Certain Types of Cancer Can Be Slowed With Vaccines

Examining How Vaccines Can Be Used to Fight Existing Cancer

injection
Photographer/Getty Images

Immunotherapy is rapidly emerging as a dynamic tool to fight disease, especially disease that is hard to treat. With cancer immunotherapy, the immune system is leveraged to fight tumors in novel ways. Immunotherapy interventions can either directly stimulate the immune system or present the immune system with artificial proteins, or antigens, to thus train the immune system on tumors.

Cancer treatment vaccines are a form of immunotherapy used to treat cancers that already exist.

More generally, cancer treatment vaccines are biologics, or biopharmaceuticals. Other biologics include blood components, gene therapy, allergenics, and other vaccines.

Currently, the only cancer vaccine that the FDA has approved is called Provenge to treat prostate cancer.

How Do Cancer Treatment Vaccines Work?

Antigens are substances that trigger an immune system response. Many cancer treatment vaccines in development provide cancer-associated antigens to dendritic cells. These dendritic cells are immune cells that lie directly in the point of injection (dermis) and process the antigen. Furthermore, immunostimulatory molecules present in the cancer vaccine upregulate, or increase production, of molecules needed to eventually interact with T cells. Of note, cancer-associated antigens can be specific either to one type of cancer or a group of several cancers.

These activated dendritic cells migrate to lymph nodes, which are small clumps of immunologic tissue located throughout the body.

Once these activated dendritic cells make it to a lymph node, they present the cancer-specific antigen to T cells. Activated T cells then travel throughout the body and target cancer cells that present with the antigen and lyse, or break down, the cancer cell. (More technically, activated CD4+ T cells produce cytokines which facilitate the maturation of CD 8 cells, which after maturation travel throughout the body.)

According to the FDA, several cancer vaccines currently in development use bacteria, viruses, or yeast as vehicles, or vectors, to transport antigens. Bacteria, viruses, yeast and so forth are naturally immunogenic and trigger an immune response on their own; however, they are modified so as not to cause disease.

Alternatively, cancer treatment vaccines can be formulated using DNA or RNA that code for antigens. This genetic material is then incorporated into cells which then produce the antigens. The hope is that these modified body cells will then produce enough cancer-associated antigens to induce a vigorous immune response to kill off tumor cells.

Ultimately, three criteria must be met for tumor cells to be destroyed by a vaccine:

  • a sufficiently large quantity of immune cells with pronounced affinity for cancer cells must be produced
  • these T cells must be able to infiltrate the tumor
  • these T cells must start working at the tumor site to cause site-specific damage

How Effective Are Cancer Vaccines?

During the past several years, hundreds of cancer (dendritic-cell) vaccines have been tested.

However, response rates to these vaccines is very low—about 2.6 percent. In fact, other types of immunotherapy have proven to be much more effective, which has influenced many experts to question our "obsession" cancer therapeutic vaccines.

So if cancer therapeutic vaccines are rarely effective in humans, why are we continuing to invest resources and time into the development of cancer vaccines? There are at least three reasons explaining our interest in this type of intervention.

First, vaccines have been effective at preventing cancer, and this success has carried over to treatment of cancer with vaccines. In other words, the work we've done developing preventive cancer vaccines has taught us lots about the immunology of cancer cells and has provided a theoretical framework for the development of cancer treatment vaccines. There are currently two vaccines that prevent cancer: the hepatitis B vaccine prevents liver cancer, and the human papilloma virus (HPV) vaccine prevents throat, cervical, anal and other cancers

Second, cancer therapeutic vaccines are easy to administer and cause few serious adverse effects.

Third, researchers are often biased in their interpretation of results of trials involving cancer therapeutic vaccines, which feeds into the hype surrounding this type of intervention. Specifically, researchers tend to focus on meaningless histological, or cellular, changes and lymphocte (T cell) inflitration of tumors instead of focusing on real change: decrease in tumor size or improvement in clinical symptoms.

Moreover, principal investigators examining cancer vaccines often use misleading descriptions and words to characterize results, such as "symptoms disappeared," "temporary growth cessation in some individual metastases," "tumor necrosis" and "unexpectedly long survival." Without further details, these terms mean little. 

On a related note, much cancer vaccine research has been done on the basic medical sciences level using animal models. Mice, as one can probably infer from their size, behaviors and furry appearance, are different from human beings. Thus, any success we see in treating these animals with cancer therapeutic vaccines doesn't necessarily translate to humans.

More specifically, although cancer vaccines have been proven to be effective in animals, it's infrequent to discover any such effect in humans. Specifically, there is only one cancer therapeutic vaccines approved by the FDA for the treatment of cancer in humans: Provenge. However, there's another prostate cancer vaccine currently in Phase 3 trials that has proven to be effective: Prostvac.

Before we look at both Provenge and Prostac, let's all remind ourselves a little about prostate cancer.

What Is Prostate Cancer?

Aside from skin cancer, prostate cancer is the most common cancer affecting American men. Although nearly 1 in 7 American men develops prostate cancer, far fewer die of the disease (about 1 in 39). Instead, men often die of some other disease first, like heart disease. Nevertheless in 2016, there were 26,120 deaths caused by prostate cancer.

