Rationale for Patient- Specific Vaccine Therapy for Non-Hodgkin Lymphoma

Rationale for Patient- Specific Vaccine Therapy for Non-Hodgkin Lymphoma Maribeth Hohenstein, RN, BSN, OCN Clinical Research Nurse Coordinator University of Nebraska Medical Center Objectives Review the Immune System and it s function Define Vaccine Therapy Discuss how the Immune System is utilized in Vaccine Therapy Discuss the components of Vaccine Therapy Discuss the rationale for Vaccine Therapy in the treatment of Follicular NHL NHL and the Immune System NHL is a disease that starts in and affects the immune system NHL arises from B cells or T cells It s important to understand how a healthy immune system functions to in turn understand lymphoma and its treatment Immune System General Overview Primary Function Recognize and eliminate foreign substances (non-self) that enter the body Small army that is always on guard to protect the body Distinguish between self and non-self Innate or Nonspecific Immunity Adaptive or Acquired Immunity Innate (Non-specific) Immunity Primary line of defense Non-specific (natural immunity) No Memory Complement Phagocytes Natural Killer cells Adaptive (Acquired) Immunity Secondary line of defense Specific Memory Lymphocytes (T cells and B cells) 1

Immunotherapeutic Responses Passive (Adaptive) Immunity Transfer of antibodies or short-lived anti-tumor activities Monoclonal antibody therapy (Rituxan ) Active (Acquired) Immunity Stimulates host s immune system Creates memory Vaccine therapy Specific Immune Responses Cellular (Cell-mediated) Immunity Antigen-specific responses are mediated by T-lymphocytes Humoral (Antibody-mediated) Immunity Antigen-specific responses are mediated by serum antibodies produced by B-cells Cellular and humoral responses work together to induce tumor regression and long-lasting immunity to the disease being treated Workman, M.L. (1998). The lymphoid system and its role in maintaining immunocompetence. Seminars in Oncology Nursing, 14(4), 248-255. Antigen and Antibody Stem cells develop into myeloid stem cells, which can become red blood cells, megakaryocytes (pre-platelets), and a variety of leukocytes (white blood cells) including dendritic cells. Together, all of these cells constitute the immune system. Image Not Available Antigen Anything that causes the immune system to react Produce a response that can lead to the destruction of both the antigen and whatever the antigen is attached to Antibody Produced by B cells Used by the immune system to fight foreign invaders or disease An antibody matches an antigen much like a key matches a lock Whenever antibody and antigen interlock, the mechanism is put in place for cellular destruction B Cells Made in the bone marrow Each B cell produces one specific antibody or immunoglobulin Also called, B-Lymphocytes B cells do not have direct cytotoxic (killing) effect on cells Immunoglobulins on the cell surface act as antigen or foreign substance receptors Complement system helps antibodies to destroy antigens Stimulated B cells develop into: Plasma cells with the first antigen exposure Memory cells with the subsequent exposures Can also act as antigen-presenting cells to T-cells DeMeyer, E. and Barr, J. (2003). Dendritic Cells: The Sentry Cells of the Immune System, OES Monograph 2

T Cells Mature in the thymus Where T cells learn to distinguish self from nonself T cells communicate by releasing cytokines Recognize and destroy foreign antigens Activate macrophages Assist in making antibodies T Cells (Continued) Helper/inducer T cells (T 4 or CD4 or Th) Immunoregulatory cells Activate other cells of the immune system Recruit killer T cells by providing cytokine (e.g. IL-2, GM-CSF) Instruct B cells to make antibodies Activate NK cells and macrophages Cytotoxic/cytolytic T cells (T 8 or CD8 or Tc) Killer T cells Rid the body of foreign antigens or infected cells by attacking antigens and releasing cytotoxic substances DeMeyer, E. and Barr, J. (2003). Dendritic Cells: The Sentry Cells of the Immune System, OES Monograph DeMeyer, E. and Barr, J. (2003). Dendritic Cells: The Sentry Cells of the Immune System, OES Monograph Mechanisms of Immune Destruction T of Tumor Cells H 1, T H 2 cytokines Stimulates macrophages, NK cells, B cells B cell Tumor antigenspecific antibodies Ab Tumor cell CD4+ T cell activates ADCC NK cell or macrophage Tumor cell lysis/death CD8+ T cell Cytotoxic T-cell activity Miller, Jeffrey, General Principles of Tumor Immunology and Future Directions in Dendritic Cell Therapy from Oncology and Transplantation: Current Standards of Care to Immune-based Therapies. Sponsored by Medical Education Resources, Inc. Antigen Presenting Cells (APCs) Cells that present antigen on its surface to other cells of the immune system Very important step of the immune response APCs include Macrophages Dendritic cells B cells Dendritic Cells Dendritic cells (DCs) present the antigen to the T cell = antigen presenting cell (APC) Potent cells of the immune system Play a significant role in the development of acquired immunity Circulate, capture, and express the antigen on the surface membranes that are bound to MHC antigens to attract T cells DeMeyer E. and Buchsel, P. (2005) A Dendritic Cell Primer for Oncology Nurses, CJON, 9(4), 460-464. DeMeyer, E. and Barr, J. (2003). Dendritic Cells: The Sentry Cells of the Immune System, OES Monograph 3

