Immunotherapy: Vaccines & Cancer Treatment PDF

12/2/24 IMMUNOTHERAPY Definition Immunotherapy is a medical term defined as treatment of disease by inducing, enhancing, or suppressing an immune response. 1 ...

12/2/24 IMMUNOTHERAPY Definition Immunotherapy is a medical term defined as treatment of disease by inducing, enhancing, or suppressing an immune response. 1  12/2/24 Classifications n Activation immunotherapies: to elicit or amplify an immune response. n Suppression immunotherapies: to reduce, suppress or more appropriately direct an existing immune response, as in autoimmunity or allergy. Activation immunotherapies can be achieved by: n Active immunotherapy: make the patient’s immune system actively produces stronger immune response (HI or CMI or both) by using: ¨ Vaccine ¨ Cytokines ¨ Adjuvants n Passive immunotherapy: provide the patient’s body with pre-made antibodies. 2  12/2/24 Activation immunotherapies can be achieved by: n Adoptive immunotherapy: provide the patient’s body with primed specific lymphocytes. n Cell based immunotherapies: (proven to be effective for cancers): make the immune cells such lymphocytes, macrophages, dendritic cells, NK cell, cytotoxic T lymphocytes (CTL), etc., that work together to defend the body against cancers and attacks by "foreign" or "non-self" invaders such as bacteria and viruses. CANCER IMMUNOTHERAPY The main strategies for cancer immunotherapy currently in practice include introduction of antitumor antibodies and autologous T cells that recognize tumor antigens and enhancing patients’ own antitumor immune responses with antibodies that block immune checkpoints and vaccination. 3  12/2/24 CANCER IMMUNOTHERAPY n Adjuvants ¨ BCG (Bacilus Calmette Guerin) ¨ Dinitrocholorobenzene (DNCB) n Passive immunotherapy (mAbs) n Active immunotherapy ¨ Cytokine ¨ Tumour/cancer vaccine ¨ Immuno Cell therapy Adjuvant activity Formation of a depot of antigen primarily at the site of application from which the antigen is released during a variable period Increased uptake of antigen into APCs Induction of synthesis and secretion of enhancing factors, such as cytokines. 4  12/2/24 Adjuvant activity Facilitation of antigen transport, uptake and presentation by antigen-capturing and processing cells Repeated or prolonged release of antigen (depot effect) Signaling of receptors activating innate immune cells to release cytokines which upregulate co-stimulatory molecule ‘Danger signals’ from stressed or damaged tissues activate APCs Signaling by recombinant cytokines or co-stimulatory molecules mimics classical adjuvant activity Passive Immunotherapy With Monoclonal Antibodies Ø A limited number of tumors for decades relies on the injection of monoclonal antibodies which target cancer cells for immune destruction or inhibition of growth. Ø Monoclonal antibodies against various tumor antigens have been used in many cancers. 5  12/2/24 Passive Immunotherapy With Monoclonal Antibodies Immune serum globulin – (gamma- globulin) contains immunoglobulin extracted from the pooled blood of at least 1,000 human donors. n Treatment of choice for preventing measles, hepatitis A and replacing Ab in the immune deficient. n Lasts 2-3 months. Passive Immunotherapy With Monoclonal Antibodies Specific immune globulin- prepared from convalescent patients in a hyperimmune state n Contains high titer of specific Ab n Pertussis, tetanus, chickenpox, hepatitis B n Sera produced in horses are available for diphtheria, botulism, spider and snake bites n Act immediately and can protect patients for whom no other useful medication exists 6  12/2/24 Effectors functions of antibodies n Neutralization prevent contacts with host cell reduce the pathogen load Cell Inhibit bacterial toxins n Complement mediated lyses inhibits the pathogen penetration of the host cell Ä Complement binding è pathogen destruction Mechanisms by which antibodies clear out antigens Basic Immunology 6th Ed © Saunders 2020 Abbas A. K, Lichtman A. H, and Pillai S. 7  12/2/24 Antibodies neutralize microbes and toxins Sources of Passive Immunity n Almost all blood or blood products n Homologous pooled human antibody (immune globulin) n Homologous human hyperimmune globulin n Heterologous hyperimmune serum (antitoxin) 8  12/2/24 Passive immunity Mother’s antibody transferred to SAT injections for prevention baby via placenta and milk and treatment of tetanus Snake antivenom 9  12/2/24 Classification the serum preparations n Homogeneous serum: serum obtained from blood donor volunteers, have been immunized. n Heterogeneous serum: serum obtained from blood of animals hyperimmunized. 