ng WF, Steinman RM (2001) Dendritic cells in transplantation—friend or foe? Immunity 14:357–368PubMedCrossRefGoogle Scholar
  36. 36.
    Cools N, Van Tendeloo VF, Smits EL et al (2008) Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4+ regulatory T cells. J Cell Mol Med 12:690–700PubMedCrossRefGoogle Scholar
  37. 37.
    Roncarolo MG, Levings MK, Traversari C (2001) Differentiation of T regulatory cells by immature dendritic cells. J Exp Med 193:F5–F9PubMedCrossRefGoogle Scholar
  38. 38.
    Jonuleit H, Giesecke-Tuettenberg A, Tuting T et al (2001) A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 93:243–251PubMedCrossRefGoogle Scholar
  39. 39.
    Maier T, Tun-Kyi A, Tassis A et al (2003) Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. Blood 102:2338–2344PubMedCrossRefGoogle Scholar
  40. 40.
    Bedrosian I, Mick R, Xu S et al (2003) Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 21:3826–3835PubMedCrossRefGoogle Scholar
  41. 41.
    de Vries IJ, Lesterhuis WJ, Barentsz JO et al (2005) Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol 23:1407–1413PubMedCrossRefGoogle Scholar
  42. 42.
    Slingluff CL Jr, Petroni GR, Yamshchikov GV et al (2004) Immunologic and clinical outcomes of vaccination with a multiepitope melanoma peptide vaccine plus low-dose interleukin-2 administered either concurrently or on a delayed schedule. J Clin Oncol 22:4474–4485PubMedCrossRefGoogle Scholar
  43. 43.
    Escobar A, Lopez M, Serrano A et al (2005) Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients. Clin Exp Immunol 142:555–668PubMedGoogle Scholar
  44. 44.
    Wojtowicz ME, Hamilton MJ, Benrnstein S et al (2000) Clinical trial of mutant ras peptide vaccination along with IL-2 or GM-CSF. Proc Am Soc Clin Oncol 19:463a (abstr 1818)Google Scholar
  45. 45.
    Lemoine FM, Cherai M, Giverne C et al (2009) Massive expansion of regulatory T-cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer. Int J Oncol 35:569–581PubMedCrossRefGoogle Scholar
  46. 46.
    Green DS, Dalgleish AG, Belonwu N, Fischer MD, Bodman-Smith MD (2008) Topical imiquimod and intralesional interleukin-2 increase activated lymphocytes and restore the Th1/Th2 balance in patients with metastatic melanoma. Br J Dermatol 159:606–614PubMedCrossRefGoogle Scholar
  47. 47.
    Simon RM, Steinberg SM, Hamilton M et al (2001) Clinical trial designs for the early clinical development of therapeutic cancer vaccines. J Clin Oncol 19:1848–1854PubMedGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Osama E. Rahma
    • 1
  • Ed Ashtar
    • 2
    • 10
  • Malgorzata Czystowska
    • 5
  • Marta E. Szajnik
    • 5
    • 11
  • Eva Wieckowski
    • 5
  • Sarah Bernstein
    • 2
  • Vincent E. Herrin
    • 4
  • Mortada A. Shams
    • 2
  • Seth M. Steinberg
    • 6
  • Maria Merino
    • 7
  • William Gooding
    • 5
  • Carmen Visus
    • 5
  • Albert B. DeLeo
    • 5
  • Judith K. Wolf
    • 8
  • Jeffrey G. Bell
    • 9
  • Jay A. Berzofsky
    • 2
  • Theresa L. Whiteside
    • 5
  • Samir N. Khleif
    • 3
  1. 1.Vaccine Branch, CCR, NCIBethesdaUSA
  2. 2.Vaccine Branch, CCR, NCIBethesdaUSA
  3. 3.Vaccine Branch, CCR, NCIBethesdaUSA
  4. 4.University of MississippiJacksonUSA
  5. 5.University of Pittsburgh Cancer InstitutePittsburghUSA
  6. 6.Biostatistics and Data Management SectionCCR, NCIRockvilleUSA
  7. 7.Department of PathologyClinical Center, NIHBethesdaUSA
  8. 8.Department of GYN/OncologyMD Anderson Cancer CenterHoustonUSA
  9. 9.Division of Gynecologic OncologyRiverside Methodist Hospital (Columbus Cancer Council)ColumbusUSA
  10. 10.Mount CarmelUSA
  11. 11.Department of Gynecology OncologyUniversity of Medical SciencesPoznanPoland

Personalised recommendations