Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful Clinical Responses in Advanced Metastatic Melanoma

Abstract

Advanced Stage IV and IIIc melanoma has a dismal survival, with or without, standard chemotherapy. New therapies are required to improve survival and reduce morbidity. Repeated vaccine dosing does not appear to have been explored, so Vaccinia Melanoma Cell Lysate (VMCL) vaccine repetitive therapy was tested, either alone, or combined with chemotherapy. 37 patients (31 Stage IV [M1a(6), b(7), c(18)] and 6 Stage IIIc) were studied using intra-dermal VMCL vaccine therapy. If disease progressed, vaccine was continued with standard chemotherapy (DTIC and/or Fotemustine). Overall survival was assessed and clinical responses were also recorded. From vaccine commencement, median overall follow-up was 10 months. Survivals ranged from 4 to 73 months. Median (mean) overall survival was 10 (23.5) months; overall survival at 1, 2 and 3 years was 40.5%, 21.6% and 10.8% respectively. CR and PR occurred in 18.9% (7) and 18.9% (7) of patients; these were durable for up to 6.1 years in 4 patients. Stable disease was noted in a further 17 patients (45.9%). In 6 patients (16.2%) no response to therapy was apparent. Repeated vaccinations with or without chemotherapy produced strong, durable clinical responses with overall survival > 23 months occurring in nearly 25% of advanced melanoma patients. The overall disease control rate (CR, PR and SD) was 83.7%, including CR in very advanced cases. These results, in a largely unselected population of advanced metastatic melanoma patients, compare very favourably with other regimens, and notably were associated with minimal, if any, toxicity. Further analysis of this approach appears warranted.

Share and Cite:

