Cancer Immunology, Immunotherapy

, Volume 53, Issue 5, pp 422–430 | Cite as

Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3

  • Deanne M. R. Lathers
  • Joseph I. Clark
  • Nicholas J. Achille
  • M. Rita I. Young
Original Article

Abstract

Patients with head and neck squamous cell carcinoma (HNSCC) have profound immune defects. These defects are associated with a poor prognosis and are mediated, in part, by immune inhibitory CD34+ progenitor cells, whose numbers are increased in the peripheral blood of HNSCC patients. Immune inhibitory CD34+ cells are also present within HNSCC tumors. A phase IB clinical trial was conducted with HNSCC patients to determine if treatment with the differentiation-inducer 25-hydroxyvitamin D3 could diminish CD34+ cell levels and improve a panel of immune parameters. Here we present the results of treatment with orally administered escalating doses (20, 40, 60 μg) of 25-hydroxyvitamin D3, with an emphasis on the six patients who received the maximum dosage of 60 μg per day. Peripheral blood was collected at 0, 1, 2, 4, and 6 weeks, and assessed for markers of immune activity. Although no clinical responses were observed, results of this pilot study demonstrated that treatment of HNSCC patients with 25-hydroxyvitamin D3 reduces the number of immune suppressive CD34+ cells, increases HLA-DR expression, increases plasma IL-12 and IFN-γ levels, and improves T-cell blastogenesis. In contrast, 25-hydroxyvitamin D3 treatment did not modulate plasma IL-1β, IL-2, IL-4, IL-6, IL-10, GM-CSF, or TGF-β levels.

Keywords

CD34+ cells Cytokines HNSCC patients Immunotherapy Vitamin D3 

Abbreviations

GM-CSF

granulocyte-macrophage colony-stimulating factor

high CD34+ patients

patients with greater than 1% baseline CD34+ cell levels

HLA

human leukocyte antigen

IFN

interferon

IL

interleukin

low CD34+ patients

patients with less than 1% baseline CD34+ cell levels

OD

optical density

TGF

transforming growth factor

Notes

Acknowledgements

This work was supported by grants from the Medical Research Service of the Department of Veterans Affairs (M.R.I.Y., D.M.R.L.), and by Grants R01-CA85266, R01-CA45080 and R21-CA77108 from the National Institutes of Health (M.R.I.Y.). We gratefully acknowledge the contributions to these studies by the nursing staff of 11 West at the Hines VA Hospital, the laboratory staff at the Cardinal Bernardin Cancer Center of Loyola University Medical Center, and the Hematology/Oncology Clinical Research Nurses at Loyola University Medical Center and the Hines VA Hospital.

