What is Mesothelioma Immunotherapy?

Immunotherapy is a cancer treatment available to people with mesothelioma only through clinical trials. The first immunotherapy study on mesothelioma took place in the 1980s, and since then researchers have tested a number of immunotherapy tactics on the cancer with varying degrees of success.

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When combined with other anti-cancer treatments like chemotherapy, immunotherapy can improve survival rates and reduce symptoms for people with mesothelioma.

Immunotherapy can enhance the immune system response to mesothelioma cancer, but it has not been able to cure the cancer. Doctors hope to use immunotherapy in the future as part of a multimodal treatment plan to better manage mesothelioma like a chronic disease.

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How Does Immunotherapy Work?

A basic understanding of the immune system helps people understand how immunotherapy works. The immune system has evolved to protect the body from foreign pathogens (like viruses and bacteria) and disease development, and it also removes damaged or dead cells. Your immune system recognizes internal and external causes of illness, including cancerous cells.

The two primary mechanisms of the immune response are called passive and active. The passive part of the immune system is our primary defense system that evolved first and is present at birth. The active part, also called the adaptive immune system, develops over time as it learns to recognize foreign pathogens like viruses and bacteria.

Immune Agents

  • Antigens are compounds on the surface of diseased cells and foreign pathogens like viruses that stimulate an immune system response.

  • Antibodies are proteins made by B cells that identify and attack antigens.

  • Cytokines are proteins made by T cells that coordinate immune responses against cancer and foreign pathogens.

Immune Cells

  • Lymphocytes are white blood cells. The three types include:

    1. B cells make antibodies that attack antigens.

    2. T cells make cytokines and attack damaged or diseased cells.

    3. Natural killer cells detect and destroy damaged cells.

  • Dendritic cells carry antigens to T cells and B cells to initiate an immune response.

  • Macrophage cells can swallow and digest worn-out cells and debris.

Active Immunotherapy

Active immunotherapy attempts to stimulate the immune system by presenting antigens in a way that triggers an immune response.

The presence of an antigen (a term derived from antibody generator) in the body springs the immune system into action. For the immune system to garner a response against a tumor, the tumor must have an antigen that distinguishes it from the surrounding normal tissue.

Antigens on the surface of tumor cells can be detected by the immune system, but they must first enter into a lymph node where they can be identified by dendritic cells. Once a tumor antigen is found in a lymph node, the dendritic cell delivers it to T cells and B cells, and the immune response begins.

Mesothelioma tumors tend to grow locally and do not spread to distant parts of the body as often as some other cancers. The tumors can grow considerably before spreading to the lymph nodes, where the immune system can recognize tumor antigens.

Tumor Antigens

Few mesothelioma tumor antigens seem to exist. The most therapeutically valuable antigen is mesothelin.

To test the effectiveness of mesothelin as an immunotherapeutic agent, researchers developed a protein known as SS1P made up of a certain fragment of the anti-mesothelin antibody and linked it to the toxin secreted by the bacteria known as Pseudomonas.

The bacteria toxin is used as a vector, a substance used to transfer the SS1P protein to the cell. It was tested in mice and was found to be so effective that researchers initiated a Phase I clinical trial. Twenty-one patients with mesothelioma were tested, four of which had a partial response and 19 of which experienced disease stabilization. The Phase I trial is ongoing and researchers plan to conduct larger trials.

Other antigens that showed limited use as markers and possible targets for immunotherapy include osteopontin and MUC-1. Their use is limited for the treatment of mesothelioma because they are common in many types of tumor, which makes them less specific than mesothelin.

Cell Immunotherapy

Transferring live, whole immune cells into patients is a practice that researchers use on patients with advanced metastatic melanoma or renal cell carcinoma. It is also being investigated for use in patients with mesothelioma.

Injection of dendritic cells following chemotherapy has been tested in a Phase I clinical trial. Ten patients previously treated with cisplatin and pemetrexed tolerated the therapy well, and an immune response was documented in the study's participants.