Major Histocompatibility Complex MHC (Major Histocompatibility Complex) Group of genes that distinguish self from non-self Referred to in humans as human leukocyte antigen (HLA) complex Act as markers for antigen presentation by B cells, macrophages and T cells Unique in every individual, just like fingerprints MHC class I stimulate CD8+ killer cells MHC class II stimulate CD4+ helper cells MHC class III consists of complement components DeMeyer, E. and Barr, J. (2003). Dendritic Cells: The Sentry Cells of the Immune System, OES Monograph Action of APCs and MHC Dendritic cells (DCs) circulate throughout the body looking for antigens from other cells Other cells = invaders, abnormal or normal self tissue Goal: make antigen recognizable to T cells The DCs (APCs) present antigen to T cells DCs express both MHC class I and class II Therefore, stimulates both CD8 (killer cells) and CD4 cells (helper cells), respectively Naïve T cells are activated to trigger a complex immune response to either fight or tolerate antigens. Activated T cells can stimulate other cells of the immune system B cells for antibody formation Macrophages for cytokine release Cell targets for lysis DeMeyer, E. and Barr, J. (2003). Dendritic Cells: The Sentry Cells of the Immune System, OES Monograph The Immune Response IMMUNE RESPONSE to a FOREIGN ANTIGEN requires the presence of APC in combination with B CELLs or T CELLs. The B CELL is signaled to proliferate and produce ANTIBODIES to bind to the ANTIGEN. ANTIBODIES initiate the COMPLEMENT CASCADE to cause destruction of the ANTIGEN. APCs present ANTIGEN to T CELLs CD8 cells activated to kill target cells (Cellular Response) CD4 cells activated to regulate production (Humoral Response) of ANTIBODIES and activity of CD8 cells Mechanisms of Immune Destruction of Tumor Cells Cellular and Humoral Immunity Humoral-Mediated Mechanisms Lysis by antibody and complement Antibody-mediated and complement-mediated opsonization Cell-Mediated Mechanisms Antibody-dependent cellmediated cytotoxicity Destruction by cytotoxic T cells Destruction by activated macrophages Destruction by natural killer cells Image Not Available Benjamini E, et al. Immunology: A Short Course. 3rd ed. 1996. 4

Personalized Vaccines: Multiple Levels of Attack Polyclonal Anti-tumor Antibodies A Cancer Vaccine is. Monoclonal Antibody T-Cell Antigen Lymphoma B-cell Cytokines T-cell a substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. A vaccine can help the body to recognize and destroy cancer cells or microorganisms. CD4+ Helper CD8+ Cytotoxic History of Vaccine Therapy The first successful vaccination procedure was described by Edward Jenner in the 1790 s. William Coley was the first to work with the idea of vaccination for cancer in the 1890 s. Chang, A. (2000). Cancer vaccines. Retrieved August 18, 2005 from http://cancernews.com/printer.asp?cat=26&aid=183 Waldman, T. (2003). Immunotherapy: past, present and future [Electronic Version]. Nature Medicine. 9(3), 269-277. Retrieved August 18, 2005 from http://www.nature,com/cgi-taf/dynapage.taf?file=/nm/journal/v9/n3/full/nm0303-269.html Goal of Cancer Vaccines is to produce a strong immune response that involves the cellular and humoral arms of the immune system resulting in a T cell and antibody response is to present the target to the immune system resulting in a much larger activation of T cells than is occurring naturally in the host Prophylactic Vaccines Stimulate a long-lasting (years or even a lifetime) immune response that prevents one from getting sick Not yet possible for cancer because of the variation among different cancers even within the same type of cancer Viral targets for cancer have been identified Hepatitis B virus (HBV) Epstein-Barr virus (EBV) Human Papillomavirus (HPV) Hepatitis B vaccine FDA approved Reduction of cirrhosis and hepatocellular carcinoma HPV quadrivalent vaccine clinical trials May reduce the incidence of cervical cancer Therapeutic Vaccines Designed to treat people affected with a disease, with the goal of stimulating or boosting the body s immune defenses to fight the disease Therapeutic vaccines for cancer are effective because the immune system can develop acquired immunity to disease after initial exposure 5

