Immunotherapy Pharmacology Concepts 2024 PDF

# Immunotherapy Pharmacology Concepts ## Bruce Cuevas, PhD ### High Yield Pharmacology Info - Red text indicates High Yield information - We will discuss Pharmacology principles during Week 3. Please remember these details for now: - Mechanism of action - Major adverse effects - Major...

# Immunotherapy Pharmacology Concepts ## Bruce Cuevas, PhD ### High Yield Pharmacology Info - Red text indicates High Yield information - We will discuss Pharmacology principles during Week 3. Please remember these details for now: - Mechanism of action - Major adverse effects - Major drug interactions - Any contraindications ### Learning Objectives At the end of this module, you should be able to: - Explain the molecular mechanism of action of each drug in each drug class. - Relate the main effects of each drug to its molecular mechanism of action. - Describe the route of administration and the relevant pharmacokinetic features of each drug in each drug class. - Describe the principal adverse effects of the drugs of each class. - Describe the clinically important drug interactions of the drugs of each class. - Describe the principal contraindications of the drugs of each class. - Outline the main therapeutic uses of the drugs of each class. ### Suggested Readings - Lippincott Illustrated Reviews: Pharmacology - Chapter 36 – Immunosuppressants - Flashcard Hero files - http://flashcardhero.com/free-flashcard-app/ - http://flashcardhero.com/windows/ - I will post "decks" pertaining throughout this block, but you are encouraged to supplement the card inventory as needed. - Transplant immunosuppressants video - https://www.youtube.com/watch?v=W6QABmSosnw - Some of the drugs mentioned in the video will be covered later. ### Why suppress the immune system? - Stop and/or prevent transplant rejection - Reduce immune activation/efficacy to treat autoimmunity/chronic inflammation, such as: - Rheumatoid arthritis - Psoriasis - Inflammatory bowel disease - Lupus ### Transplantation data | | | | :----------------- | :------------- | | South Dakota | 63 | | North Dakota | 47 | | Iowa | 247 | | Nebraska | 316 | | Minnesota | 1078 | | 5 state region | 1751 | | Nationally | 42,889 | | **United Network for Organ Sharing data** | **https://unos.org/data/** | ### Immunosuppressive Agents - Goal: to reduce activation or efficacy of the immune system - Autoimmune disorders - Organ transplantation rejection prophylaxis - Overall approach: - Alter lymphocyte function with drugs or antibodies against immune proteins - Combination therapy (2-4 agents) at low doses ### Mechanisms of immunosuppression - Blockade of T cell signal transduction - Inhibit T cell activation - Interfere with cytokine production - Reduces immune cell proliferation - Impairs immune response - Disrupt T cell metabolism ### Focus on 3 signaling pathways - **T cell receptor** - Activation of the T-cell receptor results in increased intracellular Ca2+ - Activation of calcineurin, a Ca2+-dependent phosphatase - **CD28 receptor co-stimulation** - Signal 1 - Signal 2 - Release of IL-2 - **IL-2 receptor** - As a result of dephosphorylation by calcineurin, NFAT moves from the cytoplasm to the nucleus - FK-binding proteins (FKBP) - NFAT associates with other nuclear components, leading to activation of genes - IL-2 gene encoding cytokines - IL-2 mRNA - mTOR ### Transplant induction vs. maintotherapy - Powerful suppression at time of transplant - Antibody +/- corticosteroids - **Maintenance therapy** - Less potent than induction therapy - Provides long-term immunological protection with less risk of infection - Drugs have different MOA to reduce AE ### Induction and Rejection Immunosuppressant Drugs - **Biologics/Antibodies** - Monoclonal - Polyclonal - **Corticosteroids** - **Proteasome inhibitors** ### A little bit about antibodies - Mouse - Chimeric - Humanised - Muromonab - Rituximab - Alemtuzumab - Human - Intravenous immunoglobulin (IVIg) ### Rituximab (Rituxan) - Chimeric monoclonal anti-CD20 antigen on B lymphocytes - Depletes B cells, reduces antibody production - Also indicated for lymphoma and some autoimmune - IV administration following premedication with glucocorticoids to reduce infusion