Therapeutic vaccines work on the premise that the immune system can be trained or optimized to take action against elements of a diseased state or condition already present in an individual. However, perhaps because of the immune system’s complexity and incomplete knowledge of its pathways of action, only a few therapeutic vaccines have been approved to date.
Disease areas most commonly targeted by this immunotherapeutic approach are unsurprisingly those that have proven difficult to treat or cure through other means: AIDS, hepatitis B, and various autoimmune diseases are good examples. However, the use of therapeutic vaccines in oncological indications appears to have garnered the most interest. Researchers in this area found great promise in April 2010, when Dendreon’s Provenge (Sipuleucel-T) became the first therapeutic cancer vaccine to be approved by FDA. Provenge is an autologous cellular immunotherapeutic for the treatment of asymptomatic or minimally symptomatic metastatic hormone refractory prostate cancer. Looking ahead, the market for cancer vaccines certainly has the potential for huge growth, with some reports indicating compound annual growths rates over 100% in the next few years (1).
CANCER VACCINESMost cancer cells express tumor-associated antigens (TAAs) that can be recognized by the immune system as “foreign” and thus serve as potential targets for cancer vaccines. MART-1, MAGE-3, NY-ESO-1, prostate specific antigen, and prostatic acid phosphatase (PAP) are all examples of TAAs. Cancer vaccines seek to trigger a strong immune response to tumors by introducing TAAs into the patient possibly alongside adjuvants or immunostimulators and tend to fall into two camps. Tumor antigen-based vaccines can use peptides, recombinant proteins, tumor lysates, or killed tumor cells as TAAs. Cell-based vaccines, on the other hand, use ex vivo–prepared TAA-loaded antigen presenting cells (APCs) as the vaccine. In fact, it is the patient’s own APCs that are isolated from peripheral blood cells and loaded with TAAs in cell culture. Often, the precursor monocytes are cultured with cytokines to create dendritic cells (DCs), which are particularly potent APCs. Provenge is an example of this kind of cell-based vaccine; a recombinant antigen—a fusion protein consisting of PAP and the cytokine granulocyte-macrophage colony-stimulating factor (GM–CSF)—is cultured with the patient’s APCs in Dendreon’s manufacturing facility. Once the APCs have matured, they are infused back into the patient.
Looking at a few cancer vaccines in development pipeline, the picture looks quite bright, with tumor-antigen vaccines dominating over cell-based vaccines. Galena Biopharma’s NeuVax (E75) for breast cancer falls into the peptide-based category and has successfully completed a Phase II trial. The E75 peptide is derived from human epidermal growth factor receptor 2 (HER2) and also uses GM–CSF; together they stimulate cytotoxic T cells to target cells expressing any level of HER2. FDA has granted NeuVax a Special Protocol Assessment (SPA) for its Phase III Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment (PRESENT) study, which the company indicates will begin in the first half of 2012. Galena also announced in November 2011, the establishment of a clinical development collaboration with Genentech (a membr of the Roche group) and The Henry M. Jackson Foundation for the Advancement of Military Medicine in which the two companies will sponsor a Phase II clinical study using NeuVax in combination with Genentech/Roche’s Herceptin (trastuzumab). Herceptin, a monoclonal antibody therapy, is currently available for patients with higher levels of HER2 expression.
Antigen Express, a subsidiary of Generex, has a similar product in development for breast cancer that is also a peptide fragment of the HER2 receptor called AE37. This is the company’s first candidate to take advantage of its Ii-Key Hybrid technology platform, which modifies fragments of antigens with the intention of increasing their potency in eliciting an immune response. Antigen Express is conducting a controlled, randomized, and single-blinded Phase II clinical study in HER2 expressing patients with either node positive or high-risk node-negative breast cancer. As with NeuVax, AE37 is administered with GM-CSF. The company released positive interim results for the study in August 2011. As HER2 is expressed in numerous cancer types, it has possibilities beyond breast cancer. Antigen Express has also completed a Phase I trial for prostate cancer.