References

  1. 1.
    Akhter J, Goerdel M, Morris DL (1996) Vitamin D3 analogue (EB 1089) inhibits in vitro cellular proliferation of human colon cancers. Br J Surg 83:229–230PubMedGoogle Scholar
  2. 2.
    Alleva DG, Burger CJ, Elgert KD (1994) Tumour growth causes suppression of autoreactive T-cell proliferation by disrupting macrophage responsiveness to interferon-γ. Scan J Immunol 39:31–38Google Scholar
  3. 3.
    Alleva DG, Walker TM, Elgert KD (1995) Induction of macrophage suppressor activity by fibrosarcoma-derived transforming growth factor-β1: contrasting effects on resting and activated macrophages. J Leuko Biol 57:919–928PubMedGoogle Scholar
  4. 4.
    Alpdogan O, Ozgun S, Lawrence R, Ozener C, Akoglu E, Akoglu T (1995) The effect of 1,25 dihydroxyvitamin D3 on lymphocyte transformation in patients with chronic renal failure. Intern Med 34:240–242PubMedGoogle Scholar
  5. 5.
    Clayman GL, Taylor DL, Liu FJ, Lavedan P, Savage HE, Schantz SP (1993) Serum and acute phase protein modulation of the effector phase of lymphokine-activated killer cells. Laryngoscope 103:299–307PubMedGoogle Scholar
  6. 6.
    D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F, Panina-Bordignon P (1998) Inhibition of IL-12 production by 1,α25-dihydroxyvitamin D3: involvement of NF-κB downregulation in transcriptional repression of the p40 gene. J Clin Invest 101:252–262PubMedGoogle Scholar
  7. 7.
    DeLuca HF, Cantorna MT (2001) Vitamin D: its role and uses in immunology. FASEB J 2001:2514–2579Google Scholar
  8. 8.
    Duits AJ, Dimjati W, van de Winkel JG, Capel PJA (1992) Synergism of interleukin 6 and 1,α25-dihydroxyvitamin D3 in induction of myeloid differentiation of human leukemic cell lines. J Leuko Biol 51:237–243PubMedGoogle Scholar
  9. 9.
    Garrity T, Pandit R, Wright MA, Benefield J, Young MRI (1997) Increased presence of CD34+ cells in the peripheral blood of head and neck cancer patients and their differentiation into CD1a+ cells. Int J Cancer 73:663–669PubMedGoogle Scholar
  10. 10.
    Griffin MD, Lutz WH, Phan VA, Bachman LA, McKean DJ, Kumar R (2000) Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun 270:701–708CrossRefPubMedGoogle Scholar
  11. 11.
    Hadden JW, Endicott J, Baekey P, Skipper P, Hadden EM (1994) Interleukins and contrasuppression induce immune regression of head and neck cancer. Arch Otolaryngol Head Neck Surg 120:395–403Google Scholar
  12. 12.
    Haug CJ, Muller F, Aukrust P, Froland SS (1998) Different effect of 1,25-dihydroxyvitamin D3 on replication of Mycobacterium avium in monocyte-derived macrophages from human immunodeficiency virus-infected subjects and healthy controls. Immunol Lett 63:107–112CrossRefPubMedGoogle Scholar
  13. 13.
    Kaffenberger W, Holzer-Muller L, Auberger T, Clasen BP, Hohlmeier G, van Beuningen D (1995) An immunological outcome predictive score for head and neck carcinoma patients. Strahlenther Onkol 171:444–453PubMedGoogle Scholar
  14. 14.
    Lathers DMR, Lubbers E, Beal NM, Wright MA, Young MRI (1999) Cultures derived from peripheral blood CD34+ progenitor cells of head and neck patients and from cord blood are functionally different. Human Immunol 60:1207–1215Google Scholar
  15. 15.
    Lathers DMR, Lubbers E, Wright MA, Young MRI (1999) Dendritic cell differentiation pathways of CD34+ cells from the peripheral blood of head and neck patients. J Leuko Biol 65:623–628PubMedGoogle Scholar
  16. 16.
    Lathers DMR, Achille NJ, Kolesiak K, Hulett K, Sparano A, Young MRI (2001) Increased levels of immune inhibitory CD34+ progenitor cells in the peripheral blood of patients with node positive head and neck cancer and the ability of the CD34+ cells to differentiate into antigen presenting dendritic cells. Otolaryngol Head Neck Surg 125:205–212CrossRefPubMedGoogle Scholar
  17. 17.
    Lathers DMR, Clark JI, Achille NJ, Young MRI (2001) Phase 1B study of 25-hydroxyvitamin D3 treatment to diminish suppressor cells in head and neck cancer patients. Human Immunol 62:1282–1293CrossRefGoogle Scholar
  18. 18.
    Maeda N, Sagara Y (1993) Analysis of immunosuppressive mechanism to cytotoxic T lymphocyte generation in patients with advanced cancer. Asia-oceana J Ob Gyn 19:309–318Google Scholar
  19. 19.
    Mann EA, Spiro JD, Chen LL, Kreutzer DL (1992) Cytokine expression by head and neck squamous cell carcinomas. Am J Surg 164:567–573PubMedGoogle Scholar
