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Oncology Exam 3
Immune Checkpoint Inhibitors Smith A
| Term | Definition |
|---|---|
| Immune checkpoint inhibitors work in the "inter-play" between your ____, ____, _____ | APC cells, tumor cells, and your T-cells |
| Signal 1 for the Antigen presenting cell to the T-cell is the? | MHC presenting/coupling to TCR (APC handing off some antigen to the T-cell for the T-cell to start recognizing that antigen. |
| Tell me what signal 2 is? | coupling of B7 to CD28 (+ signal) and B7 to CTLA-4 (- signal) *(-) stops T-cell from activating |
| Communication b/w the tumor cell and the T-cell (some tumors are great at evaiding the immune system), how do they do this? | mimicking the communication that normally happens between the APC and T-cell, so significiant (uses that signal 2_ |
| how do we get the T-cell to start seeing tumor cells again? | We're going to block some of these receptors so that the tumor cell cannpt "fool" T-cell |
| We have immune checkpoint inhibitors for what targets? | MHC; PD-L1 (*remember that PD-1 is the receptor on the T-cell_; whereas PD-L1 is a receptor on the tumor cell) |
| If we block CTLA-4, we are preventing? | the T-cell from acting on a (-) signal |
| MOA of Ipilimumab? | Fully human monoclonal antibody targeting CTLA-4 |
| Indications of Ipilimumab? | -First approved for treatment of metastatic melanoma in 2011 -Demonstrated proof of concept: targeting negative immune regulation can lead to tumor regression |
| AE of Ipilimumab | -Significant autoimmune toxicities common: dermatitis, enterocolitis, hepatitis, and hypophysitis -Most common adverse reactions (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis. |
| Key information of Ipilimumab? | -Seem to have long-term response -Challenges: optimal dosing strategy still not know. Trying to determine how to prevent toxicities – maybe by using corticosteroids -Being used in combination with nivolumab |
| MOA of Pembrolizumab? | -Humanized monoclonal antibody targeting PD-1 |
| What are the indications for Pembrolizumab? | -Metastatic NSCLC with >50% PD-L1 expression after progression on platinum-based therapy -Head and neck squamous cancer after platinum chemo |
| What are the AE of Pembrolizumab? | -Fatigue, pruritus, rash, decreased appetite, and dyspnea |
| Key information of Pembrolizuman | -Seems to have long-term response |
| MOA of Nivolumab? | -Fully human monoclonal antibody targeting PD-1 (⭐️) |
| What are the indications of Nivolumab? | -initially approved for metastatic melanoma in 2014 |
| What are the AE of Nivolumab? | -Fatigue, skeletal muscle pain, pruritis, diarrhea, cough, nausea, constipation, back pain, shortness of breath, fever, rash, decreased appetite, upper respiratory tract infection, weakness |
| What is the MOA of Cemiplimab? | -Fully human monoclonal antibody targeting PD-1 *different binding location on the PD-1 (blocking PD-1 on the T-cell side and preventing interaction with the PD-L1 receptor as well as the more recently discovered PD-L2) ⭐️ -Blocks PD-1 interaction with PD-L1 and PD-L2 (which is a second ligand for PD-1) |
| What is the indication for Cemiplimab-rwlc? | -for the treatment of advanced cutaneous squamous cell carcinoma |
| What are the AE's of Cemiplimab-rwlc? | -monitor for immune related adverse events (irAEs ⭐️) including pneumonitis, colitis, dermatologic conditions, hepatitis, nephritis, and endocrine dysfunction. |
| What is the MOA of Dostarlimab-gxly? | -humanized monoclonal antibody targeting PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 |
| What is the indication for Dostarlimab-gxly? | -endometrial cancer; other solid tumors |
| What are the AE of Dostarlimab-gxly? | -Common: Side effects may include fatigue/asthenia, nausea, diarrhea, anemia, and constipation -Serious: immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions and any other immune-mediated adverse reactions |
| What is the MOA of Durvalumab? | -Fully human monoclonal antibody targeting PD-L1 |
| What is the indication Durvalumab? | -Treats locally advanced or metastatic urothelial carcinoma |
| What are the AE of Durvalumab? | -fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infection, cough, fatigue, pneumonitis, upper respiratory tract infections, shortness of breath, rash |
| What is the MOA of Atezolizumab? | -humanized monoclonal targeting PD-L1 |
| What is the indication for Atezolizumab? | -Treats various advanced or metastatic cancers; these cancers usually need to have high PD-L1 expression |
