Cancer Immunotherapy Monoclonal Antibodies 2024 PDF

Cancer Immunotherapy Professor Ciaren Graham Intended Learning Outcomes ▪Monoclonal Antibodies ▪Immune checkpoint inhibitors Cancer Immunotherapy ▪ Drug therapies generally fall into four broad categories ▪ Chemotherapy - usually aimed at blocking DNA synthesis and cell division ▪ Hormo...

Cancer Immunotherapy Professor Ciaren Graham Intended Learning Outcomes ▪Monoclonal Antibodies ▪Immune checkpoint inhibitors Cancer Immunotherapy ▪ Drug therapies generally fall into four broad categories ▪ Chemotherapy - usually aimed at blocking DNA synthesis and cell division ▪ Hormonal therapies- interfere with tumour-cell growth ▪ Targeted therapies - such as small molecule inhibitors of cancer ▪ Immunotherapies - induce or enhance the anti-tumour immune response Cancer Immunotherapy ▪ Monoclonal antibodies can be targeted to tumour cells ▪ Monoclonal antibody (mAb)-based therapeutics are now standard in the treatment of cancer ▪ Successes include: ▪ mAb against CD20 B-cell marker (Rituximab) for non-Hodgkin’s lymphoma ▪ Immunotoxins, coupling toxic molecules with mAb ▪ mAb against HER2 receptor in breast cancer Monoclonal antibody production ▪ Nobel prize awarded in 1984 to Georges J.F. Köhler and César Milstein for the hybridoma technique for production of monoclonal antibodies ▪ Early hybridoma technology, developed by fusing immortal mouse myeloma cells and splenic B cells from hyperimmune animals, allowed the development of fully murine mAbs during the 1970s Monoclonal Antibodies Muromonab-CD3 Adalimumab Antibody-mediated effector functions 2 1 3 5 4 6 Monoclonal -Antibody-mediated effector functions ▪ Complement Activation: results in the generation of the membrane attack complex (MAC), creating pores in pathogen membranes and killing the microbe ▪ Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): activates the killing activity of several types of cytotoxic cells, e.g., NK cells ▪ Antibody-Dependent Degranulation and Mediator Release: triggers mediator release from granulocytes Breast Cancer and HER2 ▪ Overexpression of human epidermal growth factor receptor type 2 (HER2) in breast cancer is associated with decreased overall survival. HER2 is a 185-kDa transmembrane oncoprotein (p185) encoded by the HER2/neu gene Overexpressed in approximately 20 to 25% of invasive breast cancers  HER2, also known as ErbB2, is a tyrosine kinase (TK) receptor. It is a member of the HER (or ErbB) growth factor receptor family. Homo- or heterodimerization of these receptors results in phosphorylation of residues from the intracellular domain of the receptor. This results in the recruitment of signalling molecules from the cytoplasm and initiation of several signaling pathways. The most studied HER2 downstream signaling pathways are the RAS/Raf/Mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K)/Akt cascades Paula R. Pohlmann et al. Clin Cancer Res 2009;15:7479- 7491 Trastuzumab ▪ Trastuzumab (Herceptin) a humanized monoclonal antibody that targets HER2 ▪ A humanized IgG1 kappa light chain monoclonal antibody ▪ Binds to amino acids present on domain IV of the HER2 ectodomain ▪ Results in cell cycle arrest via upregulation of the cyclin- dependent kinase (Cdk) inhibitor p27 ▪ It blocks intracellular signaling via the PI3K/Akt pathway ADCC NK cell ▪ The Fc region of trastuzumab can bind to Fcγ receptor III (RIII) CD16 present on the surface of effector cells such as NK cells and trigger tumour cell death via ADCC HER2 Rituximab ▪ Rituximab – monoclonal antibody treatment ▪ Human/murine chimeric, glycosylated immunoglobulin (Ig) G1-κ mAb ▪ Used in the therapy for a broad variety of B‐cell malignancies ▪ Rituximab specific to CD20 Rituximab ▪ CD20 is a human B lymphocyte restricted differentiation antigen. It is expressed during early pre B cell development just before the expression of cytoplasmic heavy chains Rituximab ▪ In some B cell malignancies, rituximab alone can induce high response rates and long term remissions while in others, adding rituximab to chemotherapy enhances the complete response, long term remission and cure rate ▪ Present on ▪ 95% of non‐ Hodgkin lymphoma cells ▪ 98% of diffuse large cell lymphomas express CD20 ▪ 20% of patients with multiple myeloma ▪ up to 50% of patients with plasma cell leukaemia and ▪ 75 - 100% of patients with Waldenstrom’s macroglobulinaemia Rituximab in Diffuse B Cell Lymphoma ▪ Standard treatment was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ▪ Complete response rate