B. Coventry, P. Hersey, A. Halligan and A. Michele, "Immuno-Chemotherapy Using Repeated Vaccine Treatment Can Produce Successful Clinical Responses in Advanced Metastatic Melanoma," Journal of Cancer Therapy, Vol. 1 No. 4, 2010, pp. 205-213. doi: 10.4236/jct.2010.14032.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] E. L. Korn, P-Y Liu, S. J. Lee, J-A W. Chapman, D. Niedzwiecki, V. J. Suman, J. Moon, V. K. Sondak, M. B. Atkins, E. A. Eisenhauer, W. Parulekar, S. N. Markovic, S. Saxman and J. M. Kirkwood, “Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials,” Journal of Clinical Oncology, Vol. 26, No.4, 2008, pp 527-534.
[2] A. Y. Bedikian, M. Millward, H. Pehamberger, R. Conry, M. Gore, U. Trefzer, A. C. Pavlick, R. DeConti, E. M. Hersh, P. Hersey, J. M. Kirkwood and F. G. Haluska “Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group,” Journal of Clinical Oncology, Vol. 24, No.29, 2006, pp 4738-4745.
[3] P. Hersey, S. W. Menzies, G. M. Halliday, T. Nguyen, M. L. Farrelly, C. DeSilva and M. Lett “Phase I/II Study of Treatment with Dendritic Cell Vaccines in Patients with Disseminated Melanoma,” Cancer Immunol Immunother, Vol. 53, No.2, 2004, pp 125-34.
[4] P. Hersey, “Active Immunotherapy with Viral Lysates of Micrometastases Following Surgical Removal of High Risk Melanoma,” World Journal of Surgery, Vol. 16, 1992, pp 251-60.
[5] P. Hersey, “Evaluation of Vaccinia Viral Lysates as Therapeutic Vaccines in the Treatment of Melanoma,” Annals of the New York Academy of Sciences, Vol. 690, 1993, pp 167-77.
[6] P. Hersey, A. S. Coates, W. H. McCarthy, J. F. Thompson, R. W. Sillar, R. McLeod, P. G. Gill, B. J. Coventry, A. McMullen, H. Dillon and R. J. Simes, “Adjuvant Immunotherapy of Patients with High-risk Melanoma Using Vaccinia Viral Lysates of Melanoma: Results of a Randomized Trial,” Journal of Clinical Oncology, Vol. 20, No.20, 2002, pp 4181-90.
[7] WHO Handbook for Reporting Results of Cancer Treatment. World Health Organization, 1979.
[8] C. M. Balch, A. N. Houghton, A. J. Sober and S-JS Eds., “Cutaneous Melanoma,” 5th Edition, St Louis, Missouri, Quality Medical Publishing, 2008.
[9] M. B. Atkins, “Cytokine-based Therapy and Biochemotherapy for Advanced Melanoma,” Clinical Cancer Resesrch, Vol. 12, 2006, pp 2353-2358.
[10] M. F. Avril, S. Aamdal, J. J. Grob, A. Hauschild, P. Mohr, J. J. Bonerandi, M. Weichenthal, K. Neuber, T. Bieber, K. Gilde, V. Guillem Porta, J. Fra, J. Bonneterre, P. Sa?ag, D. Kamanabrou, H. Pehamberger, J. Sufliarsky, J. L. Gonzalez Larriba, A. Scherrer and Y. Menu “Fotemustine Compared with Dacarbazine in Patients with Disseminated Malignant Melanoma: a Phase III Study,” Journal of Clinical Oncology, Vol. 22, No.6, 2004, pp 1118-25.
[11] I. Quirbt, S. Verma, T. Petrella, K. Bak, M. Charette and the members of the Melanoma Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care, “Temozolomide for the Treatment of Metastatic Melanoma” Current Oncology, Vol. 14,No.1, 2007, pp 27-33.
[12] A. S. Mansfield and S. N. Markovic, “Novel therapeutics for the treatment of metastatic melanoma,” Future Oncology, Vol. 5, No.4, 2009, pp 543-57.
[13] E. C. Hsueh, R. Essner, L. J. Foshag, D. W. Ollila, G. Gammon, S. J. O'Day, P. D. Boasberg, S. L. Stern, Y. Xe and D. L. Morton, “Prolonged Survival after Complete Resection of Disseminated Melanoma and Active Immunotherapy with a Therapeutic Cancer Vaccine,” Journal of Clinical Oncology, Vol. 20,No.23, 2002, pp 4549-54.
[14] A. K. Nowak, B. W. Robinson and R. A. Lake, “Synergy between Chemotherapy and Immunotherapy in the Treatment of Established Murine Solid Tumors,” Cancer Research, Vol. 63, No.15, 2003, pp 4490-6.
[15] J. Taieb, N. Chaput, N. Schartz, S. Roux, S. Novault, C. Ménard, F. Ghiringhelli, M. Terme, A. F. Carpentier, G. Darrasse-Jèze, F. Lemonnier and L. Zitvogel, “Chemoimmunotherapy of Tumors: Cyclophosphamide Synergizes with Exosome Based Vaccines,” Journal of Immunology, Vol. 176, No.5, 2006, pp 2722-9.
[16] B. J. Coventry, M. L. Ashdown, M. A. Quinn, S. N. Markovic, S. L. Yatomi-Clarke, A. P. Robinson, “CRP Identifies Homeostatic Immune Oscillations in Cancer Patients: A Potential Treatment Targeting Tool?” Journal of Translational Medicine, Vol. 7, 2009, pp 102-109
