Trivedi_Immunology and immunotherapy in cancer-2_2024.pdf

Introduction to Cancer Immunology and Immunotherapy Meghana V. Trivedi, Pharm.D., Ph.D., BCOP University of Houston, College of Pharmacy [email protected] Integrated Hematology/Oncology Module PHAR 5367 Jan 18, 2024 Learning Objectives 1. 2. Classify different types of cancer, terminology,...

Introduction to Cancer Immunology and Immunotherapy Meghana V. Trivedi, Pharm.D., Ph.D., BCOP University of Houston, College of Pharmacy [email protected] Integrated Hematology/Oncology Module PHAR 5367 Jan 18, 2024 Learning Objectives 1. 2. Classify different types of cancer, terminology, and nomenclature. Differentiate between various cancer pathophysiology and common cancer hypotheses. 3. 4. Classify different roles of immune system in prevention of cancer Identify mechanism of action for monoclonal antibodies, cytokines, cell-based therapies, checkpoint inhibitors, and other immunologic therapies in the treatment of cancer. 2 Summary of MOA of mABs Monoclonal antibodies Cytotoxicity Neutralization Inactivation of growth factors Inactivation of growth factor receptors Target is important in tumor initiation and progression ADCC CDC Apoptosis Target is selectively expressed on tumor cells ADCC= antibody-dependent cell-mediated cytotoxicity CDC= complement-dependent cytotoxicity 3 Selection of target antigen • Cell surface protein • Key driver of tumor growth • Predictor of efficacy if mAb is an antagonist • Can be present on tumors of a small subset of patients • E.g., HER2 (Trastuzumab) is highly expressed on ~20% all breast cancer patients • Abundant expression and/or increased activity on cancer cells versus healthy cells • Predictor of efficacy and safety • E.g., EGFR (Cetuximab and Panitumumab) • Toxicity: rash (skin epithelial cells also express EGFR) • Cell recognition for conjugated antibodies 4 Production of mAbs 5 Human mAb • Fully human antibodies are now available • Derived using one of the following ways 1. Transgenic mice with ‘human’ immune system, which when challenged by an antigen, will produce human antibodies 1. Library of antibody fragments (e.g. Fab) is made from shuffling human genetic material to produce many different variations of antibodies and is used to fish out the ones that bind to the target/antigen of interest • Are 100% human • Have minimal immunogenicity • Infusion reactions can occur with mABs requiring preventive measures and treatment 6 mAbs: nomenclature Both chimeric and humanized antibodies are made using recombinant DNA technologies For more information on nomenclature- go to 7 http://www.who.int/medicines/services/inn/generalpoliciesmonoclonalantibodiesjan10.pdf Bispecific T cell Engager (BiTE) Blinatumomab: Fab of anti-CD3 fused with Fab of anti-CD19 Fab portion Fab portion When one Fab portion binds to CD19 on tumor cells, and another Fab portion binds to CD3 on T cells, it forces T cells to come in close proximity of tumor cells, inducing T-cell dependent cytotoxicity. 8 Question Can blinatumomab (CD19/CD3) cause antibody-dependent cell-mediated cytotoxicity (ADCC)? 1. Yes 2. No 9 mABs: Mechanism of action (cytotoxicity) Targets highly expressed on cancer cells (not essential for cancer cell function) Drug names Target Expression Mechanism of action Rituximab CD20 Ofatumumab Obinutuzumab B cells & other BM cells ADCC and CDC, apoptosis Blinatumomab CD19/ CD3 CD19: B cells & other BM cells; CD3: T cells Activation of T-cell mediated cytotoxicity Inotuzumab ozogamicin CD22 (ADC) B cells & other BM cells ADCC and CDC, cytotoxicity from ADC Brentuximab vedotin CD30 (ADC) B and T lymphocytes ADCC and CDC, cytotoxicity from ADC Gemtuzumab ozogamicin CD33 (ADC) Myeloid cells ADCC and CDC, cytotoxicity from ADC Abbreviations: ADC= antibody-drug conjugate, ADCC= antibody-dependent cell-mediated cytotoxicity, 10 BM= bone marrow, CDC= complement-dependent cytotoxicity mABs: Mechanism of action (neutralization) Targets important for cancer cell function (directly or indirectly) Drug names Cetuximab Panitumumab Target EGFR Expression Mechanism of action Cancer cells, epithelial cells ADCC, CDC, apoptosis, neutralization Trastuzumab (T) HER2 Pertuzumab Cancer cells, cardiac cells ADCC, CDC, apoptosis, neutralization T emtansine T deruxtecan HER2 (ADC) Cancer cells, cardiac cells ADCC, CDC, apoptosis, neutralization, cytotoxicity from ADC Bevacizumab VEGF Blood vessels/ endothelial cells