Because of widespread testing for prostate-specific (PSA) antigen, a biomarker for prostate cancer, we've been able to detect cases of prostate cancer earlier, while the cancer is still confined to the prostate, More rarely, men present with prostate cancer that has metastasized or spread to the bones and becomes deadly.

Factors that increase risk for prostate cancer include older age, African American race and family history.

Most people with prostate cancer don't need treatment and instead are observed by their physicians. Treatment for prostate cancer can include expectant management (active surveillance), surgery (prostatectomy or removal of the prostate), radiotherapy and androgen, or sex hormone, deprivation. 

What Is Provenge?

Provenge or sipuleucel-T is a dendritic-cell vaccine that was approved by the FDA in 2010. Provenge is what's known as an autologous cellular immunotherapy and is used to treat metastatic disease that hasn't spread very far yet (minimally invasive). Furthermore, Provenge treats prostate cancer that isn't sensitive to hormones (hormone refractory).

On a related note, hormone refractory cancers respond to hormone-deprivation therapies, or drugs that mess with androgens, or sex hormones (think medical castration).

Provenge is prepared using a patient's white blood cells (peripheral blood mononuclear cells) pulsed with a protein called granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostatic acid phosphatase, or PAP, a prostate cancer antigen.

The reason why GM-CSF is given with the antigen PAP is because researchers believe that GM-CSF facilitates the presentation of the antigen. Of note, the peripheral blood mononuclear cells serve as the dendritic cells to which the antigen is presented.

Unfortunately, Provenge extends life by only about 4 months. Nevertheless, this time may allow a person to get his affairs in order and spend a little more time with his family.

Adverse effects of Provenge include the following:

  • fever
  • chills
  • fatigue
  • back pain
  • headache

During clinical trials of Provenge, a few men experienced more serious adverse effects including difficulty breathing, chest pain, irregular heartbeat, fainting dizziness and fluctuations in blood pressure. Thus, people with heart and lung problems should discuss these conditions with their health care provider.

What Is Prostvac?

The mechanism of Prostvac differs from Provenge.

Prostvac consists of a poxvirus (fowlpox) vector, prostate-specific antigen (PSA) and a costimulatory complex called TRICOM. This PSA-TRICOM vaccine infects antigen-presenting cells causing them to express prostate-specific antigen proteins on their surface. These antigen-presenting cells then present to T cells and train them to attack prostate cancer cells.

Prostvac Phase 2 clinical trials included 82 participants of which 42 received Prostvac. Prostvac extended life in the experimental group by a median value of 8.5 months. Currently, Prostvac is in Phase 3 clinical trials, and researchers are not only trying to confirm survival benefit of the drug but also trying to figure out whether GM-CSF should be added to the vaccine.

During Phase 2 clinical trials, adverse effects of Prostvac were included the following:

  • injection site reactions (pain, swelling, redness and so forth)
  • fatigue
  • fever
  • swelling
  • chills
  • joint pains
  • dizziness
  • nausea
  • vomiting
  • diarrhea
  • constipation

How Are Prostate Cancer Vaccines Used?

Prostate cancer vaccines aren't meant to be used as first-line treatment of prostate cancer. Instead, they are administered in addition to chemotherapy.

On a Related Note: What Is Imlygic?

I should probably mention that in 2015, the FDA approved an Imlygic, an oncolytic vaccine for the treatment or malignant melanoma that's inoperable. Although technically not a cancer therapeutic vaccine, Imlygic has secodnary effects similar to cancer therapeutic vaccines.

Oncolytic viruses are a type of immunotherapy where a genetically engineered virus is injected directly into a melanoma tumor and lyses or breaks tumor cells down. In addition to breaking down the cells, these viruses have a more general effect of eliciting an antitumor effect similar to anticancer vaccines.

What Do Cancer Therapeutic Vaccines Mean to Me?

Currently, the use of cancer vaccines in clinical settings is limited. Additionally, as mentioned earlier, it's been really hard to find cancer vaccines that have any effect on human participants. It's unlikely that we'll see cancer vaccines used to treat a variety of cancers any time soon.

Nevertheless, cancer vaccines represent advancements of the immune system as well as the field of immunotherapy. The better we understand the specifics immune system, the better we can target therapies that could someday save lives.

Sources:

Goswami S, Allison JP, Sharma P. Immuno-Oncology. In: Kantarjian HM, Wolff RA. eds. The MD Anderson Manual of Medical Oncology, 3e. New York, NY: McGraw-Hill; 2016. Accessed May 19, 2016.

Kantoff PW et al. Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2010 Mar 1; 28(7): 1099–1105.

Pienta KJ. Chapter 96. Prostate Cancer. In: Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, Asthana S. eds. Hazzard's Geriatric Medicine and Gerontology, 6e. New York, NY: McGraw-Hill; 2009. Accessed May 22, 2016.

Rosenberg SA, Yang JC Restifo NP. Cancer Immunotherapy: Moving Beyond Current Vaccines. Nat Med. 2004 September: 10(9): 909-915.

Continue Reading