| What are the AE's of Atezolizumab? | -Common: fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation -Patients with urothelial carcinoma: risk of urinary tract infection -Possible immune-related adverse effects: hepatitis, colitis, hypophysitis, thyroid disorders, adrenal insufficiency, and rarely, type 1 diabetes mellitus, pancreatitis, myasthenia gravis, Guillain-Barré syndrome, and ocular inflammation; these may require discontinuation of treatment -Potential embryofetal toxicity |
| Cell surface antigen Monoclonal antibodies---> | -Most hematologic malignancies express specific cell-surface antigens -MoAbs have provided opportunity for targeted therapy -MOA not fully understood; probably related to induction of antibody dependent cell-mediated cytotoxicity and apoptosis |
| What is the MOA of Rituximab? | -chimeric IgG1 monoclonal antibody against the cluster of differentiation 20 (CD20) antigen found on normal mature B-cells and cancerous B-cells ⭐️ -The Fab domain binds to the CD 20 antigen⭐️; the Fc domain recruits the immune system to kill the cells by antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity⭐️ -Possibly has a direct apoptotic effect |
| Therapeutic uses for Rituximab includes? | -CD20 positive NHL and CLL -also indicated for the treatment of a variety of immune-mediated diseases, including rheumatoid arthritis⭐️ |
| Primary AE's with Rituximab includes? | -⭐️Immunosuppression (severe) due to targeting of normal mature B cells -⭐️Hypersensitivity (chimeric) related to chimeric nature of Ab |
| MOA of Obinutuzumab is? | -humanized anti-CD20, but binds CD20 in a different orientation compared to Rituximab -Fc portion has been glycoengineered to reduce ⭐️fucosylation⭐️ resulting in improved receptor affinity and enhanced ADCC potency -Kills the B-cell by causing programmed cell death (PCD) and antibody-dependent cell-mediated cytotoxicity (ADCC) |
| Therapeutic uses for Obinutuzumab includes? | approved for CLL and follicular lymphoma |
| What are the AE's of Obinutuzumab? | -infusion reactions, myelosuppression, nausea, and diarrhea -⭐️HBV reactivation and Progressive Multifocal Leukoencephalopathy (PML)⭐️ have also been reported *Myelosuppression --> risk for opportunistic infections ⭐️ *drug causes CNS effects and neurological symptoms⭐️ |
| What is the MOA of Blinatumomab? | -An anti-CD19/CD3⭐️ monoclonal antibody -Binds to CD19 on malignant B-cells and CD3 on T-cells, physically linking the T cells and tumor cells. The two cell membranes touch, triggering a signaling cascade in the T-cell for target cell lysis ⭐️linker target cell lysis (punch holes in leukemic cells) and uses a LIGHT chain/ not heavy chain |
| What are the therapeutic uses for Blinatumomab? | -Indicated for the treatment of B-cell precursor ALL ⭐️⭐️Linker will fold and membrane-membrane (trigger T-cell to kill B-cell via lysis (exudes chemicals that “punches holes” unique new therapy (considered monoclonal (using the “ligiht chain(still considered a monoclonal -ALL (acute lymphcytic leukemia) |
| What are the AE of Blinatumomab? | -Common: fever, headache, peripheral edema, and rash -Monitor patients for cytokine release syndrome, neurological toxicities, and infections |
| What are the B-cell lymphoma 2 (BCL-2) inhibitors? | -The B-cell lymphoma (BCL) 2 protein family are proteins that govern mitochondrial outer membrane permeabilization and apoptosis -Some of the BCL-2 proteins are pro-apoptotic; some are anti-apoptotic -Some anti-apoptotic BCL-2 proteins are overexpressed in CLL and other tumors, resulting in tumor cell survival and resistance to cancer treatments |
| MOA and indication for Venetoclax? | -A selective inhibitor of BCL-2, allowing apoptosis -Approved for CLL, small lymphocytic lymphoma, and newly diagnosed AML in older adults ⭐️slow-dose escalation |
| AE of Venetoclax? | -myelosuppression, fatigue, diarrhea, cough, and upper respiratory tract infection |
| Dosing requirements for Venetoclax includes? | -Weekly dose escalation over the first 5 weeks is required to reduce risk of tumor lysis syndrome (TLS); -⭐️PO; take with food |
| What is the MOA of Asparaginase? | -Leukemic cells cannot synthesize L-asparagine for protein synthesis; they must acquire it from plasma -Asparaginase hydrolyzes circulating asparagine, depriving malignant cells of the asparagine needed for protein synthesis. -Need to give this med in the proper order |
