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:  

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.