Neutralization (Inhibition of neoangiogenesis) Ramucirumab VEGFR Blood vessels/ endothelial cells Neutralization (Inhibition of neoangiogenesis) Abbreviations: ADC= antibody-drug conjugate, ADCC= antibody-dependent cell-mediated cytotoxicity, 11 BM= bone marrow, CDC= complement-dependent cytotoxicity mAb Pharmacokinetics • Route of administration: IV infusion (not by IV push/bolus) • Distribution • By convective transport, driven by the blood-tissue hydrostatic gradient and by the sieving effect of the paracellular pores in the vascular epithelium. • By transcytosis through vascular epithelial cells, mediated via the Fc receptor • Elimination • Too large to be eliminated by kidneys • Mostly through receptor-mediated endocytosis and lysosomal degradation • Fc receptors also mediate recycling of IgG’s contributing to longer half-lives (18-21 days) • Thus, IgG elimination occurs mostly through intracellular catabolism by lysosomal degradation to amino acids after uptake by either pinocytosis, an unspecific fluid phase endocytosis, or by a receptor-mediated endocytosis process 12 mABs: Mechanism-based ADR (BM suppression) Targets highly expressed on cancer cells and normal hematopoietic cells Drug names Target Rituximab CD20 Ofatumumab Obinutuzumab Expression B cells & other BM cells Mechanism-based ADRs BM suppression (neutropenia, thrombocytopenia), hepatitis B virus reactivation, progressive multifocal leukoencephalopathy Blinatumomab CD19/ CD3 CD19: B cells & other BM cells; CD3: T cells Febrile neutropenia, Cytokine release syndrome Inotuzumab ozogamicin CD22 (ADC) B cells & other BM cells Neutropenia, thrombocytopenia Brentuximab vedotin CD30 (ADC) B and T lymphocytes Neutropenia, progressive multifocal leukoencephalopathy Gemtuzumab ozogamicin CD33 Myeloid cells BM suppression Abbreviations: ADC= antibody-drug conjugate, ADR= adverse drug reaction, BM= bone marrow13 mABs: Mechanism-based ADR (cell-specific) Targets highly expressed on cancer cells and some other normal cells Drug names Target Expression Mechanism-based ADRs Cetuximab Panitumumab EGFR Cancer cells, epithelial cells Acneiform rash (skin epithelial cells), diarrhea (gastrointestinal epithelial cells) Trastuzumab (T) Pertuzumab HER2 Cancer cells, cardiac cells Cardiotoxicity T emtansine T deruxtecan HER2 (ADC) Cancer cells, cardiac cells Cardiotoxicity, neutropenia (from ADC) Bevacizumab VEGF Blood vessels/ endothelial cells Bleeding, hypertension, proteinuria Ramucirumab VEGFR Blood vessels/ endothelial cells Bleeding, hypertension, proteinuria Abbreviations: ADC= antibody-drug conjugate, ADR= adverse drug reaction, BM= bone marrow14 Cancer immunotherapy – general principles • Cytotoxic T cells are major mechanism of tumor cell killing. Activation of T cells is critical. • Dendritic cells play an important role as antigenpresenting cells. • When tumors have escaped the immune surveillance, they are not engaging with immune system because of immunosuppression. • There is pro-tumorigenic environment created by some immune cells. • Cancer immunotherapy is used to educate immune cells such as (1) dendritic cells to recognize and engage with the cancer cells and (2) T cells to get primed as well as recognize tumor cells and induce cytotoxicity. 15 Cytokines • Endogenous hormones of immune system • Examples of cytokines used to treat cancer: • Interferon α-2a • Interferon α-2b • IL-2 or Aldesleukin • Denileukin diftitox (Ontak®) [IL-2 + diphtheria toxin] (for cancer expressing CD25 of IL-2 receptor) 16 Viral vaccine The 9-valent HPV vaccine is prepared from various virus capsid proteins. 17 It does not contain any live or attenuated virus. Cellular immunotherapy: dendritic cells • The dendritic cell are antigen presenting cells. • Because a cancer antigen alone is not enough to rally activation of T cells, we need help of dendritic cells. 1. Fuse a cytokine to a tumor antigen. 2. Grow patient's dendritic cells in the incubator and let them take up this fused cytokine-tumor antigen. • This enables the dendritic cells to mature and eventually display the same tumor antigens as appear on the patient's cancer cells. • When these special mature dendritic cells are given back to the patient, they activate the T cells that can mount an attack on the patient's cancer cells. 