Cancer And The Immune System II PDF

Cancer and The Immune System II PRESENTED BY: DR. AMIRA ZAITOUN Cancer and The Immune System In 1909, the German scientist Paul Ehrlich proposed that the incidence of cancer would be much higher were it not for the action of our immune system in recognizing and eliminating tumor cells. Half a...

Cancer and The Immune System II PRESENTED BY: DR. AMIRA ZAITOUN Cancer and The Immune System In 1909, the German scientist Paul Ehrlich proposed that the incidence of cancer would be much higher were it not for the action of our immune system in recognizing and eliminating tumor cells. Half a century later, two scientists, Lewis Thomas and Frank M. Burnet proposed the model of “immunosurveillance,” where cells of the immune system actively patrol the body looking for cancerous cells and eliminate them as they arise. Cancer and The Immune System This idea became a grounding principle of the new field of cancer immunology that took shape beginning in the 1950s. An important breakthrough came in 2001, when Robert D. Schreiber, Lloyd J. Old, and Mark J. Smyth, showed that mice genetically engineered to lack important immune system components had higher rates of cancer. Patients with HIV/ AIDS, whose immune systems are severely compromised, were noted to have higher rates of a rare cancer called Kaposi sarcoma. Cancer and The Immune System Patients receiving organ transplants whose immune systems were medically suppressed to prevent organ rejection also had higher rates of several types of cancer. These data clearly showed that the immune system helps to protect us from cancer. Cancer immunotherapy In the early 1890s, William B. Coley, M.D., a New York-based surgeon, stumbled upon a surprising finding in case files at the hospital where he worked: a patient’s cancer had regressed after he came down with an acute bacterial infection. Coley decided to try an experiment in which he deliberately injected live bacteria into a patient with inoperable cancer to see whether the patient’s tumor would regress. To his astonishment, the experiment worked, and the patient lived for another 26 years until a heart attack took his life. Cancer immunotherapy Coley continued to pursue his approach and ultimately developed a mixture of killed bacteria that became known as Coley’s mixed bacterial toxins, or simply “Coley’s toxins.” He and other physicians treated over 1,000 cancer patients with these toxins, with varied success. Though the treatment clearly worked in some cases, the results were unpredictable, and neither Coley nor the medical community at large could explain precisely why his mixture worked when it did. As other cancer treatments—first radiation, then chemotherapy—became popular, Coley’s method faded from view and was virtually forgotten for years.  Cancer immunotherapy Renewed interest in Coley’s work was sparked by his daughter, Helen Coley Nauts, who, in the 1940s, began compiling and disseminating information on patients treated with the toxins. Nauts’s work showed clearly that many patients had indeed benefited—sometimes achieving complete remissions—from Coley’s toxins. Gradually, as scientists learned more about the immune system, they began to understand how Coley’s preparation worked: the bacterial products of which it was composed had acted as immune stimulants, goading the immune system into killing the cancer cells along with the bacteria. Cancer immunotherapy To support research into this area, Nauts founded the Cancer Research Institute in 1953, which ever since has funded the work of scientists studying the link between cancer and the immune system. Today, cancer immunology is a thriving field and Coley has come to be regarded as the “Father of Cancer Immunotherapy.” Types of Immunotherapy A. Non-specific immune stimulants These treatments rev up the immune system against all types of pathogens and cancers, they are sometimes referred to as “non-specific immunotherapy”. Although first introduced decades ago, these treatments can still be helpful in some instances and may be the best treatment for certain cancers. Non-specific immune stimulants 1. Bacillus calmette-guérin (BCG) The first modern non-specific cancer immunotherapy was Bacillus Calmette- Guérin (BCG), a weakened form of the bacterium that causes tuberculosis. In the early 20th century, BCG was used as a vaccine against tuberculosis. In the late 1950s, researchers began experimenting with BCG in cancer. Bacillus calmette-guérin (BCG) A now-classic paper published in 1959 by Lloyd J. Old, M.D., and colleagues described the effect of BCG on tumor growth in mice. Old injected BCG into mice and then transplanted tumors into them. Remarkably, he found that mice injected with BCG had increased resistance to tumor growth compared to mice that had not received BCG. The BCG-treated mice also lived longer. Bacillus calmette-guérin (BCG) In 1990, BCG was approved by the FDA as first-line treatment for early forms of bladder cancer, for which it is still used as a mainstay of therapy. BCG is now known to be a Toll-like receptor (TLR) agonist and a potent activator of the immune response. Non-specific immune stimulants 2. Cytokines Cytokines promote tumor immunity in several ways. Some cytokines, such as tumor necrosis factor alpha (TNFα) and interferon alpha (IFNα), interact directly with tumor cells, inducing them to either commit suicide or stop growing. Other cytokines, such as IL-2 and GM-CSF, activate important immune cells such as natural killer (NK) cells, T cells, and dendritic cells. Cytokines Cytokine therapy is approved for clinical use in several cancers. For example, IL-2 is FDA approved for the treatment of melanoma and kidney cancer. IFNα is FDA approved for the treatment of melanoma and certain types of leukemia, lymphoma and sarcoma. Because they stimulate the immune system in a general way, cytokines are often combined with other immunotherapies. Cytokines Cytokines are also being studied for their role in contributing to cancer