
Mechanisms of Disease 2 HC31: Targeted therapy and hematological malignancies
HC31: Targeted therapy and hematological malignancies
Monoclonal antibodies
Tumor specific monoclonal antibodies:
CD20 is an IgG isotype expressed antigen on normal and malignant B-cells. It is used for treatment of many B-cell lymphomas → by targeting CD20 antigens, both malignant and normal B-cells are depleted.
Rituximab:
Chemotherapy combined with CHOP monoclonal antibodies leads to a significant increase of survival rates. Rituximab, a monoclonal antibody against CD20, leads to:
- Complement system activation
- A MAC is formed
- NK-cell recruitment
- Receptors bind to the humanized tail of rituximab
- Apoptosis
- Macrophages are attracted
Mechanisms of action:
Monoclonal antibodies can have different mechanisms of action:
- Complement dependent cytotoxicity (CDC)
- The complement system is activated
- Hollow pipes are made in the cell surface
- Water enters the cell
- The cell explodes
- Antibody dependent cellular cytotoxicity (ADCC)
- A B-lymphocyte plasma cell secretes antibodies which bind to an antigen on the pathogen
- The pathogen is phagocytosed by macrophages, destroyed by NK-cells or lysed via the complement system
- Radio immunotherapy
- A radioactive particle such as yttrium is coupled to an IgG monoclonal antibody such as CD20 → can get close to the tumor cells
- A form of local treatment
- Yttrium gives a small dose of β- or γ-radiation
- The tumor is directly targeted
- A radioactive particle such as yttrium is coupled to an IgG monoclonal antibody such as CD20 → can get close to the tumor cells
- Antibody drug conjugate
- A drug is bound to a monoclonal antibody such as CD30 → an ADC-CD30 complex is created
- CD30 is expressed in Hodgkin lymphomas and anaplastic large cell lymphomas
- The ADC-CD30 complex travels to the lysosome
- MMAE is released in the cell → disrupts the microtubule network
- Physical cell division is prevented by binding on a microtubule during cell division
- The G2-/M-phase is arrested → the cell cycle stops → apoptosis
- A drug is bound to a monoclonal antibody such as CD30 → an ADC-CD30 complex is created
Bispecific antibodies
Bispecific antibodies are a combination of 2 different antibodies to target B-cells with CD8 T-cells. A bispecific T-cell engager (BiTE) causes proliferation of T-cells via the following mechanism:
- 2 antibodies are coupled to create a bispecific monoclonal antibody with binatunumab → an antibody against CD3 antibody is coupled with an antibody against CD19
- Anti-CD3 antibodies target T-cells
- Anti-CD19 antibodies target B-cells
- The T-cell becomes activated and starts its immune function → cytokines are made
- A T-cell can kill more cells than 1 B-cell
- The T-cell attacks malignant B-cells → perforins enter the B-cells and kill them
CAR T-cells
A T-cell has a T-cell receptor, which can recognize a peptide presented in an HLA molecule. To activate a T-cell receptor, additional costimulatory signals such as CD28 are necessary as well. If a T-cell receptor is activated, the T-cell proliferates and kills the target cell. A Chimeric antigen receptor (CAR) T-cell uses the intracellular part of a TCR and the extracellular part of a monoclonal antibody:
- T-cells are extracted through a leukapheresis procedure
- T-cells are expanded if necessary
- Usually there already are enough T-cells
- CARs are reprogrammed into the T-cell
- Using a viral vector, T-cells with a new gene part are transfused with costimulatory signals and the extracellular part is transfused with part of a monoclonal antibody
- The CD3 zeta-chain of the TCR is used
- An anti-CD19 antibody is used as monoclonal antibody
- Using a viral vector, T-cells with a new gene part are transfused with costimulatory signals and the extracellular part is transfused with part of a monoclonal antibody
- Re-infusion of the CAR T-cells
- Chemotherapy is used for lymphocyte depletion to make the CAR T-cells more effective
- The target cell is killed
(Dis)advantages:
CAR T-cells have several risks, but also benefits:
- Risks
- Normal B-cells are also destroyed
- T-cells are activated and cytokines are excreted → cytokine release syndrome can occur
- For this reason, CAR T-cells are only used in hospitals with good IC-departments
- Benefits
- Upon activation, CAR T-cells go into a memory state → a reaction is induced in case of tumor relapse
- However, CAR T-cell survival is not as good as normal T-cell survival
- Upon activation, CAR T-cells go into a memory state → a reaction is induced in case of tumor relapse
Side effects
Side effects of monoclonal antibodies, BiTEs and CAR T-cells are:
- Allergic reactions at the beginning of the infusion
- Caused by monoclonal antibodies
- Cytokine release syndrome
- Symptoms
- Hypotension
- Fever
- Tachycardia
- Dyspnea
- Released cytokines
- TNF-α
- IFN-γ
- Interleukin-6
- Interleukin-2
- Caused by blina and CAR T-cells
- People have died due to treatment with CAR T-cells
- Symptoms
- Tumor lysis syndrome
- Lysis causes renal failure due to formation and release of uric acid crystals
- Prevention with rasburicase or allopurinol → no release of uric acids
- LDH release
- Lysis causes renal failure due to formation and release of uric acid crystals
- Polyneuropathy
- Monomethyl auristatin E (MMAE) conjugates to anti-CD30
Small molecules
Small molecules are also a form of targeted therapy. Small molecules can be used to treat chronic myeloid leukemia, where due to a translocation of chromosome 9 and 22 a fusion protein is made. This causes constitutive activation and increased proliferation. Targeted therapy consists of a drug that can take up the place of an ATP molecule, inhibiting phosphorylation of substrates → the effector mechanism doesn’t take place anymore. Imatinib is an example of target therapy.
