Letters to the Editor  |   August 2012
The Failed Theratope Vaccine: 10 Years Later
Author Affiliations
  • Simon B. Zeichner, DO
    Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, Florida
Article Information
Preventive Medicine
Letters to the Editor   |   August 2012
The Failed Theratope Vaccine: 10 Years Later
The Journal of the American Osteopathic Association, August 2012, Vol. 112, 482-483. doi:
The Journal of the American Osteopathic Association, August 2012, Vol. 112, 482-483. doi:
To the Editor: 
The year was 2002. There was excitement in the air. Immunology and oncology were finally coming together in what appeared to be the most novel agent in the field of breast cancer treatment since the revolutionary introduction of trastuzumab. A vaccine had been shown to stimulate antibody- and cell-mediated immune responses against tumor-associated antigens.1 Phase I and II studies provided convincing evidence that this highly touted therapeutic breast cancer vaccine, dubbed Theratope (synthetic O-linked disaccharide, sialyl-Tn-keyhole limpet hemocyanin [STn-KLH]; Biomira Inc, Edmonton, Alberta, Canada), was the next big idea in the field.1 Hundreds of researchers around the world were eager to see the results of phase III clinical trials of this promising agent. 
One of the first studies describing the use of Theratope in clinical practice had been published in 1996 by MacLean and colleagues.2 They described how Theratope produced clinically significant antibody titers and a marked increase in survival in patients with breast cancer.2 Vaccine activity was also associated with expression of CD69+ lymphocytes and CA27.29 (MUC-1), a high-molecular-weight glycoprotein rich in serine and threonine residues.3 Two phase II trials compared the use of low-dose cyclophosphamide with and without Theratope and found that there was a statistically significant increase in survival among patients treated with the STn-KLH vaccine (overall median survival, 19.1 months; n=50), compared with those patients not treated with the vaccine (overall median survival, 9.2 months; n=104).4,5 The trials reported minimal toxic effects with mild injection-site reactions and flulike symptoms.4,5 Sandmaier et al6 tested Theratope in vitro in 33 high-risk patients with breast cancer after stem cell transplantation. The researchers reported in 1999 that they observed STn antigen-specific T-cell proliferation and peripheral blood lymphocyte lytic activity.6,7 
The stage was set for mid-2003. Numerous in vitro and phase II studies had delivered encouraging results for Theratope. There was a wave of optimism in the air. One June day in 2003, however, there was breaking news8:

Biomira Inc. (Nasdaq: BIOM) (TSX:BRA) and Merck KGaA of Darmstadt, Germany, announced today that the results from a large pivotal Phase III trial of Theratope(R) vaccine for women with metastatic breast cancer did not meet the two pre-determined statistical endpoints of time to disease progression and overall survival. However, one prestratified subset of patients in the treatment group, women on hormonal treatment following chemotherapy, appeared to show a favourable trend to improvement in survival. … The Phase III randomized, double-blind trial was designed and powered primarily as a survival study. Enrolment [sic] in the trial totaled 1,030 women at more than 120 sites in 10 countries and, to date, is believed to be the largest trial of a therapeutic vaccine conducted in women with metastatic breast cancer.

In the study referred to in this June 2003 news report8—the final results of which were published in 20119—week-12 antibody testing revealed high specific immunoglobulin G titers in the group treated with Theratope and no detectable antimucin antibodies in the control group. However, median survival time between the treatment and control groups (23.1 months vs 22.3 months, respectively) was not significantly different.9 
Researchers were shocked by the initial phase III results reported in 2003.8,9 The idea that vaccines could be given to stimulate antibody- and cell-mediated immune responses against tumor-associated antigens made so much sense at the cellular level, and results of phase I and II clinical trials were so promising! Patients treated with the Theratope vaccine produced clinically significant antibody titers, but—for some reason—this result was not translating into increased survival for the patients. What had gone wrong? Researchers went back to the drawing board to elucidate a clear mechanism describing the efficacy of the vaccine. 
