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Researchers have been working on cancer vaccines and trying to induce the immune system to attack tumors for a couple of decades and they have failed. Why is it so hard to develop cancer vaccines?
Cancer vaccines are designed to activate the patient's immune system to kill tumor cells and leave normal tissue alone. The vaccine must be able to activate antibodies and/or lymphocytes against tumor-associated antigens (TAAs) on the tumor.
There are two types of therapeutic approaches, passive and active immune therapy. Passive immune therapy uses antibodies to directly target tumor cells. Active immune therapy uses cancer vaccines composed of tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-idiotype antibodies that mimic TAAs or look like antigens, to "trick" the immune system into generating an immune response against the antigen that they "look like."
Nonspecific immune-based therapies such as immune stimulant Bacillus Calmette-Guérin (BCG) for bladder cancer stimulates a general immune response, while with "active" specific immunotherapy, the goal is to activate the immune system to fight tumor cells and spare the surrounding normal tissue. Developing a specific immunotherapy as a vaccine will activate a unique lymphocyte (such as a B cell or T cell) response, that will have an immediate anti-tumor effect and also a "memory response" to help fight future tumor challenges.
There are two basic types of tumor cell vaccines: 1) autologous vaccines - made from the patient's own tumor cells. These cells are extracted from the patient, inactivated (killed), made into a vaccine in the lab, and then re-injected into the patient; and 2) allogeneic vaccines - developed in the lab from tumor cell lines or other sources of tumor products that do not come from the patient's tumor cells.
But there are many different type of tumor cell vaccines:
- Autologous tumor vaccines
- Allogeneic whole-cell vaccines
- Dendritic cell vaccines
- Viral oncolysates
- Polyvalent shed antigen vaccines
- Peptide vaccines
- Anti-idiotype vaccines
- Genetically modified vaccines
- Recombinant viral vaccines
- DNA vaccines
The goal of a therapeutic cancer vaccine is to activate the immune system by way of antibodies or lymphocytes, against tumor-associated antigens presented by the tumor. Antibodies must recognize antigens on the tumor cell's surface and once bound, these molecules can cause tumor cell death. However, T lymphocytes can recognize proteins as fragments (or, peptides) of varying size as major histocompatibility (MHC) antigens on the surface of the cells (MHC antigens affect immune response by recognizing "foreign" versus "non-foreign".) While the mechanism of action is beyond the scope of this article, as you can see the immune system is very complex and many potential cancer vaccines have failed to materialize.
There are two types of cancer vaccines, prophylactic and therapeutic. To date, there is only one therapeutic vaccine available, Provenge for prostate cancer, which is an autologous active specific vaccine made from the patient's immune cells.
The treatment is indicated for patients with advanced prostate cancer who've already had therapy and failed hormonal therapy. It has been shown to prolong survival by a little more than four months. However, this process is very time consuming and costly.
The reason cancer vaccines have failed miserably over the past two decades is because while T cells in the immune system could be trained to recognize the tumor, the tumor had its own tricks to evade them, said Dr. Samir N. Khleif, Director of the Georgia Regents University Cancer Center (GRU).
The problem is that the tumor has developed a "tumor immune regulatory network, where the tumor is really through a network, having multiple levels of strategies inhibiting the immune response," Khleif said.
His lab is working with an antibody in combination with the chemotherapy drug cyclophosphamide, to inhibit a mechanism that tells the T cells to go to sleep, rather than help in the immune response, as a key part of his strategy.
Researchers must disrupt multiple tumor defense mechanisms, which allows the immune-boosting response from the immune cells to kill or suppress the tumor, Khleif said.
He said that this method provides "a better environment with less obstacles (for the vaccine) to work and it also provides them a better environment to come to the tumor itself."
According to Kenneth A. Foon, MD, and Malek M. Safa, MD in an article regarding cancer vaccines, there are 5 mechanisms by which a tumor cell can escape immune system surveillance.
1. "Dendritic cells are actively inhibited in the tumor milieu. Both immature and defective dendritic cells are described in a variety of tumors. In addition, dendritic cells that present tumor antigens may fail to reach the T cells in lymph nodes that generate active immune responses against tumors. The immune response may be skewed toward a Th2 response, which is antibody directed rather than cytolytic T cell directed, or T cells may be anergic, unable to generate an immune response.
2. Immune regulatory cells may contribute to immune tolerance to cancer cells. CD4 positive T cells (T-reg) with a high affinity receptor for CD25 that co-express the intracellular marker Foxp3 also play an important role in immune tolerance.20,21
3. Mutation or down regulation of immunodominant tumor antigens, MHC molecules, or molecules involved in the antigen processing machinery may also, in part, explain the escape of tumor cells from immune recognition. 22-24 Down regulation or mutation of pro-apoptotic molecules and expression of anti-apoptotic molecules may also render tumor cells resistant to apoptosis.
4. Tumor cells may acquire mechanisms that may actively contribute to immune tolerance. For instance, Fas ligand (FasL)-expressing tumors can deliver an apoptotic signal to activated T cells and natural killer cells expressing Fas receptor.
5. The tumor micro-environment may also contain soluble factors that inhibit T cell function. Factors such as TGF beta, prostaglandins, IL-10, and catabolizing enzymes produced by tumor cells themselves or by stromal cells that may lead to T cell hyporesponsiveness."