  20. 20.
    Mocellin S, Wang E, Marincola FM (2001) Cytokines and immune response in the tumor microenvironment. J Immunother 24:392–407Google Scholar
  21. 21.
    Muller K, Bendtzen K (1992) Inhibition of normal human T lymphocyte proliferation and cytokine production by 1,α25-dihydroxyvitamin D3. Differentiational effects on CD45RA+ and CD45RO+ cells. Autoimmunity 14:37–43PubMedGoogle Scholar
  22. 22.
    Oghiso Y, Yamada Y, Ando K, Ishihara H, Shibata Y (1993) Differential induction of prostaglandin E2-dependent and -independent immune suppressor cells by tumor-derived GM-CSF and M-CSF. J Leuko Biol 53:86–92PubMedGoogle Scholar
  23. 23.
    Penna G, Adorini L (2000) 1α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impairedalloreactive T-cell activation. J Immunol 164:2405–2411PubMedGoogle Scholar
  24. 24.
    Pettersson F, Colston KW, Dalgleish AG (2000) Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro. Br J Cancer 83:239–245CrossRefPubMedGoogle Scholar
  25. 25.
    Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V (2000) Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 164:4443–4451PubMedGoogle Scholar
  26. 26.
    Schmidt-Pak A, Wright MA, Matthews JP, Collins SL, Petruzzelli G, Young MRI (1995) Mechanisms of immune suppression in patients with head and neck cancer: Presence of CD34+ cells which suppress immune functions within cancers that secrete GM-CSF. Clin Cancer Res 1:95–103PubMedGoogle Scholar
  27. 27.
    Testa U, Masciulli R, Tritarelli E, Pustorino R, Mariani G, Martucci R, Barberi T, Camagma A, Valtieri M, Peschle C (1993) Transforming growth factor-β potentiates vitamin-D3-induced terminal monocytic differentation of human leukemic cell lines. J Immunol 150:2418–2430PubMedGoogle Scholar
  28. 28.
    Wang X, Chen X, Akhter J, Morris DL (1997) The in vitro effect of Vitamin D3 analogue EB-1089 on a human prostate cancer cell line. Br J Urology 80:260–262CrossRefGoogle Scholar
  29. 29.
    Wiers KM, Lozano Y, Messingham KA, Metz RJ, Young MRI (1997) 1,α25-dihydroxyvitamin D3 activates T cells of tumor bearers through protein phosphatase 2A. Cancer Immunol Immunother 44:97–102CrossRefPubMedGoogle Scholar
  30. 30.
    Wiers KM, Wright MA, Vellody K, Young MRI (1998) Failure of tumor-reactive lymph node cells to kill tumor in the presence of immune-suppressive CD34+ cells can be overcome with Vitamin D3 treatment to diminish CD34+ cell levels. Clin Exp Metastasis 16:275–282CrossRefPubMedGoogle Scholar
  31. 31.
    Wiers KM, Wright MA, Lathers DMR, Young MRI (2000) Vitamin D3 treatment to diminish the levels of immune suppressive CD34+ cells increases the effectiveness of adoptive immunotherapy. J Immunother 23:115–124CrossRefPubMedGoogle Scholar
  32. 32.
    Woods KV, El-Naggar A, Clayman GL, Grimm EA (1998) Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. Cancer Res 58:3132–3141PubMedGoogle Scholar
  33. 33.
    Young MRI, Ihm J, Lozano Y, Wright MA, Prechel M (1995) Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immune suppression, and reduces tumor metastasis and recurrence. Cancer Immunol Immunother 41:37–45PubMedGoogle Scholar
  34. 34.
    Young MRI, Wright MA, Lozano Y, Matthews JP, Benefield J, Prechel MM (1996) Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer. Int J Cancer 67:333–338PubMedGoogle Scholar
  35. 35.
    Young MRI, Wright MA, Matthews JP, Malik I, Prechel M (1996) Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-β and nitric oxide. J Immunol 156:1916–1922PubMedGoogle Scholar
  36. 36.
    Young MRI, Wright MA, Pandit R (1997) Myeloid differentiation treatment to diminish the presence of immune suppressive CD34+ cells within human head and neck squamous cell carcinomas. J Immunol 159:990–996PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Deanne M. R. Lathers
    • 1
    • 3
  • Joseph I. Clark
    • 5
  • Nicholas J. Achille
    • 4
  • M. Rita I. Young
    • 1
    • 2
    • 3
  1. 1.Research Service (151)Ralph H. Johnson Veterans Affairs Medical CenterCharlestonUSA
  2. 2.Department of MedicineMedical University of South CarolinaCharlestonUSA
  3. 3.Department of OtolaryngologyMedical University of South CarolinaCharlestonUSA
  4. 4.Department of PathologyLoyola University Stritch School of MedicineMaywoodUSA
  5. 5.Cardinal Bernardin Cancer CenterLoyola University Stritch School of MedicineMaywoodUSA

Personalised recommendations