| What are the 3 preparations of Aspiraginase? | -E. coli preparation; t1/2=14-24 hours; dosed every third day for 3-4 weeks -Erwinia preparation (Asparaginase erwinia chrysanthemi (recombinant)-rywn; for patients hypersensitive to the E. coli prep; t1/2=16 hours -Pegaspargase is a pegylated; t1/2=6 days; dosed every week; much lower immunogenicity |
| We are giving pts Asparaginase which is responsible for? | causing the breakdown of asparagine (cant synthesize their own AA); borrow asparagine that is circulating in pt’s blood |
| We give the pt asparaginase (use it to breakdown circulating asparagine therefore not allowing the leukemic cells from using them) We need to give this med in the proper order--> | -asparaginase is given with other chemo drugs (some classics require cells moving along cell cycle some traditional therapies hit in parts of the cell cycle but we need to let the leukemic cells progress through the cell cycle then give asparaginase to prevent the leukemic cells form getting the asparagine; means they won’t have the tools to progress in the cell cycle |
| Administration of Asparaginase is? | parenterally |
| What are the AE's of Asparaginase? | -Hypersensitivity in 5-20% of patients -Inhibition of protein synthesis in normal tissues may cause hyperglycemia, clotting abnormalities, hypoalbuminemia, suppression of immune function -Coma (rare) may be due to ammonia toxicity from asparagine hydrolysis -Pancreatitis ⭐️Patient can develop antibodies that may inactivate the enzyme |
| Combo: Single-drug therapy is limited because? | -Therapy must eliminate every malignant cell, requiring high doses -Toxicity limits their doses -Resistance can develop through genetic alterations (heterogeneous tumor cell population) -Most meds are less effective against large solid tumors with low growth fractions |
| Combo: As tumors get larger, the rate of division is ______ and single drug therapy is limited since they target rapidly dividing cells | slower |
| Combo: Combine medications with? | -Different molecular targets -Affect different phases of cell cycle -Different dose-limiting toxicities *multi-stage model heterogenous (solid tumors) ⭐️"we will combine therapies because we can target them when they are not necessarily synchronized in the cell |
| Combo: Rationale for combining therapies: | -Targets asynchronously dividing tumor cells -Reduces emergence of drug resistance -Each drug can be given at highest tolerable dose -Takes advantage of synergistic MOAs |
| Combo: There are 2 types of resistance? | -Primary (or inherent) resistance is drug resistance in the absence of prior exposure -Secondary (or acquired) resistance develops in response to exposure to a given anticancer agent |
| Combo: What are some MOR (resistance)? | -decreased activation of prodrugs -decreased uptake of drugs secondary to alterations in drug transport systems -changes in drug target -alterations in the ability to repair drug-induced damage -increased drug inactivation -decreased apoptosis abilities in the cells |
| Combo: Pleiotropic (or multidrug) drug resistance can develop? | Yes, often cancer cells become resistant to several structurally unrelated antineoplastic drugs at the same time |
| Combo: Several cytotoxic natural products are associated with development of pleiotropic resistance such as? | anthracyclines, actinomycin D, mitomycin C, vinca alkaloids, epipodophyllotoxins, and taxanes; -The resistant cancer cells have an amplification of P-glycoprotein expression, increasing the cell’s ability to export these drugs |
| Combo: Genetic testing is done to? | optimize efficacy AND To decrease toxicity |
| Paper by Leev? study used? | 30 colorectal pts; looked for markers to genotype; BAD RAS in colorectal pts; blood was not drawn, but looked at biopsies of tumors. 11 responded to Cetuximab. looked at tumors for RAS, RAF, and EGFR. -1 thing i mentioned about EGFR being a target for Cetuximab, is that some mutations of the genes for EGFR make that receptor more hyperactive. -some other mutations in the EGFR gene make the cells express too many of those receptors, so too many--> BAD. |
| Combo: Paper confirms? | that overexpression of the receptors was related to a better reponse to cetuximab. So the idea that mutations and receptors or mutations in our targets might not just affect the activity of the target byt might affect the expression amount of the target. *not just the hyperactivitiy byt could also be related to the # |
Created by:
Xander635
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