18 http://www.cancer.gov/cancertopics/understandingcancer/immunesystem/AllPages Cellular immunotherapy: Sipuleucel-T ADRs: acute infusion reactions (chills, fatigue, fever, nausea, joint ache, headache) Abbreviations: APC- antigen-presenting cell, GM-CSF- granulocyte-macrophage colonystimulating factor, PAP- prostatic acid phosphate 19 Di Lorenzo, G. et al. Nat. Rev. Clin. Oncol., 2011. Cellular immunotherapy: CAR-T cells CAR-T therapy Tisagenlecleucel Axicabtagene ciloleucel 20 Klebanoff, et al., Nature Reviews Clinical Oncology, 2014. FDA-approved CAR-T therapy in Cancer: MOA Components of the Chimeric Antigen Receptor (CAR) scFv: Single-chain variable fragment A ligand recognition domain CD3ζ: Intracellular signaling moduleInduce T cell activation upon antigen binding CD28 and 4-1BB: Signaling endodomains with inducible T cell co-stimulator to mimic the costimulation provided during TCR recognition by antigen presenting cells (APCs). This co-stimulatory signal is required for robust T cell activation Tisagenlecleucel Axicabtagene ciloleucel Vector lentiviral vector ϒ-retroviral vector Co-stimulatory domain 4-1BB (CD137, TNFRSF9, ILA) Shows greater persistence or longevity and are more likely to differentiate into central memory T cells CD28 Exhibits a greater peak expansion and produce a larger proportion of effector memory cell subsets 21 https://science.sciencemag.org/content/359/6382/1361/tab-figures-data FDA-approved CAR-T therapy in Cancer: ADRs CAR-T therapy Target Indication CD19 ALL DLBCL Tisagenlecleucel Axicabtagene ciloleucel Mechanism-based ADRs Prolonged cytopenias, serious infections, cytokine release syndrome Milder reactions: fever, myalgias Severe reactions: vascular leak, hypotension, respiratory/renal failure, coagulopathy Can be treated with anti-IL6 antibodies (Tocilizumab) and/or steroids 22 Question What is the difference between Sipuleucel-T and Tisagenlecleucel? A. Sipluleucel-T targets antigen-presenting cells; whereas Tsagenleceleucel targets T cells. B. Sipluleucel-T does not involve leukopheresis; whereas Tsagenleceleucel requires leukopheresis. C. Sipluleucel-T involves modification of antigenpresenting cells; whereas Tsagenleceleucel does not modify any cells. 23 FDA-approved Immune checkpoint inhibitors in Cancer Nobel Prize in Medicine 2018 Name Ipilimumab Target CTLA4 Pembrolizumab PD-1 receptor Nivolumab PD-1 receptor Atezolilumab PD-L1 Durvalumab PD-L1 Tasuku Honjo, MD, PhD Jim Allison, PhD 24 Abbreviations: CTLA4- cytotoxic T-lymphocyte-associated protein-4, PD-1- program death receptor-1 Cancer Immunity cycle CTLA4 Ipilimumab Atezolizumab Durvalumab PD-1/PD-L1 Pembrolizumab Nivolumab 25 Chen and Mellman, Immunity, 2013 Rationale for immune checkpoints in physiology • Regulators of immune system; prevent autoimmunity. • A balance between co-stimulatory and inhibitory signals (referred to as immune checkpoints) 26 Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) pathway APC- antigen presenting cells MHC- major histocompatibility complex TCR- T cell receptor • When APC presents antigen through MHC, which is recognized by T cells, T cell activation requires stimulation through both the TCR and CD28. Ipilimumab • Activation of T cells occur when CD28 on T cells binds to B7 family member proteins on APCs. • With persistent T cell activation, CTLA-4 expression increases. • When it binds to B7 proteins, it inhibits T cell function. • Anti–CTLA-4 antibodies such as ipilimumab block CTLA-4 binding to B7 proteins and prevent inhibition of T cell function. 27 https://www.jci.org/articles/view/84236 Program Death Receptor pathway PD-1/PD-L1 • PD1 pathway regulates inflammatory responses in tissues by effector T cells recognizing antigen in tumor. • Activated T cells upregulate PD1 and continue to express it. • Inflammatory signals in the tumors induce the expression of PD-L1, which is also a safeguard mechanism to downregulate the activity of T cells and thus limit collateral tissue damage from autoimmunity in normal tissues. 28 https://www.nature.com/articles/nrc3239 Immune checkpoint inhibitors- Mechanismbased ADRs • Warning or precaution Some cases of cytokine release syndrome have been reported but is not very common. 29 Immune checkpoint inhibitors- Mechanismbased ADRs https://www.nature.com/articles/s41571-019-0218-0 30 Cost of cancer drugs 31 Question The PD1/PD-L1 pathway is important for ____________. A. B. C. D. Priming and activation of T cells Trafficking of T cells to the site of cancer Recognition of cancer cells by T cells Killing of cancer cells by T cells 32