Vaccine Immunotherapy and Monoclonal Antibody Immunotherapy2-1.pdf

Vaccine Immunotherapy and Monoclonal Antibody Immunotherapy Vaccine Immunotherapy  Introduction What are Cancer Vaccines? Vaccines are medicines that help the body fight disease. They can train the immune system to find and destroy harmful germs and c...

Vaccine Immunotherapy and Monoclonal Antibody Immunotherapy Vaccine Immunotherapy  Introduction What are Cancer Vaccines? Vaccines are medicines that help the body fight disease. They can train the immune system to find and destroy harmful germs and cells. There are many vaccines that you receive throughout your life to prevent common illnesses. There are also vaccines for cancer. There are vaccines that prevent cancer and vaccines that treat cancer. Are there vaccines that prevent cancer? There are vaccines that can prevent healthy people from getting certain cancers caused by viruses. Like vaccines for the chicken pox or the flu, these vaccines protect the body from these viruses. This type of vaccine will only work if a person gets the vaccine before they are infected with the virus. There are 2 types of vaccines that prevent cancer approved by the U.S. Food and Drug Administration (FDA):  HPV vaccine. The vaccine protects against the human papillomavirus (HPV). If this virus stays in the body for a long time, it can cause some types of cancer. The FDA has approved HPV vaccines to prevent: Cervical, vaginal, and vulvar cancers Anal cancer Genital warts HPV can also cause other cancers the FDA has not approved the vaccine for, such as oral cancer. Hepatitis B vaccine. This vaccine protects against the hepatitis B virus (HBV). This virus can cause liver cancer. Are there vaccines that treat cancer? There are vaccines that treat existing cancer, called treatment vaccines or therapeutic vaccines. These vaccines are a type of cancer treatment called immunotherapy. They work to boost the body's immune system to fight cancer.. Doctors give treatment vaccines to people who already have cancer. Different treatment vaccines work in different ways. They can: Keep the cancer from coming back Destroy any cancer cells still in the body after treatments end Stop a tumor from growing or spreading How do cancer treatment vaccines work? Antigens, found on the surface of cells, are substances the body thinks are harmful. The immune system attacks the antigens and, in most cases, gets rid of them. This leaves the immune system with a "memory" that helps it fight those antigens in the future. Cancer treatment vaccines boost the immune system's ability to find and destroy antigens. Often, cancer cells have certain molecules called cancer- specific antigens on their surface that healthy cells do not have. When a vaccine gives these molecules to a person, the molecules act as antigens. They tell the immune system to find and destroy cancer cells that have these molecules on their surface.  Some cancer vaccines are personalized. This means they are made for just 1 person. This type of vaccine is produced from samples of the person's tumor that are removed during surgery. Other cancer vaccines are not personalized and target certain cancer antigens that are not specific to an individual person. Doctors give these vaccines to people whose tumors have those antigens on the surface of the tumor cells. Most cancer vaccines are only offered through clinical trials, which are research studies that use volunteers. In 2010, the FDA approved sipuleucel- T (Provenge) for people with metastatic prostate cancer, which is prostate cancer that has spread. Sipuleucel-T is tailored to each person through a series of steps: White blood cells are removed from the person's blood. White blood cells help the body fight infection and disease. The white blood cells are altered in a laboratory to target prostate cancer cells.  Next, the doctor puts the altered cells back into the person through a vein. This is similar to a blood transfusion. These modified cells teach the immune system to find and destroy prostate cancer cells. Another vaccine uses a weakened bacteria called Bacillus Calmette-Guérin (BCG) that is injected into the body. This weakened bacteria activates the immune system to treat early-stage bladder cancer. What are the challenges of using treatment vaccines? Making treatment vaccines that work is a challenge because: Cancer cells suppress the immune system. This is how cancer is able to begin and grow in the first place. Researchers are using adjuvants in vaccines to try to fix this problem. An adjuvant is a substance added to a vaccine to improve the body's immune response. Cancer cells start from a person's own healthy cells. As a result, the cancer cells may not "look" harmful to the immune system. The immune system may ignore the cells instead of finding and fighting them.  Larger or more advanced tumors are hard to get rid of using only a vaccine. This is 1 reason why doctors often give a cancer vaccine along with other treatment. People who are sick or older can have weak immune systems. Their bodies may not be able to produce a strong immune response after they receive a vaccine. That limits how well a vaccine works. Also, some cancer treatments may weaken a person's immune system. This limits how well the body can respond to a vaccine. For these reasons, some researchers think cancer treatment vaccines may work better for smaller tumors or cancer in its early stages.  Mechanism of Cancer Vaccine To understand the mechanism of cancer vaccines, we should firstly learn the tumor immune cycle. The immune response that effectively kills tumor cells involves steps that allow repetition and expansion called the tumor immune cycle. After administration of the tumor vaccine, dendritic cells uptake and process tumor antigens then present them to the major histocompatibility complexes known as HLA. Antigen-loaded dendritic cells migrate to lymph nodes to recruit and activate B cells and T cells. Activated B cells and T cells kill tumor cells directly or induce tumor cell apoptosis. Immunogenic dead tumor cells can release tumor-associated antigen danger signaling molecules to increase the depth and breadth of the response in the subsequent cycles.  