Drs. Foon and Safa concluded that "the platform for therapeutic vaccines is broad... Dendritic cells are an extremely appealing vaccine approach; however, they are limited by the difficulties associated with patient-specific cell therapies. To date, no specific approach to vaccine therapy has emerged as clearly superior. Strategies to enhance the immune response will be the next most important step in therapeutic cancer vaccines. Monoclonal antibodies inhibiting T-regs, the use of a variety of cytokines, and toll-like receptor stimulation are among the strategies that will be employed."
Since there are a number of approaches to making a cancer vaccine. I will discuss three approaches that three different institutions are working on currently.
1) Dr. Samir N. Khleif, Director of the Georgia Regents University Cancer Center and Advaxis Inc. of Princeton, N.J have entered into a collaboration to develop and target the human papilloma virus for cervical cancers or HPV-related cancers such as head and neck cancers.
"We're developing multiple mechanisms to not only enhance this T cell part, but also to actually restructure the microenvironment of the tumor to make the T cell able to kill the tumor," Khleif said.
In the case of the Advaxis technology, it uses a live, but deactivated, form of the Listeria monocytogenes bacteria as a delivery vehicle not only for the T cell targeting aspect, but also to attack tumor defenses with what it calls "checkpoint inhibitors," said Greg Mayes, the Chief Operating Officer for Advaxis.
"It is a disruptive technology that when combined with the checkpoint inhibitors, could be a really just fantastic solution and approach to cancer immunotherapy," said Mayes.
"It's a natural process and very targeted and utilizes the power of what we have already, what God gave us already in our body, to try to actually utilize it to fight cancer. This is why it is a beautiful antigen because when you generate a response of T cells against it, the antigen is present in the cancer and not in the normal cells, so you are not going to generate an autoimmune disease based on that antigen," Khleif said.
 | | The Jantibody fusion protein, combining an antibody fragment targeting an antigen found on tumor cells with an immune-response-inducing protein (MTBhsp70), activates dendritic cells against several tumor antigens and induces a number of T-cell-based immune responses. Image: Jianping Yuan, Mass General Vaccine and Immunotherapy Center. |
2) Investigators from Harvard Medical School and the Massachusetts General Hospital Vaccine and Immunotherapy Center have engineered a protein that is able to prolong survival in animal models of ovarian cancer and mesothelioma. Their success came from combining a molecule that targets a tumor-cell-surface antigen with another protein that stimulates several immune functions as reported in the Journal of Hematology & Oncology.
The vaccine would stimulate the patient's own dendritic cells, which monitors an organism's internal environment for the presence of viruses or bacteria. These cells also ingest and digest pathogens they encounter and display antigens from those pathogens on their surfaces, to direct the activity of other immune cells.
Unlike existing cancer vaccines that use dendritic cells which are extracted from a patient, modified and then give it back to the patient, their approach is done inside the patient's body. The Mass. General team first engineered a protein by linking a single-chain antibody variable fragment (scFv) targeting mesothelin-overexpressed on the surface of mesothelioma, ovarian cancer and pancreatic cancer tumors-to a protein called Mycobacterium tuberculosis (MTB) heat shock protein 70 (Hsp70), which is a potent immune activator. When injected, this fused protein stimulates the activity of dendritic and other immune cells. In mouse models of both ovarian and mesothelioma, treatment with the fusion protein significantly slowed tumor growth and extended survival, believed to be through the activity of cytotoxic CD8 T cells.
"Many patients with advanced cancers don't have enough functioning immune cells to be harvested to make a vaccine, but our protein can be made in unlimited amounts to work with the immune cells patients have remaining," explained study co-author Jeffrey Gelfand, HMS clinical professor of medicine at Mass. General. "We have created a potentially much less expensive approach to making a therapeutic cancer vaccine that, while targeting a single tumor antigen, generates an immune response against multiple antigens. Now if we can combine this with newly described ways to remove the immune system's 'brakes'-regulatory functions that normally suppress persistent T-cell activity-the combination could dramatically enhance cancer immunotherapy."
3) For the first time, scientists at the Walter and Eliza Hall Institute in Parkville, Victoria, Australia, in collaboration with other immunologists, protein chemists and structural biologists, have identified a protein called Clec9A (C-type lectin domain family 9A) on the surface of specialized types of dendritic cells also called antigen-presenting cells (APCs) that recognizes and responds to damaged and dying cells by waking up resting T cells for an immune response.
Dr Mireille Lahoud, co-leader of the team and now at the Centre for Immunology at the Burnet Institute in Melbourne, told the media that she and co-author Irina Caminschi, also at the Burnet Institute, have found that Clec9A recognizes and binds to fibres of actin, a type of internal cell protein, that is present in all cells of the body.
"Actin is only exposed when the cell membrane is damaged or destroyed, so it is an excellent way of finding cells that could harbor potentially dangerous infections and exposing them to the immune system," explained Lahoud.
Targeting Clec9A could lead to a new, more modern class of vaccines, one that is more effective and has fewer side effects. The new vaccines could bind to Clec9A and trick dendritic cells into reacting as if damaged cells were present and launch an immune response to the infectious agent for that specific type of vaccine.
Professor Ken Shortman at the Walter and Eliza Hall Institute and co-leader of the team, said that with this approach specific cells are targeted and you would need significantly less, about 100 to 1,000 times less, vaccine to generate immunity, as opposed to "traditional vaccine technology, where large amounts of vaccine is needed to encounter the correct immune cells, and incorporate other substances (adjuvants) that are needed to signal to the immune system that something foreign is happening."
"There is also the possibility that the system could be used to develop therapeutic vaccines for treating diseases, such as some forms of cancer, as well as for preventing them," said Lahoud.
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