development. One way they might do this is by promoting chronic inflammation, which has been linked to the development of several types of cancer, including colorectal, bladder, and pancreatic cancer. Therapies designed to reduce the levels of inflammatory cytokines in and around tumors are currently being tested as a way to improve responses to immunotherapies. Types of Immunotherapy B. Antibody immunotherapies All the immunotherapies discussed in the previous section have in common the fact that they are not directed at any particular antigen in particular; they stimulate immune cells in a general way. By contrast, the immunotherapies discussed in this section are specific immunotherapies—ones that target particular antigens. Antibody immunotherapies 1. Monoclonal antibodies Since the mid-1970s, it has been possible to generate abundant quantities of specific antibodies in the laboratory for use as medicines. These purified molecules, called monoclonal antibodies, can be likened to heat-seeking missiles, selectively targeting one specific antigen. Monoclonal antibodies Monoclonal antibodies can provide therapeutic benefits in several different ways: 1. They can physically interfere with important signaling molecules on cancer cells and halt their growth 2. They can promote destruction by macrophages or NK cells 3. They can activate complement that causes tumor cells to burst. 4. Monoclonal antibodies can also be fitted with poisons or radioactive isotopes that deliver a deadly payload to cancer cells. Monoclonal antibodies To date, nearly 20 monoclonal antibodies have been approved by the FDA for use in cancer treatment. Three of the most common are Rituxan®, Herceptin®, and Avastin®. Rituxan (rituximab) is a monoclonal antibody specific for an antigen called CD20, found on the surface of both normal and cancerous B cells. Rituxan destroys cells displaying the CD20 marker by promoting phagocytosis and complement lysis. Monoclonal antibodies Rituxan was approved by the FDA in 1997 for the treatment of relapsed or refractory B cell non-Hodgkin lymphoma. In February 2006, Rituxan received FDA approval as first- line treatment of diffuse large B cell lymphoma (DLBCL) in combination with chemotherapy (R-CHOP). It is also approved for the treatment of CD20-positive chronic lymphocytic leukemia (CLL). Monoclonal antibodies While the CD20 marker is found on both normal B cells and cancerous B cells, it is absent from the plasma cells that make antibodies, so humoral immunity is not completely interrupted by this treatment. And because new B cells are continually born, blood levels of B cells will likely return to normal following treatment with Rituxan. Antibody immunotherapies 2. Bispecific antibodies A newer form of antibody therapy involves bispecific antibodies— antibodies genetically engineered to recognize two different targets. These two-pronged proteins are formed by physically joining two different monoclonal antibodies together. The most common form of bispecific antibodies are bispecific T cell engagers (BiTEs), which bind to a tumor antigen on one end and a “killer” T cell on the other. Bispecific antibodies Through this dual action, the BiTE brings the T cell in close contact with the tumor cell, allowing the T cell to kill the tumor cell. One BiTE is currently FDA approved for the treatment of B cell leukemia. Called Blincyto® (blinatumomab), this drug recognizes CD3 on T cells and CD19 on B cells. The FDA approval of this drug was based on a phase II clinical trial showing that, of the 185 patients treated, 41.6 percent achieved complete remission with Blincyto. Types of Immunotherapy C. Adoptive cell therapy Adoptive cell therapy involves removing immune cells from a patient, expanding them outside the body, and then reinfusing them into the patient. Most often, the cells are manipulated in some way in the lab before giving them back to a patient. Adoptive cell therapy 1. Tumor-infiltrating lymphocytes In patients with cancer, immune cells will often be found associated with the tumor. Among these immune cells are tumor-infiltrating lymphocytes (TILs) that recognize cancer. TILs can be isolated from a tumor and expanded in the lab by treating them with the T cell growth factor IL-2. These pretreated TILs can then be infused back into the patient. 1. Tumor-infiltrating lymphocytes In a 2011 study, 20 of 93 melanoma patients (22 percent) treated with TILs achieved complete tumor regression, and 19 of these 20 (93 percent) were in complete remission nearly 5 years later. Care must be taken when interpreting such results since the trial was not randomized, but still the results show that the approach can work very well for some patients.  Tumor-infiltrating lymphocytes It appears necessary to first ablate, or kill off, the patient’s immune system with high dose chemotherapy or full-body radiation—called lymphodepletion. This somewhat drastic-seeming step is necessary to “make room” for the new cells and also to remove suppressive cells and molecules in the immune system that might interfere with the TILs’ ability to combat cancer. Though this step is not without risks, studies have shown that lymphodepletion significantly increases the effectiveness of adoptive T cell therapy in patients. Adoptive cell therapy 2. Engineered T cells T cells can also be genetically engineered in the lab before they are infused back into a patient. Special viruses are used as vectors to deliver genes encoding specific proteins to T cells. Typically, these genes code for T cell receptors (TCRs) with known specificity for distinct tumor antigens—for example, NY-ESO-1. Engineered T cells Through such genetic engineering techniques, T cells can be generated that will attack any known tumor antigen. These techniques greatly expand the number of cancer types, beyond melanoma, that can be treated with adoptive cell therapy, including neuroblastoma, synovial cell sarcoma, leukemia, and lymphoma. Task no. 3 Let’s Summerize ALL of the cancer immunotherapies