Passive Immunotherapy

Rather than attempting to trigger an immune system response, passive immunotherapy for cancer more directly targets the disease at hand and involves the injection of immune compounds that attack the cancer. These immune compounds include antibodies, cytokines, T cells and macrophages. The objective of passive immunotherapy is to provide immediate protection against tumor antigens.

Passive immunotherapies are specific or non-specific.

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Specific Passive Immunotherapy

Specific passive immunotherapies directly target tumor antigens with monoclonal antibodies, cytotoxic T cell clones or tumor infiltrating lymphocytes.

Monoclonal Antibodies

Monoclonal antibody therapy (mAb) is the most commonly used form of cancer immunotherapy, but not necessarily the most common immunotherapy for mesothelioma. It is considered a targeted therapy because it is focused on a single site within the cancer cell, either an antigen on the surface of the cell or an enzyme or protein within the cell.

Monoclonal antibodies are produced synthetically in a laboratory by the cloning of a single cell line. Monoclonal antibodies have identical antibody molecules as the antibodies from which they were cloned.

These monoclonal antibodies target only specific antigens on the surface of a mesothelioma cancer cell, such as the antigen mesothelin. When the antibody recognizes the antigen it normally fights, it sets off a chain reaction that ends with the death of the tumor cell. Monoclonal antibodies usually do not need the immune system to destroy cancer cells.

However, there are limitations to monoclonal antibodies. Among them:

  • Their effectiveness is diminished because they are not used as first-line therapy. Typically, this type of therapy is used after the patient undergoes surgery, chemotherapy and/or radiation therapy without success. The toll these therapies take on the body may limit the ability of the mAb therapy to work.

  • Not every patient may have the antigen against which the mAb therapy is directed. Two patients with mesothelioma do not necessarily have the same antigens associated with the disease. The success rate for targeted therapies is judged at 20 to 30 percent.

  • Patients who undertake chemotherapy or radiation therapy may have tumor cells that have mutated. That alters the antigen on the cell surface at which the mAb therapy is directed. If the antigen is altered, the monoclonal antibody will not recognize it.

  • Finally, a high level of toxicity is associated with this kind of therapy.

Amatuximab (known as MORAb-009) is a monoclonal antibody that made it to a Phase II clinical trial on mesothelioma patients. Not enough patients responded to the therapy to warrant a Phase III trial. Overall survival was 14.8 months, and the average survival for mesothelioma is around one year.

Non-specific Passive Immunotherapy

Non-specific passive immunotherapies involve the use of cytokines, lymphocyte activated killer cells (LAK), macrophages or bacillus Calmette-Guerin.

Cytokines

Cytokines such as tumor necrosis factor, interferon and interleukin-2, are used in immunotherapy to cause cancer cells to die or to stop creating new cells. They interact directly with the tumor cells and are given individually or in combination to take advantage of the effect of all of them working together, which is more effective than what each can do individually.

Using cytokines non-specifically to boost the immune response includes:

  • Interleukin-2 to stimulate the creation of T-cell and natural killer (NK) cells.

  • Interferon to make antigen-presenting cells (such as dentritic cells) more effective and increase the production of immune molecules like MHC, which help T cells recognize antigens.

Bacillus Calmette-Guerin

During the 1970s, researchers discovered that administering weakened forms of a mycobacterial strain called bacillus Calmette-Guerin (BCG) was effective in treating cancer. BCG is made from a live strain of tuberculosis virus found in oxen and cows.

BCG is approved for treating bladder cancer and as a vaccine for tuberculosis. In the 1970s and '80s, studies were conducted on its usefulness as a treatment for mesothelioma and pleural effusions. In one study, BCG was injected into mesothelioma patients and repeated monthly. The injections prevented reaccumulation of fluid in the lung cavity.