After the administration of the tumor vaccine, dendritic cells uptake and process tumor antigens then present them to the cell surface of MHCI and MHCII molecules through cross-presentation. Antigen-loaded dendritic cells migrate to lymph nodes to recruit and activate immune cells. Interaction between MHC peptide complex T-cell receptor and cognate receptor ligand pairs activates T cells. Then activated CD8+ T cells proliferate and differentiate into memory T cells and effector T cells. Effector T cells travel to the tumor microenvironment killing tumor cells directly or inducing tumor cell apoptosis. Activated CD4+ T cells induce B cells to differentiate into memory B cells and plasma cells that produce antibodies. Antibodies recognize tumor antigens inducing FC-mediated effector functions such as antibody-dependent cellular cytotoxicity and phagocytosis to kill the tumor cell.  Resistance of Cancer Vaccines Immune resistance or tumor immune escape is a barrier in vaccine therapy which results in resistance to cancer vaccines. Tumor immune escape can be divided into intrinsic mechanisms determined by the characteristics of tumor cells and external mechanisms involving tumor matrix components. These two mechanisms determine the efficiency of cancer vaccine for tumor external resistance. Immunosuppressive cells such as cancer-associated fibroblasts, myeloid- derived suppressor cells, regulatory T cells, and M2 macrophages. Immunosuppressive cytokines can inhibit the activation of effector T cells and dendritic cell-mediated T cells directly or indirectly in the tumor microenvironment.  Intrinsic resistance of the tumor contains six aspects: 1-Mutation in signaling pathways supporting tumor immune control. 2-Loss of tumor antigen expression. 3-Changes in antigen processing pathways. 4-Loss of HLA expression. 5-Increased expression of immunosuppressive ligands. 6-Epigenetic changes. Several strategies have been developed to solve tumor escape and tumor microenvironment immunosuppression, including improving immunotherapy delivery platforms and improving antigen selection and combination therapy with radiotherapy and chemotherapy.  Cancer vaccine in clinic As we know cancer is characterized by accumulation of genetic alternation. Somatic mutation can generate cancer-specific neoepitopes that are recognized by autologous T_cells as foreign and constitute ideal cancer vaccine targets. Every tumor has its unique composition of mutations with only small fraction shared between patients. Technological advances in genomics data science and cancer immunotherapy now enable the rapid mapping of mutations within a genome rational selection of vaccine targets and on demand production of a therapy customized to a patient's individual tumor.  Customizing a patient specific cancer vaccine include several processes: - 1-Patient tumor biopsies and healthy tissue such as peripheral blood white blood cells are subjected to next generation sequencing by comparing the sequence obtained from tumor and normal DNA tumor specific non synonymous single nucleotide variations or short indols in protein coding genes are identified. 2-A computational pipeline is used to examine the mutant peptide regions for binding to the patient's HLA and other features of the mutant protein deemed relevant for prioritization of potential vaccine targets. 3-These data can facilitate the selection of multiple mutations to design unique neoepitope vaccines that manufactured under comp conditions.  Basic neoantigen pipeline Neoantigens are encoded by genes containing non synonymous mutations in tumor cells which result in unique amino acid changes with the potential to be targeted by immune system. Neoantigens are preceived to be key to unique and personalized cancer vaccine. In the past, the comprehensive and fast identification of research was limited by technologies. Today advancements in the field of screening including whole genome sequencing is contributing to the identification of neoantigens closing the gap between theory and practice. These pipelines include the sequencing and comparison of healthy and cancer tissues to identify tumor specific non synonymous mutations. A basic neoantigen vaccine pipeline can be divided into six processes including Monoclonal Antibody Immunotherapy  Monoclonal Antibodies Antibodies are molecules that our body makes to help fight germs. Monoclonal Abs are similar molecules that are made in laboratories and are used by doctors to find or treat cancer and other diseases.  How monoclonal Antibodies treat cancer? (Block, flag, deliver) Antibodies are Y shaped molecules that attach tightly to a target. They are very specific, meaning that each Ab attach to only one target. An Ab and its target fit together like pieces of puzzle. In the laboratory, scientists can make many identical copies of monoclonal antibody that can attach to a specific target such as a molecule on surface of target cells. These monoclonal antibodies can block molecules. Cancer cells need to grow, flag cancer cells for destruction by the immune system or deliver harmful substances to cancer cells. This makes them a valuable type of targeted therapy for treating cancer. For example, a monoclonal Ab called trastuzumab attaches to a molecule called HER2 on the surface of some cancer cells.  Blocking HER2 keeps it from sending signals the cancer cells need to grow. Another example involving VEGF which is molecule that makes blood vessels grow. A monoclonal Ab called Bevacizumab blocks VEGF. Blocking VEGF stops the growth of new blood vessels that tumor needs to survive. A third example is the monoclonal Ab permbrolizumab. Permbrolizumab attaches to molecules called checkpoints on immune cells. Blocking immune checkpoints helps the immune cells kill cancer cells for destruction..  Other monoclonal Ab treat cancer by flagging cancer cells for destruction. For example, when monoclonal Ab called rituximab attaches to a molecule called CD20 on cancer cells, it acts like a flag for immune cells. The immune system sees this flag and destroys the cancer cells. Some monoclonal antibodies fight cancer by delivering drugs, toxins or radioactive particles to cancer cells. For example, brentuximab vedotin is a monoclonal Ab that is linked to a chemotherapy drug. When the antibody attaches to its target on cancer cells, it delivers the chemotherapy drug which kills them. Cancer researchers are continuing to investigate new ways to use the precision of monoclonal antibodies to treat cancer patients.