10  12/2/24 mAb attack cancer cells Use mAb specific to tumor markers mAb kill cancer cell by various ways MØ NK Induce Activate C’ ADCC Conjugate with apoptosis leading to cell toxin or isotope lysis “Active” immunotherapy Cytokine - IL-2 / IFNs / TNFα Vaccine - single peptide mixture of peptide with HSP and cancer cell Cell therapy - Specific CTL TIL cell DC 11  12/2/24 q Cytokine n Directly administrering IL-2. n Indirectly insert cytokine gene. IL-2 Before After few years Rosenberg (2001) Nature, 411;381-4 12  12/2/24 q Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens DNA vaccine Ø Tumor vaccines are meant to be therapeutic, in that they stimulate immune responses to attack cancers that have already developed. Ø Most tumor vaccines tried to date have used antigens that are shared by the same type of cancers in different patients there has been interest in developing personalized cancer vaccines tailored for each patient’s tumor Ø Tumor-specific vaccines may be administered as a mixture of the antigen with adjuvants, just like antimicrobial vaccines. In another approach, a tumor patient’s dendritic cells are expanded in vitro from blood precursors, the dendritic cells are exposed to tumor cells or tumor antigens, and these tumor-antigen–pulsed dendritic cells are used as vaccines Ø Tumors caused by oncogenic viruses can be prevented by vaccinating against these viruses. 13  12/2/24 SOME APPROACHES AVAILABLE q Cell Therapy Adoptive T Cell Therapy 14  12/2/24 Adoptive T Cell Therapy Ø CAR-T cell therapy targeting the B cell protein CD19, and more recently CD20 Ø The most serious toxicity associated with CAR-T cell therapy is a cytokine release syndrome, mediated by massive amounts of inflammatory cytokines, including IL-6, interferon- γ Ø CAR-T cell therapy may also be complicated by on-target, off- tumor toxicities, if the CAR-T cells are specific for an antigen present on normal cells as well as tumors Ø Although CAR-T cell therapy is effective against leukemias and tumors in the blood (to which the injected T cells have ready access), it has so far not been successful in solid tumors LAK and TIL cells n LAK: lymphokine-activated killer n TIL: tumour infiltrating lymphocytes Isolate from patient, activate in vitro then inject back to patient 15  12/2/24 DC treatment Immune Checkpoint Blockade 16  12/2/24 ID patient Re-construct the immune system by stem cell transplantation Immune Checkpoint Blockade Ø Although the efficacy of checkpoint blockade therapies for many advanced tumors is superior to any previous form of therapy, only a subset of patients (25% to 40% at most) respond to this treatment. The reasons for this poor response are not well understood. Ø One of the most reliable indictors that a tumor will respond to checkpoint blockade therapy is if it carries a high number of mutations, which correlates with high numbers of neoantigens and host T cells that can respond to those antigens. Ø The combined use of different checkpoint inhibitors, or one inhibitor with other modes of therapy, will likely be necessary to achieve higher rates of therapeutic success. The first approved example of this is the combined use of anti-CTLA-4 and anti-PD-1 to treat melanomas, which was shown to be more effective than anti-CTL-4 alone. This reflects the fact that the mechanisms by which CTLA-4 and PD-1 inhibit T cell activation are different Ø The most common toxicities associated with checkpoint blockade are autoimmune damage to organs. 17  12/2/24 CANCER IMMUNOTHERAPY Vaccines Provide an antigenic stimulus that does not cause disease but can produce long-lasting, protective immunity 18  12/2/24 Principles and Effects of Vaccination Sterile protection Non sterile protection Specific Specific Quick amplification Pathogen neutralization Specific Clearance of the pathogen Clearance of the pathogen before spreading after infection Extra cellular pathogens Intracellular pathogen with or free intracellular cell to cell transmission pathogens Antibody mediated Cell mediated Types of Vaccines and Their Characteristics 19  12/2/24 Vaccine technologies Live vaccines Examples Recombinant vaccines polio, yellow fever RSV Killed vaccines influenza, pertussis Plasma derived vaccines Hepatitis B Polysaccharide conjugates Hib, Pneumo Peptide vaccines Malaria Subunit vaccines HIV candidates DNA vaccines Influenza Combination vaccines DPT 20