[17] M. L. Ashdown and B. J. Coventry “A Matter of Time,” Australasian Science, Vol. 5, 2010, pp 18-20.
[18] B. J. Coventry, J. M. Austyn, S. Chryssidis, D. Hankins and A. Harris, “Identification and Isolation of CD1a Positive Putative Tumour Infiltrating Dendritic Cells in Human Breast Cancer,” Advances in Experimental Medicine and Biology, Vol. 417, 1997, pp 571-7.
[19] B. J. Coventry, “CD1a-Positive Putative Tumour Infiltrating Dendritic Cells in Human Breast Cancer” Anticancer Research, Vol. 19(4B), 1999, pp 3183-7.
[20] E. E. Hillenbrand, A. M. Neville and B. J. Coventry, “Immunohistochemical Localization of CD1a-positive Putative Dendritic Cells in Human Breast Tumours,” British Journal of Cancer, 79(5-6), 1999, pp 940-4.
[21] B. J. Coventry, P. L. Lee, D. Gibbs and D. N. Hart, “Dendritic Cell Density and Activation Status in Human Breast Cancer -- CD1a, CMRF-44, CMRF-56 and CD-83 expression,” British Journal of Cancer, Vol.86, No.4, 2002, pp 546-51.
[22] A. H. Barbour and B. J. Coventry, “Dendritic Cell Density and Activation Status of Tumour Infiltrating Lymphocytes in Metastatic Human Melanoma: Possible Implications for Sentinel Node Metastases,” Melanoma Research, Vol. 13, No.3, 2003, pp 263-269.
[23] B. J. Coventry and J. Morton, “CD1a-positive Infiltrating-dendritic Cell Density and 5-year Survival from Human Breast Cancer,” British Journal of Cancer, Vol.89, No.3, 2003, pp 533-8.
[24] N. Chaput, G. Darrasse-Jèze, A. S. Bergot, C. Cordier, S. Ngo-Abdalla, D. Klatzmann, “Azogui O Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites,” Journal of Immunology, Vol. 179, No.8, 2007, pp 4969-78.
[25] S. Nizar, J. Copier, B. Meyer, M. Bodman-Smith, C.Galustian, D. Kumar and A. Dalgleish, “T-regulatory cell modulation: the future of cancer immunotherapy?” Minireview British Journal of Cancer, Vol. 100, 2009, pp 1697-1703.
[26] H. Y. Wang and R. F. Wang, “Regulatory T cells and Cancer," Current Opinion in Immunology, Vol.19, No.2, 2007 217-23.
[27] B. J. Coventry, S. C. Weeks, S. E. Heckford, P. J. Sykes, J. Bradley and J. M. Skinner, “Lack of IL-2 Cytokine Expression despite Il-2 Messenger RNA Transcription in Tumor Infiltrating Lymphocytes in Primary Human Breast Carcinoma: Selective Expression of Early Activation Markers,” Journal of Immunology, Vol.156, No.9, 1996, pp 3486-92.
[28] B. Coventry and S. Heinzel, “CD1a in Human Cancers: A New Role for an Old Molecule,” Trends in Immunology. Vol. 25, No.5, 2004, pp 242-8.
[29] N. G. Chakraborty, S. Chattopadhyay, S. Mehrotra, A. Chhabra and B. Mukherji, “Regulatory T-cell Response and Tumor Vaccine-induced Cytotoxic T Lymphocytes in Human Melanoma,” Human Immunology, Vol.65, No.8, 2004, pp 794-802.
[30] M. Ahamadzadeh and S. A. Rosenberg, “IL-2 Increases CD4+CD25+Foxp3+ Regulatory T Cells in Cancer Patients,” Blood, Vol. 107, No.6, 2006, pp 2409-2414.
[31] D. K. Sojka, Y. H. Huang and D. J. Fowell “Mechanisms of Regulatory T-cell Suppression - a Diverse Arsenal for a Moving Target,” Review Immunology, Vol.124, No.1, 2008, pp. 13-22.
[32] G. Darrasse-Jèze, A. S. Bergot, A. Durgeau, F. Billiard, B. L. Salomon, J. L. Cohen, B. Bellier, K. Podsypanina and D. Klatzmann, “Tumor Emergence is Sensed by Self-specific CD44hi Memory Tregs that Create a Dominant Tolerogenic Environment for Tumors in Mice,” Journal of Clinical Investigation, Vol. 119, No.9, 2009, pp 2648-62.
[33] G. Darrasse-Jèze, S. Deroubaix, H. Mouquet, D. Victora, T. Eisenreich, K. H. Yao, R. F. Masilamani, M. L. Dustin, A. Rudensky, K. Liu and M. C. Nussenzweig, “Feedback Control of Regulatory T Cell Homeostasis by Dendritic Cells in Vivo,” Journal of Experimental Medicine, Vol. 206, No.9, 2009, pp 1853-62.
[34] L. Zitvogel and G. Kroemer, “Anticancer Immunochemotherapy Using Adjuvants with Direct Cytotoxic Effects,” Journal of Clinical Investigation, Vol.119, No.8, 2009, pp 2127-30.

Journals Menu
Follow SCIRP
Contact us
+1 323-425-8868
customer@scirp.org
WhatsApp +86 18163351462(WhatsApp)
Click here to send a message to me 1655362766
Paper Publishing WeChat

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.