Another study involved 30 patients with various stages of malignant pleural mesothelioma. Patients first underwent a thoracotomy in which as much of the cancerous tissue as possible was removed. Following chemotherapy or radiation, BCG injections were administered every three weeks. After six weeks, the treatment interval was lengthened to four, five and then six weeks.

Twenty-eight out of 30 patients continued to receive injections, and they reported that the injections made them feel much better and that pain was significantly reduced. The researchers noted that the best prognosis was achieved when BCG was used in patients with a relatively light tumor load who had undergone thoracotomy. These patients survived an average of 21.5 months, and one patient was alive six years after treatment.

While BCG showed early promise in the 1970s and '80s, it is not currently being offered as a treatment for mesothelioma. However, current immunotherapy studies have been conducted with other forms of mycobacterium, including SRL 172, which failed to find it effective against mesothelioma and non-small-cell lung cancer.

Future of Immunotherapy for Mesothelioma

There are reasons to believe that immunotherapy will become effective for mesothelioma in the future, especially when combined with other cancer therapies. Some studies have combined chemotherapy with immunotherapy, and the results indicate a small survival benefit in certain patients. Further immunotherapy research for mesothelioma continues in clinical trials.

Researchers have discovered a direct correlation between penetrating lymphocytes and mesothelioma prognosis, indicating that enhanced immune response may improve patient outcome. Additionally, laboratory studies of asbestos suggest the mineral compromises immune cells, which could contribute to the mineral's carcinogenic effect in people. Preventative immunotherapy strategies in people exposed to asbestos could offer chemopreventative benefit in the future, but identifying who could biologically benefit from such therapy is currently challenging.

Additional Resources

  1. Gregoire, M. (2010). What’s the place of immunotherapy in malignant mesothelioma treatments? Cell Adhesion & Migration, 4(1): 153-161. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852572/
  2. Hegmans, J.P., Veltman, J.D., Lambers, M.E., de Vries, I.J., Figdor, C.G., Hendriks, R.W., … Aerts, J.G. (2010). Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. American Journal of Respiratory and Critical Care Medicine, 181(12): 1383-1390. doi: 10.1164/rccm.200909-1465OC http://clinicaltrials.gov/show/NCT01362790
  3. Mallory, Y.D. & Hassan, R. (2014, Feb. 14). SS1P and pentostatin plus cyclophosphamide for mesothelioma. Retrieved from http://clinicaltrials.gov/show/NCT01362790
  4. National Institutes of Health. (2008, Oct. 2). Immune cells and their products. Retrieved from http://www.niaid.nih.gov/topics/immunesystem/immunecells/Pages/default.aspx
  5. O’Brien, M.E.R., Saini, A., Smith, I.E., Webb, A., Gregory, K., Mendes, R., … Souberbielle, B.E. (2000). A randomized phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small-cell lung cancer and mesothelioma. British Journal of Cancer, 83(7), 853-857. doi: 10.1054/bjoc.2000.1401
  6. O’Brien, M.E.R., Anderson, H., Kaukel, E., O’Byrne, K., Pawlicki, M., von Pawel, J., & Reck, M. (2004). SLR 172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival in patients with advanced non-small-cell lung cancer: Phase III results. Annals of Oncology, 15: 906-914. doi: 10.1093/annonc/mdh220 http://www.ncbi.nlm.nih.gov/pubmed/7058460
  7. Webster, I., Cochrane, J. W. C., & Burkhardt, K. R. (1982). Immunotherapy with BCG vaccine in 30 cases of mesothelioma. South African Medical Journal, 61(8): 277-278. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7058460
  8. Yamamura Y., Ogura, T., Yoshimoto T., Nishikawa, H., & Sakatan i, M. (1976). Successful treatment of the patients with malignant pleural effusion with BCG cell-wall skeleton. Gann Japanese Journal of Cancer Research, 67(5): 669-677. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/797625

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