In short, there are many signal transduction pathways, and many drugs which can inhibit particular molecules. In some tumors, the B-cell receptor is continuously active, which can be stopped by a small molecule.
Midostaurin:
Midostaurin is a new drug. It is an inhibitor of mutated Flt3, a surface cytokine receptor which is present on malignant acute myeloid leukemia cells. Inhibition of Flt3 results in increased cell death. Sometimes, midostaurin is used as maintenance treatment.
Join with a free account for more service, or become a member for full access to exclusives and extra support of WorldSupporter >>
Mechanisms of Disease 2 2020/2021 UL
- Mechanisms of Disease 2 HC2: Cancer genetics
- Mechanisms of Disease 2 HC3: Cancer biology
- Mechanisms of disease 2 HC4: Cancer etiology
- Mechanisms of disease 2 HC5: Hereditary aspects of cancer
- Mechanisms of Disease 2 HC6: Cancer and genome integrity
- Mechanisms of Disease 2 HC7: Clinical relevance of genetic repair mechanisms
- Mechanisms of Disease 2 HC8: General principles: diagnostic pathology
- Mechanisms of Disease 2 HC9: Nomenclature and grading of cancer
- Mechanisms of Disease 2 HC10: General principles: metastasis
- Mechanisms of Disease 2 HC11: General principles: molecular diagnostics
- Mechanisms of Disease 2 HC12: How did cancer become the emperor of all maladies?
- Mechanisms of Disease 2 HC13: Heterogeneity in cancer
- Mechanisms of Disease 2 HC14: Cancer immunity and immunotherapy
- Mechanisms of Disease 2 HC15: Framework oncology and staging
- Mechanisms of Disease 2 HC16+17: Pharmacology I&II
- Mechanisms of Disease 2 HC18: Biomarkers for early detection of cancer
- Mechanisms of Disease 2 HC19: Surgical oncology
- Mechanisms of Disease 2 HC20: Radiation oncology
- Mechanisms of Disease 2 HC21: Medical oncology
- Mechanisms of Disease 2 HC22: Chemoradiation
- Mechanisms of Disease 2 HC23: Normal hematopoiesis
- Mechanisms of Disease 2 HC24: Diagnostics in hematology
- Mechanisms of Disease 2 HC25: Myeloid malignancies
- Mechanisms of Disease 2 HC26: Malignant lymphomas
- Mechanisms of Disease 2 HC27+28: Allogenic stem cell transplantation and donor lymphocyte infusion I&II
- Mechanisms of Disease 2 HC29: HLA & minor histocompatibility antigens
- Mechanisms of Disease 2 HC30: Changes in patients’ experiences
- Mechanisms of Disease 2 HC31: Targeted therapy and hematological malignancies
- Mechanisms of Disease 2 HC32+33: Primary hemostasis
- Mechanisms of Disease 2 HC34+35: Secondary hemostasis I&II
- Mechanism of Disease 2 HC36: Fibrinolysis and atherothrombosis
- Mechanisms of Disease 2 HC37: Cancer, coagulation and thrombosis
- Mechanisms of Disease 2 HC38: Bleeding disorders
- Mechanisms of Disease 2 HC39: Thrombosis

Contributions: posts
Spotlight: topics
Mechanisms of Disease 2 2020/2021 UL
Deze bundel bevat uitwerkingen van alle hoorcolleges, patientdemonstraties en eventuele (proef)tentamens van het blok Mechanisms of Disease 2 van de studie Geneeskunde aan de universiteit Leiden.
JoHo can really use your help! Check out the various student jobs here that match your studies, improve your competencies, strengthen your CV and contribute to a more tolerant world
Add new contribution