Although interest and hope waned, further research was conducted during the next few years. Epidemiologic studies showed that STn expression was highly restricted in normal tissue and was seen in approximately 25% to 30% of breast cancer cases.10 In 2005, Braun et al10 reported that tumor cells treated in vitro with an aromatase inhibitor exhibited increased sensitivity to monocyte-medicated, antibody-dependent cellular toxicity. Gilewski and colleagues11 found that the combination of 2 vaccines—STn-KLH and the immunologic adjuvant QS-21—produced clinically significant antibody titers in high-risk patients with breast cancer, with little or no resulting toxicity. 
Today, almost 10 years after the disappointing report on the pivotal phase III clinical trial of Theratope,8,9 therapeutic vaccines for metastatic breast cancer no longer hold the same promise as they once did. Multiple vaccines have failed to show any meaningful benefits. Despite some encouraging recent results for the use of combination vaccines in the treatment of hormone-sensitive patients,11 these findings need to be verified in large randomized controlled trials. Meanwhile, vaccines have shown some success with other types of cancer, such as prostate cancer (sipuleucel-T)12 and melanoma (ipilimumab).13 
Only time will tell whether vaccines will ever have a permanent role in treating patients with breast cancer. However, the Theratope vaccine story has ultimately become a tale of caution in the field of breast oncology. 
Holmberg LA, Sandmaier BM. Theratope vaccine (STn-KLH) [review]. Expert Opin Biol Ther. 2001;1(5):881-891. [CrossRef] [PubMed]
MacLean GD, Reddish MA, Koganty RR, Longenecker BM. Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother Emphasis Tumor Immunol. 1996;19(1):59-68. [CrossRef] [PubMed]
Reddish MA, MacLean GD, Poppema S, Berg A, Longenecker BM. Pre-immunotherapy serum CA27.29 (MUC-1) mucin level and CD69+ lymphocytes correlate with effects of Theratope sialyl-Tn-KLH cancer vaccine in active specific immunotherapy. Cancer Immunol Immunother. 1996;42(5):303-309. [CrossRef] [PubMed]
MacLean GD, Miles DW, Rubens RD, Reddish MA, Longenecker BM. Enhancing the effect of THERATOPE STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J Immunother Emphasis Tumor Immunol. 1996;19(4): 309-316. [CrossRef] [PubMed]
Miles D, Papazisis K. Rationale for the clinical development of STn-KLH (Theratope) and anti-MUC-1 vaccines in breast cancer [review]. Clin Breast Cancer. 2003;3(suppl 4):S134-S138. [CrossRef] [PubMed]
Sandmaier BM, Oparin DV, Holmberg LA, Reddish MA, MacLean GD, Longenecker BM. Evidence of a cellular immune response against sialyl-Tn in breast and ovarian cancer patients after high-dose chemotherapy, stem cell rescue, and immunization with Theratope STn-KLH cancer vaccine. J Immunother. 1999;22(1):54-66. [CrossRef] [PubMed]
Hadden JW. The immunology and immunotherapy of breast cancer: an update [review]. Int J Immunopharmacol. 1999;21(2):79-101. [CrossRef] [PubMed]
Biomira and Merck KGaA announce Phase III Theratope(R) vaccine trial does not meet primary endpoints. PR Newswire Web site. Accessed May 29, 2012.
Miles D, Roché H, Martin M, et al.  Theratope(r) Study Group. Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer [published online ahead of print May 14, 2011]. Oncologist. 2011;16(8):1092-1100. [CrossRef] [PubMed]
Braun DP, Crist KA, Shaheen F, Staren ED, Andrews S, Parker J. Aromatase inhibitors increase the sensitivity of human tumor cells to monocyte-mediated, antibody-dependent cellular cytotoxicity. Am J Surg. 2005;190(4):570-571. [CrossRef] [PubMed]
Gilewski TA, Ragupathi G, Dickler Met al. Immunization of high-risk breast cancer patients with clustered sTn-KLH conjugate plus the immunologic adjuvant QS-21. Clin Cancer Res. 2007;13(10): 2977-2985. [CrossRef] [PubMed]
Kantoff PW, Higano CS, Shore ND, et al.  IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422. [CrossRef] [PubMed]
Hodi FS, O'Day SJ, McDermott DFet al. Improved survival with ipilimumab in patients with metastatic melanoma [published online ahead of print June 5, 2010]. N Engl J Med. 2010;363(8):711-723. [CrossRef] [PubMed]