Cancer vaccine

One approach to cancer vaccination is to separate proteins from cancer cells and immunize patients against those proteins as antigens, in the hope of stimulating the immune system to kill the cancer cells. Research on cancer vaccines is underway for treatment of breast, lung, colon, skin, kidney, prostate and other cancers.[5]

Another approach is to generate an immune response in situ in the patient using oncolytic viruses. This approach was used in the drug talimogene laherparepvec, a variant of herpes simplex virus engineered to selectively replicate in tumor tissue and to express the immune stimulatory protein GM-CSF. This enhances the anti-tumor immune response to tumor antigens released following viral lysis and provides a patient-specific vaccine.[6]

In a Phase III trial of follicular lymphoma (a type of non-Hodgkin's lymphoma), investigators reported that the BiovaxID (on average) prolonged remission by 44.2 months, versus 30.6 months for the control.[7]

On April 14, 2009, Dendreon Corporation announced that their Phase III clinical trial of sipuleucel-T, a cancer vaccine designed to treat prostate cancer, had demonstrated an increase in survival. It received U.S. Food and Drug Administration (FDA) approval for use in the treatment of advanced prostate cancer patients on April 29, 2010.[8][9]

On April 8, 2008, New York–based company Antigenics announced that it had received approval for the first therapeutic cancer vaccine in Russia. It is the first approval by a regulatory body of a cancer immunotherapy. The treatment, Oncophage, increased recurrence-free survival by a little more than a year according to the results of a phase III clinical trial. The approval is for a subset of kidney cancer patients who are at intermediate risk for disease recurrence. It awaits approval in the US and EU.[10] but will need a new trial for FDA approval.

Interim results from a phase III trial of talimogene laherparepvec in melanoma showed a significant tumour response compared to administration of GM-CSF alone.[6]

Oncophage was approved in Russia in 2008 for kidney cancer. It is marketed by Antigenics Inc.

Sipuleucel-T, Provenge, was approved by the FDA in April 2010 for metastatic hormone-refractory prostate cancer. It is marketed by Dendreon Corp.

Bacillus Calmette-Guérin (BCG) was approved by the FDA in 1990 as a vaccine for early-stage bladder cancer.[11] BCG can be administered intravesically (directly into the bladder) or as an adjuvant in other cancer vaccines.

CancerVax (Canvaxin), Genitope Corp (MyVax personalized immunotherapy), and FavId FavId (Favrille Inc) are examples of cancer vaccine projects that have been terminated, due to poor phase III and IV results.

Cancer vaccines seek to target a tumor-specific antigen as distinct from self-proteins. Selection of the appropriate adjuvant to activate antigen-presenting cells to stimulate immune responses, is required. Bacillus Calmette-Guérin, an aluminum-based salt, and a squalene-oil-water emulsion are approved for clinical use. An effective vaccine should also stimulate long term immune memory to prevent tumor recurrence. Some scientists claim both the innate and adaptive immune systems must be activated to achieve total tumor elimination.[12]

Tumor antigens have been divided into two categories: shared tumor antigens; and unique tumor antigens. Shared antigens are expressed by many tumors. Unique tumor antigens result from mutations induced through physical or chemical carcinogens; they are therefore expressed only by individual tumors.

In one approach, vaccines contain whole tumor cells, though these vaccines have been less effective in eliciting immune responses in spontaneous cancer models. Defined tumor antigens decrease the risk of autoimmunity, but because the immune response is directed to a single epitope, tumors can evade destruction through antigen loss variance. A process called "epitope spreading" or "provoked immunity" may mitigate this weakness, as sometimes an immune response to a single antigen can lead to immunity against other antigens on the same tumor.[12]

For example, since Hsp70 plays an important role in the presentation of antigens of destroyed cells including cancer cells,[13] this protein may be used as an effective adjuvant in the development of antitumor vaccines.[14]

A vaccine against a particular virus is relatively easy to create. The virus is foreign to the body, and therefore expresses antigens that the immune system can recognize. Furthermore, viruses usually only provide a few viable variants. By contrast, developing vaccines for viruses that mutate constantly such as influenza or HIV has been problematic. A tumor can have many cell types of cells, each with different cell-surface antigens. Those cells are derived from each patient and display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish cancer cells from normal cells. Some scientists believe that renal cancer and melanoma are the two cancers with most evidence of spontaneous and effective immune responses, possibly because they often display antigens that are evaluated as foreign. Many attempts at developing cancer vaccines are directed against these tumors. However, Provenge's success in prostate cancer, a disease that never spontaneously regresses, suggests that cancers other than melanoma and renal cancer may be equally amenable to immune attack.

However, most vaccine clinical trials have failed or had modest results according to the standard RECIST criteria.[15] The precise reasons are unknown, but possible explanations include:

• Disease stage too advanced: bulky tumor deposits actively suppress the immune system using mechanisms such as secretion of cytokines that inhibit immune activity. The most suitable stage for a cancer vaccine is likely to be early, when the tumor volume is low, which complicates the trial process, which take upwards of five years and require many patients to reach measurable end points. One alternative is to target patients with residual disease after surgery, radiotherapy or chemotherapy that does not harm the immune system.
• Escape loss variants (that target a single tumor antigen) are likely to be less effective. Tumors are heterogeneous and antigen expression differs markedly between tumors (even in the same patient). The most effective vaccine is likely to raise an immune response against a broad range of tumor antigens to minimise the chance of the tumor mutating and becoming resistant to the therapy.
• Prior treatments may have modified tumors in ways that nullify the vaccine. (Numerous clinical trials treated patients following chemotherapy that may destroy the immune system. Patients who are immune suppressed are not good candidates for vaccines.)
• Some tumors progress rapidly and/or unpredictably, and they can outpace the immune system. Developing a mature immune response to a vaccine may require months, but some cancers (e.g. advanced pancreatic) can kill patients in less time.
• Many cancer vaccine clinical trials target patients' immune responses. Correlations typically show that the patients with the strongest immune responses lived the longest, offering evidence that the vaccine is working. An alternative explanation is that patients with the best immune responses were healthier patients with a better prognosis, and would have survived longest even without the vaccine.

In January 2009, a review article made recommendations for successful oncovaccine development as follows:[16]

• Target settings with a low disease burden.
• Conduct randomized Phase II trials so that the Phase III program is sufficiently powered.
• Do not randomize antigen plus adjuvant versus adjuvant alone. The goal is to establish clinical benefit of the immunotherapy (i.e., adjuvanted vaccine) over the standard of care. The adjuvant may have a low-level clinical effect that skews the trial, increasing the chances of a false negative.
• Base development decisions on clinical data rather than immune responses. Time-to-event end points are more valuable and clinically relevant.
• Design regulatory into the program from inception; invest in manufacturing and product assays early.

• Immunotherapy
• Cancer immunotherapy
  • Coley's toxins
• Chemoprophylaxis
• HPV vaccines
• Therapeutic vaccines

• Cancer Immunotherapy Consortium (coordinated early-phase clinical trials of therapeutic cancer vaccines)
• Society for Immunotherapy of Cancer
• Association for the Immunotherapy of Cancer