1. Cancer Vaccines Advanced Immunotherapy – Fighting Cancer with Vaccines: Biological Response Modifiers “So much exists that is unknown, and this fact represents a unique opportunity for investigators, especially young scientists, to find a foothold and make very important contributions.” —Philip Vernon, University of Pittsburgh Cancer Institute

2. The Need for Cancer Vaccines Treating cancer has historically relied on a variety of treatments—surgery, chemotherapy, and radiation— known “slash, poison, and burn”. Fighting Cancer: Cancer vaccines have a potential advantage over these three options in that the body’s response is longer lasting (on a scale of years as opposed to weeks or months), which could possibly eradicate the micro- metastases that often linger after standard treatments end. Why use Cancer Vaccines? Although cancer eradication wouldn’t be achieved, vaccines would at least enable physicians to manage cancer as a chronic disease. Management as Chronic Disease

3. Two Cancer Vaccine Approaches Prophylactic Vaccines intended to prevent cancer from developing in healthy people target infectious agents that cause or contribute to the development of cancer. Similar to traditional vaccines, which help prevent infectious diseases by protecting the body against infection. Based on antigens that are carried by infectious agents and that are relatively easy for the immune system to recognize as foreign. FDA Approved preventative vaccine: Gardasil and Cervarix for cervical cancer Therapeutic Vaccines designed to treat cancers that have already developed. intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment. FDA approved treatment vaccine: PROVENGE for treatment of prostate cancer

4. Subtypes of Cancer Vaccines Tumor Vaccines Made from tumor cell preparations: actual cancer cells that have been removed during surgery. Cells are treated in the lab, usually with radiation, so they cannot form more tumors. In most cases, cells are changed further by adding chemicals or new genes, to make them more likely to be seen as foreign by the immune system. Cells are then injected into the patient. The immune system recognizes antigens on these cells, then seeks out and attacks any other cells with these antigens that are still in the body. Two basic types: allogenic or autologous Dendritic Cell Vaccines Autologous vaccines (made from the person in whom they will be used), and must be made individually for each patient. Process used to create them is complex and expensive. Immune cells from the blood expose d in lab to cancer cells or cancer antigens, as well as to other chemicals that turn them into dendritic cells and help them grow. Dendritic cells are then injected back into the patient, where they should provoke an immune response to cancer cells in the body. Antigen Vaccines Boost the immune system by using only one antigen (or a few), rather than whole tumor cells that contain many thousands of antigens. The antigens are usually proteins or pieces of proteins called peptides. May be specific for a certain type of cancer, but they are not made for a specific patient like autologous cell vaccines are. Scientists often combine several antigens in a vaccine to try to get a stronger immune response.

5. DNA Vaccines Tumor cells or antigens are injected into the body as a vaccine, they may cause the desired immune response at first, but they may become less effective over time because the immune system recognizes them as foreign and quickly destroys them. Without any further stimulation, the immune system returns to its normal (pre-vaccine) state of activity. To get around this a steady supply of antigens to keep the immune response going must be provided Vectors can be given bits of DNA that code for protein antigens. When the vectors are then injected into the body, this DNA might be taken up by cells and can instruct them to make specific antigens, which would then provoke the desired immune response. Vector-based Vaccines These vaccines use special delivery systems (called vectors) to make them more effective: vector-based antigen vaccines and vector-based DNA vaccines. May be used to deliver more than one cancer antigen at a time, which may make the body's immune system more likely to mount a response. Vectors such as viruses and bacteria may trigger their own immune responses from the body, which may help make the overall immune response even stronger. Vaccines may be easier and less expensive to make than some other vaccines.

6. Mechanism of Action Ultimate Aim To activate a component of immune system, lymphocytes or antibodies, against tumor-associated antigens presented by tumors. Opportunity to exploit Exploiting peptide recognition by T lymphocytes: sequencing of peptides derived from MHC molecules has led to the discovery of allele-specific motifs that correspond to residues that fit into specific pockets on MHC class I or II molecules. This has allowed for the discovery of new peptides associated with cancer Basic Princinple These specific peptides or proteins of the tumor cell that can then be used to stimulate an immune response included in cancer vaccine – Synthetic Peptides Whole cell (containing tumor antigens) taken from patient or another patient can be introduced to stimulate immune system to recognize tumor and mount a response – Cell-based vaccines

8. Pitfalls in Developing Cancer Vaccines Irregular and rapid tumor progress as compared to slow progress of immune response to vaccine Suppression of immune response by tumors – e.g. factors such as TGF-beta, prostaglandins, IL 10 produced by tumor cells may lead to T cell hypo-responsiveness Mutation or down regulation of immunodominant tumor antigens – for vaccine to be effective it must evoke immune response against a wider range of antigens Pre-existing treatments like chemotherapy destroy immune system to an extent that there’s little benefit for cancer vaccines to provide

9. Cancer Vaccines in Development BiovaxID produced promising results in a Phase III clinical trial of patients with advanced follicular lymphoma. individualized vaccine that is made by isolating proteins from a patient’s cancer cells and combining them with a delivery agent and a growth factor. Once injected, the vaccine stimulates immune cells to recognize and fight cancer cells that may be in the body. Use of BiovaxID significantly delayed cancer progression. Neuvax made up of a part of the HER2 protein called the E75 peptide. (HER2- contributes to the growth of some breast cancers) HER2-targeted therapies such as Herceptin have dramatically improved outcomes for women with HER2-positive breast cancer. Herceptin, NeuVax may reduce the risk of breast cancer recurrence. HSPPC-96 has shown promise in the treatment of glioblastoma multiforme—an aggressive type of brain tumor. vaccine is created from patient’s own tumor cells. In a Phase II clinical trial of patients with recurrent glioblastoma that has returned after prior treatment),

10. Promise of Cancer Vaccines 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 - Dendritic cells are an extremely appealing vaccine approach; however, they are limited by the difficulties associated with patient-specific cell therapies Identification of the mechanisms by which cancer cells evade or suppress anticancer immune responses is pivotal. A better understanding of how cancer cells manipulate the immune system could lead to the development of new drugs that block those processes and thereby improve the effectiveness of cancer treatment vaccines.