was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005) Mode of Action of Rituximab Antibody dependent cell-mediated cytotoxicity Complement dependent cytotoxicity Apoptosis Complement-Dependent Cytotoxicity - CDC 1 ▪ Binding of rituximab mAb to tumour cells results in the reorganisation of CD20 molecules into lipid rafts ▪ Subsequent activation of the classical pathway of the complement cascade (1) ▪ This generates the membrane attack 2 complex (MAC), which can directly induce B-cell lysis by CDC ▪ Augmentation of phagocytosis (2) Antibody-Dependent Cellular Cytotoxicity (ADCC) ▪ ADCC occurs as a result of an interaction between the Fc portion of rituximab in antibody-coated tumour cells and membrane-bound Fcγ receptors expressed on the surface of effector ▪ Natural killer (NK) cells via Fc receptors (FcRs) III ▪ Macrophages via Fc receptors FcR ▪ ADCC response includes the release of cytokines, chemokines, and mediators that kill target cells. ADCC and Natural Killer Cells ▪ Polymorphisms in FcγRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell- mediated cytotoxicity ▪ Two polymorphic variant types that either carry valine or phenylalanine at position158 Direct Apoptosis ▪ Rituximab binding to CD20 on B lymphocytes is thought to induce cell death via non-classical apoptosis by triggering the crosslinking of multiple CD20 molecules and Src kinases Evading the Immune System ▪ Tumour cells evade immunosurveillance ▪ One way they do this is through activation of immune checkpoint pathways ▪ Inhibitory checkpoint pathways limit the threshold for T cell activation and duration of immune responses ▪ They have diverse effects that regulate resolution of inflammation, tolerance and homeostasis. T-cell activation and the two-signal hypothesis ▪ Positive costimulatory receptors—facilitate activation ▪ CD28: Generally involved in initial activation events in T cells ▪ 44 kDa glycoprotein homodimer expressed on majority of T cells ▪ Markedly enhances TCR-induced proliferation and survival- IL-2, Bcl-xL ▪ Binds to (CD80) B7-1 and (CD86) B7-2 expressed by APCs Clonal Anergy ▪ Clonal anergy results if a costimulatory signal 2 is absent ▪ This helps provide tolerance (especially in periphery) ▪ If only signal 1 is received, the cell is rendered nonresponsive  T-cell costimulatory and coinhibitory receptors and their ligands Receptor on T cell Ligand Activity Coinhibitory receptors CTLA-4 CD80 (B7-1) or CD86 (B7-2) Negative regulation of the immune Expressed by professional APCs response (e.g., maintaining T-cell (and medullary thymic peripheral tolerance; reducing epithelium) inflammation; contracting T-cell pool after infection is cleared) PD-1 PD-L1 or PD-L2 Negative regulation of the immune Expressed by professional APCs, response, regulation of TREG some T and B cells, and tumour differentiation cells BTLA HVEM Negative regulation of the immune Expressed by some APCs, and response, regulation of TREG by T and B cells differentiation (?) CTL4 ▪ CTLA4 is immediately upregulated following T-cell receptor (TCR) engagement (signal 1) ▪ its expression peaking 2 to 3 days after activation ▪ CTLA4 dampens TCR signaling through competition with the costimulatory molecule CD28 for CD80 and CD86 ▪ CTLA4 has higher avidity and affinity for both of these than CD28 ▪ This results in regulation of TCR signal amplitude and T- cell activity ▪ Negative co-stimulation by CTLA4 is critical for tolerance Ipilimumab (Yervoy) ▪ Melanoma accounts for nearly 75 percent of skin cancer deaths. ▪ Ipilimumab, a monoclonal antibody targeting CTLA-4 ▪ By inhibiting CTLA‐4 leading to enhanced T‐cell activation ▪ Ipilimumab was the first immunotherapy to demonstrate improvement in overall survival in patients with melanoma ▪ Ipilimumab monotherapy in 1-year and 2-year survival rates of 39.3% and 24.2%, respectively (10.0 months vs. 6.4 months) Ipilimumab (anti-CTLA4) ▪ 2011 FDA approval of Ipilimumab (Yervoy) for the treatment of metastatic melanoma Monoclonal antibodies – Checkpoint Inhibitors mAb name Trade name Target Used to treat: Ipilimumab Yervoy CTLA-4 Melanoma Nivolumab Opdivo PD-1 Melanoma, Advanced renal cell carcinoma, Non-small cell lung cancer Squamous cell cancer of the head and Classical Hodgkin lymphoma Pembrolizumab Keytruda PD-1 Melanoma, non–small cell lung cancer, kidney cancer, and Hodgkin’s lymphoma‡ Atezolizumab Tecentriq PD-L1 Bladder cancer, non–small cell lung cancer, and Merkel cell carcinoma Intended Learning Outcomes ▪Monoclonal Antibodies ▪Immune checkpoint inhibitors