How do cancer vaccines really work? The tumor associated antigen (TAA) or target must be presented to the immune system in a way that stimulates an immune response Both cellular and humoral responses are necessary to create an adequate response and memory to work against the antigen Tumor Escape Mechanisms Tumor cells, are by definition, either weakly immunogenic or functionally non-immunogenic Tumors can escape Immune Surveillance SELF vs. NON-SELF Tumor cells are much like normal cells and simply cannot stimulate a strong effective immune response Cancer cells are able to trick the immune system by altering their characteristics slightly Tolerance may be due to only a minor difference between the tumor cell and the normal cell The tumor needs to be presented the immune system in a way that it appears foreign, so that an immune response can be initiated. Components of Vaccine Therapy - Tumor-specific Target - Carrier Protein - Adjuvant Targets for Cancer Vaccines Tumor-Associated Antigens (Tumor-Specific Target) Molecule on the surface of the tumor cell May be unique to the individual tumor, shared by several tumor types, or expressed on normal tissue from which the cancer grows The first human cancer antigen was discovered in the cells of patient with metastatic melanoma in 1991 More than 500 tumor antigens have been identified Examples Carcinoembryonic antigen (CEA) Prostate-specific antigen (PSA) Melanoma antigen genes (MAGE 1, 2, and 3) HER-2/neu Idiotype (tumor-specific) - NHL Battiato, L. & Wheeler, V. (2003). Biotherapy. In Yarbro, C.H., Goodman, M., Frogge, M.H., & Groenwald, S.L. (Ed.), Cancer Nursing; Principles and Practice, (5 th ed., pp. 543-579). Sudbury, MA: Jones & Bartlett. National Cancer Institute. (2003). Cancer Vaccine Fact Sheet retrieved August 16, 2005 from http://www.cancer.gov/newscenter/pressreleases/cancervaccines 6

Idiotype (Id) Each B Cell (lymphocyte) has it s own unique idiotype cell surface marker (Id) Found on the Immunoglobulin protein Unique to a tumor Isolated from the patient-specific tumor Every B Cell and T Cell carries this unique receptor (antibody) on it s surface that recognizes foreign antigen Tumor Specific Idiotype: Ideal Target for NHL To Review B Cell Lymphoma arises from the reproduction of abnormal B cells Each NHL cell arises from a single abnormal parent cell. Therefore, all the cells of one person s tumor have the same antibody with the same Id. The Id is not found on healthy B cells or any other cells in the body The Id is like a tumor-specific fingerprint Idiotype Vaccine therapy is Patient-Specific Carrier Protein Highly immunogenic Helps the immune system to recognize the attached TAAs as foreign Puts the immune system on high alert Serves as a decoy, attracting the attention of the immune system and initiating an immune response Examples Keyhole limpet hemocyanin (KLH) Bacillus calmette guerin (BCG) California Giant Keyhole Limpets Megathura crenulata Images Not Available Adjuvants Known to boost the immune system by luring dendritic cells and other immune system cells to the site of injection Examples GM-CSF IL-2 IFN-α Autologous vs. Allogeneic Autologous or Patient-specific Made using the patient s own tumor cells Customized Considered genetically identical, descended from one abnormal cell that escaped surveillance by the immune system DNA or RNA is extracted from the cell Tumor tissue obtained and delivered to manufacturer either fresh or frozen Allogeneic or off-the-shelf Made from the tumor cells of several people with the same cancer or tumor cell line Patient s tumor should be tested for the antigen in the vaccine 7

Peptide/Protein Vaccine Some of the first vaccines studied were peptide/protein vaccines Use protein fragments or peptides (tumor associated antigens) to stimulate the immune system to fight the tumor cells Antigen(s) combined with an adjuvant to stimulate an immune response Examples: Idiotype Patient-Specific Vaccine for NHL Genitope MyVax Personalized Immunotherapy Favrille - Favld Accentia Biopharmaceutical - BioVaxId Dendritic Cell (DC) Vaccines Dendritic cells are taken from a patient s blood by leukapheresis, the DCs are stimulated (primed) with the patient s own cancer antigen, grown in culture, and reinjected Activate the immune system s T cells Activation of DCs is expected to cause T cells to multiply and attack cancer cells expressing the antigen Examples: Dendritic Cell Vaccine for NHL Currently being studied at Stanford, UCLA, and Beth Israel Deaconess Medical Center Patient-Specific Vaccine Therapy for NHL Therapeutic Autologous Patient specific Custom made Components include Tumor Specific Target Idiotype (Id) Carrier Protein Keyhole limpet hemocyanin (KLH) Adjuvant GMCSF (Leukine ) Ideal for Vaccine Therapy Low tumor burden Tumor expected to recur Tumor expresses antigen that can be used as a target Competent immune system Battiato, L. & Wheeler, V. (2003). Biotherapy. In Yarbro, C.H., Goodman, M., Frogge, M.H., & Groenwald, S.L. (Ed.), Cancer Nursing: Principles and Practice (5th ed., pp. 543-579). Sudbury, MA: Jones & Bartlett. Potential Barriers for Vaccine Therapy Tumor cell escape mechanisms Inefficient antigen-presenting cells Alterations in T cell receptor signal transduction Acquired deficiencies to immune sensitivity Majority of tumor antigens are selfantigens, leading to tolerance Cytokine environment at tumor site does not support T cell growth Adapted from Muehlbauer, P.M. & Schwartzentruber, D.J. (2003). Cancer vaccines. Seminars in Oncology Nursing, 19(3), 206-216. Why study Vaccine Therapy for FOLLICULAR NHL??? Follicular B Cell Non-Hodgkin Lymphoma is ideal for patient-specific vaccine therapy Each tumor has the necessary idiotype cell surface marker The disease is slow growing, which allows time for production of the vaccine 8

Conclusion The Immune System can be stimulated to fight cancer Cellular and humoral responses work together to induce tumor regression and long-lasting immunity Follicular NHL is ideal for patient-specific vaccine therapy 9