reactions - **Black Box Warnings:** Fatal infusion reactions, fatal multifocal leukoencephalopathy ### Basiliximab (Simulect) - Chimeric monoclonal antibody to the alpha subunit (CD25) of the IL-2 receptor on activated T-cells - Masks IL-2-binding site on IL-2 receptor - Inhibits activation and proliferation ### Basiliximab Adverse Effects - Toxicity is generally low - Gastrointestinal upset - **Big 4 for monoclonal antibodies** - Hypersensitivity - Increased risk of infections - Increased risk of heart failure - Increased risk of cancer, esp. in adolescents ### Anti-thymocyte Globulin (ATGAM, Thymoglobulin) - Polyclonal, derived from rabbit, horses or sheep immunized with human T-lymphocytes - Cytotoxic antibodies to surface T-cell antigens - Direct cytotoxicity (complement and cell-mediated) and blockade of remaining lymphocytic function. - Indicated for induction and to terminate transplant rejection ### Anti-thymocyte Globulin Adverse effects - Immunosuppression - Hypersensitivity - Fever and chills - Hypotension- minimized by pretreatment with corticosteroids, acetaminophen, or antihistamines - Increased risk of cytomegalovirus infections ### Intravenous Immunoglobulin (IVIg) - Immunoglobulins from human plasma pooled from multiple donors - Modulatory, indicated for both pretransplant desensitization and antibody-mediated rejection (AMR). - Mechanism not well defined. High doses modulate B cell signaling and induce B cell apoptosis - t½ is about 3-4 weeks. - Severe AE rare but may include renal failure, thrombosis ### Glucocortiucoids - Glucocorticoids - Cholesterol - Prednisone - Cortisol - Prednisolone - Transactivation - Transrepression ### Glucocorticoids (Orapred, Deltasone, Medrol) - Prednisolone (oral), methylprednisolone (IV) - Mechanism of action - cause the death and redistribution of lymphocytes - resulting in a reduction in total blood lymphocyte numbers. - Increased apoptosis of lymphocytes by curtailed activation of NF-kB, increased expression of apoptosis-promoting proteins - Inhibit synthesis of pro-inflammatory cytokines ### Glucocorticoid Indications - Prevent and treat transplant rejection - High doses often required to terminate acute rejection - Prednisone is most commonly used option - Auto-immune disorders such as rheumatoid arthritis, inflammatory bowel disease - Allergic reactions to other immunosuppressive agents ### Glucocorticoids Adverse effects - **Short term** - Hypertension - Hyperglycemia - Psychological effects (mood swings) - **Long term** - Increased risk of infections (e.g. oral candidiasis) - Myopathy/muscle weakness - Truncal obesity/local fat deposits - Adrenal suppression - Increased risk of osteoporosis and osteopenia ### Maintenance Immunosuppressant Drugs - **Calcineurin inhibitors** - Tacrolimus Cyclosporine - Ca2+ - Cyclophilin - Inactive NFATC - Active NFATC - **mTOR inhibitors** - Everolimus Sirolimus - mTOR - G1 - IL-2 mRNA - Cell cycle - **Antiproliferatives** - **Co-stimulation blockers** - Belatacept IL-2 - CD28 - IL-2 receptor ### Calcineurin Inhibitors - Tacrolimus - Cyclosporine - Both bind to an immunophilin (chaperon proteins) - FKBP-12 (FK-binding protein) binds tacrolimus - Cyclophilin binds cyclosporine - Both binding reactions block calcineurin' s phosphatase activity, required for movement of a component of NFAT (nuclear factor of activated T-cells) into the nucleus, blocking the production of IL-2. - Primary action is on T-cell processes ### Calcineurin Inhibitor Toxicities - Renal toxicity is common & dose limiting - Cardiovascular risk elevated by hyperlipidemia - Hypertension is very common in transplant patients - Hyperglycemia and diabetes, esp. when combined with glucocorticoids ### Tacrolimus (Prograf, FK506) - More efficacious than cyclosporine and has easier monitoring - More potent - More efficacious (less rejection) - Variability in pharmacokinetics requires individualization of dosing - Variable absorption - Variable biotransformation product excretion in feces ### Tacrolimus Toxicity - Nephrotoxicity (dose limiting) - Neurotoxicity (tremors, headache, seizure) - More common than with cyclosporine - Cardiovascular risk elevated - Watch lipids and hypertension - Hyperglycemia and diabetes are common - more common among African Americans and Hispanics - Risk of secondary tumors and opportunistic infections - Gastrointestinal upset ### Tacrolimus Drug Interactions - Watch nephrotoxicity - Whole blood level monitoring recommended - Inhibits CYP3A, interactions can be intense ### Cyclosporine (Neoral) - Widely used immunosuppressive drug - Approved to treat GVH disease and prevent rejection of (kidney, heart, and liver) transplants - Also used in RA, psoriasis, dry eye, et al - Complex pharmacokinetics require modeling of individual patient blood curves - Highly lipophilic, oral administration - Complex fecal excretion of cyclosporine and active biotransformation products ### Cyclosporine Renal Toxicity - Renal toxicity is common & dose limiting - Important to monitor renal function, BUN/creatinine, CrCl - Severe toxicity treatment mostly supportive, treat hyperkalemia with dextrose/insulin and Ca++ - Drugs that exacerbate nephrotoxicity - Antibiotics: Aminoglycosides, trimethoprim - Acyclovir - Digoxin - Furosemide - indomethacin ### Cyclosporine Toxicity (other) - Cardiovascular risk elevated by hyperlipidemia - Hypertension is very common in transplant patients - Hyperglycemia and diabetes, esp. glucocorticoid combo - Hepatotoxicity - tremor - Hirsutism - Gum hyperplasia - hyperuricemia ### Cyclosporine Interactions - Very common interactions at biotransformation level - grapefruit inhibits CYP3A4, cyclosporine metabolism - Cyclosporine A is both substrate and inhibitor of P-glycoprotein, may alter exposure to other substrates - Sirolimus-cyclosporine combination increases nephrotoxicity, hyperlipidemia, and myelosuppression - Can often be used simply by separating administration by several hours ### Cyclosporine use in Dry Eye - Tear abnormality observed in autoimmunity and elderly - Estimated > 5 million over age 50 - Frequently includes inflammatory cytokine expression and lacrimal gland inflammation damage - Cyclosporine is the only prescription drug in USA for DED ### Sirolimus (Rapamune) Everolimus (Zortress) - Binds FKBP-12 that complexes with mammalian Target Of Rapamycin (mTOR) to block progression of cell cycle in T-cells. - Same binding site as tacrolimus but complex binds to mTOR, not calcineurin - Inhibits the response to interleukin-2 but does not alter production, net effect is blocked cell proliferation ### Sirolimus & Everolimus Pharmacology - Pharmacokinetics - Sirolimus is biotransformed by CYP3A4 and is transported by P-glycoprotein - Everolimus has a shorter half-life and duration of action and requires more frequent dosing - Elimination is by biotransformation with high potential for interactions - Indications: Organ transplants (renal) - Often combined with cyclosporine (synergistic effect), block T-cell activation via mechanism distinct from cyclosporine ### Sirolimus & Everolimus adverse effects - Hyperlipidemia (may require treatment) - Renal failure (and hypertension) are more common when combined with cyclosporine than cyclosporine alone. - Hyperglycemia - Angioedema (everolimus especially) - Bone marrow suppression (thrombocytopenia, leukopenia, anemia) - Neurotoxicity - Hepatoxicity - Myelosuppression ### Anti-Proliferative/Anti-Metabolic Drugs - Azathioprine - Mycophenolate Mofetil ### Azathioprine (Azasan, Imuran) - Mechanism of action - Converted first to mercaptopurine (anticancer drug) and then to false/decoy nucleotides that incorporates into RNA to block translation - Inhibits T cell function more than B cell function - Powerful anti-inflammatory action - Indications - Autoimmune disorders - Usually combined with cyclosporine and prednisone to prevent organ transplant rejection ### Azathioprine Pharmacology - Pharmacokinetics - Orally absorbed - Biotransformed - Adverse effects - Bone marrow depression - Increased risk of infections - Gastrointestinal upset and ulcers - Hepatotoxicity - Carcinogenicity ### Azathioprine Interaction with allopurinol - Allopurinol inhibits xanthine oxidase and is indicated for gout. - Allopurinol inhibits biotransformation of azathioprine and mercaptopurine increasing toxicity - Concurrent use requires azathioprine dosage reduction of 60 to 75% ### Mycophenolate Mofetil - (Mechanisnt of action - Converted