Abstract
Cancer vaccines such as MVA-5T4 (TroVax®) must induce an efficacious immune response to deliver therapeutic benefit. The identification of biomarkers that impact on the clinical and/or immunological efficacy of cancer vaccines is required in order to select patients who are most likely to benefit from this treatment modality. Here, we sought to identify a predictor of treatment benefit for renal cancer patients treated with MVA-5T4. Statistical modeling was undertaken using data from a phase III trial in which patients requiring first-line treatment for metastatic renal cell carcinoma were randomized 1:1 to receive MVA-5T4 or placebo alongside sunitinib, IL-2 or IFN-α. Numerous pre-treatment factors associated with inflammatory anemia (e.g., CRP, hemoglobin, hematocrit, IL-6, ferritin, platelets) demonstrated a significant relationship with tumor burden and patient survival. From these prognostic factors, the pre-treatment mean corpuscular hemoglobin concentration (MCHC) was found to be the best predictor of treatment benefit (P < 0.01) for MVA-5T4 treated patients and also correlated positively with tumor shrinkage (P < 0.001). Furthermore, MCHC levels showed a significant positive association with 5T4 antibody response (P = 0.01). The latter result was confirmed using an independent data set comprising phase II trials of MVA-5T4 in patients with colorectal, renal and prostate cancers. Retrospective analyses demonstrated that RCC patients who had very large tumor burdens and low MCHC levels received little or no benefit from treatment with MVA-5T4; however, patients with smaller tumor burdens and normal MCHC levels received substantial benefit from treatment with MVA-5T4.
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References
Hole N, Stern PL (1988) A 72 kD trophoblast glycoprotein defined by a monoclonal antibody. Br J Cancer 57:239–246
Southall PJ, Boxer GM, Bagshawe KD et al (1990) Immunohistological distribution of 5T4 antigen in normal and malignant tissues. Br J Cancer 61:89–95
Starzynska T, Marsh PJ, Schofield PF et al (1994) Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma. Br J Cancer 69:899–902
Damelin M, Geles KG, Follettie MT et al (2011) Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Res 71:4236–4246
Amato RJ, Hawkins RE, Kaufman HL et al (2010) Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res 16:5539–5547
Amato RJ, Shingler W, Goonewardena M et al (2009) Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial. J Immunother 32:765–772
Amato RJ, Shingler W, Naylor S et al (2008) Vaccination of renal cell cancer patients with modified vaccinia ankara delivering tumor antigen 5T4 (TroVax) administered with interleukin 2: a phase II trial. Clin Cancer Res 14:7504–7510
Hawkins RE, Macdermott C, Shablak A et al (2009) Vaccination of patients with metastatic renal cancer with modified vaccinia Ankara encoding the tumor antigen 5T4 (TroVax) given alongside interferon-alpha. J Immunother 32:424–429
Kaufman HL, Taback B, Sherman W et al (2009) Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma. J Transl Med 7:2
Elkord E, Dangoor A, Drury NL et al (2008) An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing surgical resection of colorectal cancer liver metastases. J Immunother 31:820–829
Harrop R, Connolly N, Redchenko I et al (2006) Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res 12:3416–3424
Harrop R, Drury N, Shingler W et al (2008) Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses. Cancer Immunol Immunother 57:977–986
Harrop R, Drury N, Shingler W et al (2007) Vaccination of colorectal cancer patients with modified vaccinia ankara encoding the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune responses. Clin Cancer Res 13:4487–4494
Amato RJ, Drury N, Naylor S et al (2008) Vaccination of prostate cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax): a phase 2 trial. J Immunother 31:577–585
Harrop R, Shingler W, Kelleher M et al (2010) Cross-trial analysis of immunologic and clinical data resulting from phase I and II trials of MVA-5T4 (TroVax) in colorectal, renal, and prostate cancer patients. J Immunother 33:999–1005
Harrop R, Shingler WH, McDonald M et al (2011) MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer patients. Cancer Immunol Immunother 60:829–837
Gulley JL, Arlen PM, Madan RA et al (2010) Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 59:663–674
Gulley JL, Drake CG (2011) Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research. Clin Cancer Res 17:3884–3891
Gulley JL, Madan RA, Schlom J (2011) Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr Oncol 18:e150–e157
Dangoor A, Lorigan P, Keilholz U et al (2010) Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. Cancer Immunol Immunother 59:863–873
Hoos A, Britten CM, Huber C et al (2011) A methodological framework to enhance the clinical success of cancer immunotherapy. Nat Biotechnol 29:867–870
Armstrong AJ, Eisenberger MA, Halabi S et al (2011) Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer. Eur Urol 61:549–559
Boehm DU, Lebrecht A, Schmidt M et al (2007) Prognostic impact of haemoglobin levels in breast cancer. Anticancer Res 27:1223–1226
Motzer RJ, Bacik J, Murphy BA et al (2002) Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289–296
Ganz T, Nemeth E (2009) Iron sequestration and anemia of inflammation. Semin Hematol 46:387–393
Weiss G, Goodnough LT (2005) Anemia of chronic disease. N Engl J Med 352:1011–1023
Brugnara C (2003) Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem 49:1573–1578
Chiarella P, Vulcano M, Bruzzo J et al (2008) Anti-inflammatory pretreatment enables an efficient dendritic cell-based immunotherapy against established tumors. Cancer Immunol Immunother 57:701–718
Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570
Sheng KC, Wright MD, Apostolopoulos V (2011) Inflammatory mediators hold the key to dendritic cell suppression and tumor progression. Curr Med Chem 18:5507–5518
Conflict of interest
RH, JdB, MK, GB, SN and WS wish to disclose that they are employees of Oxford BioMedica, the manufacturer and developer of TroVax®. PT wishes to disclose that he has been paid consulting fees by Oxford BioMedica.
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Harrop, R., Treasure, P., de Belin, J. et al. Analysis of pre-treatment markers predictive of treatment benefit for the therapeutic cancer vaccine MVA-5T4 (TroVax). Cancer Immunol Immunother 61, 2283–2294 (2012). https://doi.org/10.1007/s00262-012-1302-9
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DOI: https://doi.org/10.1007/s00262-012-1302-9