to mycophenolic acid, inhibits purine (GMP) synthesis - Suppresses both T and B cell activation - T and B cells are very sensitive to purine synthesis inhibition - Adverse effects - Gastrointestinal upset and ulceration - Not consistently reduced by enteric coated tablets (mycophenolate sodium) - Bone marrow suppression - Increased risk of infection ### Mycophenolate Mofetil PK - Mechanism scheme: - Mycophenolate Mofetil - IMP IMPDH, GMP GDP GTP DNA - Pharmacokinetics - Intravenous and oral administration - Biotransformation is primary elimination route - Indications - Organ transplants ### Induction/rejection therapy drugs | DRUG | CLASS | MECHANISM OF ACTION | INDICATIONS | ADVERSE EFFECTS | | :------------------ | :---------------------- | :------------------------------------------------------------------ | :---------------------------------------------------------- | :-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | | Alemtuzumab | Humanized monoclonal antibody | Binds to CD52 on Band T lymphocytes, causing T- and B-cell depletion | Induction, treatment of rejection | Infusion-related effects (chills, fever), severe and prolonged leukopenia, neutropenia, thrombocytopenia, infections (CMV, HSV, and other viruses/fungi) | | Antithymocyte globulins | Polyclonal antibodies | T-cell depletion | Induction, treatment of rejection | Infusion-related effects (chills, fever), leukopenia, thrombocytopenia, pulmonary edema, infections due to CMV or other viruses, skin rash | | Basiliximab | Chimeric monoclonal antibody | Binds to CD25 (IL-2R) and inhibits IL-2 mediated T-cell proliferation (nondepleting) | Induction | Generally well tolerated vs. placebo | | Bortezomib | Proteasome inhibitor | Proteasome inhibition leads to plasma cell depletion | Treatment of antibody-mediated rejection | Leukopenia, anemia, thrombocytopenia, nausea/vomiting, diarrhea, peripheral neuropathy, hypotension, hepatotoxicity (less common) | | Intravenous Immunoglobulin (IVig) | Immune globulin | Antibodies, B cells | Induction for highly sensitized patients, treatment of rejection | Infusion-related reactions, headache, hypotension, hemolytic anemia, pulmonary edema, thromboembolic events, aseptic meningitis, acute renal failure | | Methylprednisolone | Corticosteroid | Nonspecific interleukin and TNF inhibition | Induction, treatment of rejection, maintenance | HTN, HLD, hyperglycemia, peripheral edema, mood disturbance, osteoporosis, weight gain | | Rituximab | Chimeric monoclonal antibody | CD20+ B-cell depletion | Induction, treatment of rejection | Infusion-related effects (chills, fever), infections (reactivation of hepatitis B virus, CMV, and other viruses/fungi), PML, leukopenia, thrombocytopenia, mucocutaneous reactions | ### Maintenance suppressant therapy drugs | DRUG | CLASS | PHARMACOKINETICS | INDICATIONS | ADVERSE EFFECTS | | :------------------ | :--------------------- | :----------------------------------------------------------------- | :------------------------------------------------ | :------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | | Azathioprine | Antiproliferative | Activated by glutathione S-transferase DDI (allopurinol, warfarin) | SOT (renal), RA | Myelosuppression, nausea, vomiting, diarrhea, pancreatitis, hepatotoxicity | | Belatacept | Costimulation blockade | Elimination half-life ~10 days | SOT (renal) | Anemia, leukopenia | | Cyclosporine | Calcineurin inhibitor | Metabolism by CYP3A4 Numerous DDis | SOT (renal, liver, heart), psoriasis, RA, acute GVHD | HTN, HLD, hyperglycemia, hyperkalemia, hirsutism, gingival hyperplasia, neurotoxicity, nephrotoxicity | | Everolimus | mTOR inhibitor | Metabolism by CYP3A4 Numerous DDis | SOT (renal, liver), oncology | HTN, HLD (particularly TG, TC), stomatitis, proteinuria, impaired wound healing, rash, myelosuppression | | Methylprednisolone | Corticosteroid | Activated to prednisolone | Numerous indications | HTN, HLD, hyperglycemia, peripheral edema, mood disturbance, osteoporosis, weight gain | | Mycophenolate | Antiproliferative | Metabolism by glucuronidation DDI (bile acid sequestrants) | SOT (renal, liver, heart) | Leukopenia, thrombocytopenia, nausea, vomiting, diarrhea | | Sirolimus | mTOR inhibitor | Metabolism by CYP3A4 Numerous DDis | SOT (renal), lymphangioleiomyomatosis | HTN, HLD (particularly TG, TC), stomatitis, proteinuria, impaired wound healing, rash, myelosuppression, pneumonitis | | Tacrolimus | Calcineurin inhibitor | Metabolism by CYP3A4 Numerous DDis | SOT (renal, liver, heart) | HTN, HLD, hyperglycemia, hyperkalemia, alopecia, neurotoxicity (hand tremor, headache, seizure), nephrotoxicity | ### Immunosuppressive Drug - Muromonab-CD3 (OKT3) - CD4 - Cyclophilin + Cyclosporine - FKBP + Tacrolimus (FK-506) - FKBP + Sirolimus (rapamycin) - IL-2R - NFAT-P - Calcineurin - NFAT - Azathioprine - Dacilzumab, basiliximab - T HELPER CELL - Corticosteroids - 6-MP - Proliferation genes - NF-KB - Cytokine genes (IL-2) - DNA replication - PPRP - Amidotransferase - Purine nucleotides ### Immune enhancers - Immune checkpoint inhibitor immunotherapy - Cytokines ### Immune checkpoint inhibitors (ICI) - ICIs are used to overcome immuno-suppressive tumor microenvironment and promote anti-tumor immune response. - You will hear about Tumor Immunology in Week 5. Focus on the principle for now. - The primary ICI targets are: - PD-1 (Programmed Cell Death 1) - PDL1 (CD274, Programmed Cell Death 1 Ligand 1) ### Immune-based cancer - MHC I - Tumour antigens - B71-1 or B71-2 CD28 - APC - MHC II TCR - CD8+ T cell - CTLA4 - Helper cytokines - T1 - H cell - Lymphoid tissue TME - IFNY - T cell - reg - PDL1 - PD1 - IFNY - Macrophage - CD8+ T cell - Tumour - Nature Reviews | Cancer - Topalian et al, Nature Reviews Cancer 16, 275-287 (2016) ### Using ICI to block PD- signalinor - AKT PI3K - survival - Ras - P - P - P - P - MAP2K - proliferation - membrane ### Anti-PD-1 (receptor) antibodies - Cemiplimab/Libtayo - Nivolumab/Optivo - Pembrolizumab/Keytruda - Monoclonal antibodies (MAb) that binds PD-1 on T cells, prevents interaction with PDL1 on tumor cells. - Blocks the anti-proliferation signal that activated PD-1 produces in T cells. ### Anti-PDL1 (ligand) antibodies - Avelumab/Bavencio - Durvalumab/Imfinzi - Atezolizumab/Tecentriq - Monoclonal antibodies that bind to PDL1 on tumor cells to prevent interaction with PD-1 on T cells. - These also block the anti-proliferation signal that PD-1/PDL1 interaction produces in T cells. ### Cytokines- rIL-2 (Aldesleukin) - Recombinant interleukin-2 (rIL-2) - Lymphokine that stimulates production of T cells and activates killer cells. - Indications - Adjunctive therapy for renal carcinoma - Metastatic melanoma - Adverse reactions - Cardiovascular toxicity (capillary leak syndrome) ### Interferon therapeutics - Interferon beta is used to treat multiple sclerosis - Interferon alfa is approved to treat - Hairy cell leukemia in adults. - CML - Warts, Hep C and other viral conditions - Interferon gamma is used for chronic granulomatous disease. - Interferon-associated mechanisms are very complex and will be discussed in each section that applies. - The most common adverse effect is flu-like symptoms. ### Practice question Which of the following drugs blocks IL-2 induced proliferation but does not inhibit IL-2 production? - A. calcineurin - B. tacrolimus - C. cyclosporine - D. sirolimus ### Pharmaco-Jeopardy Review - Binds to cyclophilin to inhibit calcineurin activity. - What is cyclosporine? - Blocks purine synthesis after it is biotransformed. - What is mycophenolate mofetil? - An immunosuppressant and anticancer prodrug that inhibits ribosome function when inserted into RNA - What is azathioprine? - Binds to nuclear receptor to promote T cell death by inhibiting NFkB activation. - What are glucocorticoids? - Binds to FKBP-12 to inhibit mTOR activity. - What is sirolimus? - Immunosuppressant drug with major adverse effects that include both nephrotoxicity and neurotoxicity - What is tacrolimus? - Drug class that blocks PD-1 signaling to enhance anti-tumor immunity. - What are Immune Checkpoint Inhibitors? - The polyconal antibodies used to induce immune suppression and terminate transplant rejection. - What is Anti-thymocyte Globulin (ATGAM)? - Hypersensitivity, increased risk of infections, increased risk of heart failure and increased risk of cancer - What are the Big 4 adverse effects associated with prolonged administration of monoclonal antibodies?