Immunotherapy Flashcards
Humanization of Antibodies
Antibodies produced in MICE need to be transformed to mimic a human protein or they will be recognized as foreign by the immune system
Through biology, form a cell line that secretes antibodies that are mostly human with a mice’s complementarity determining region (CDR)–>humanized
B cells
antigen producing cells
B cell is triggered when a matching antigen is present–>B cell engulfs the antigen and digests–> displays antigen fragments bound to MHC–>recruits T cells–> T-cell secretes cytokines that multiply and mature B-cells into antibody producing cells–>antibodies
Nomenclature of Monoclonal antibodies (mab)
Mouse: -o
Chimeric: -xi
Humanized: -zu
Fully humanized: -u
Effects of antibodies in cancer
- Binding of antibodies to cell surface receptors can inhibit their function
- Binding of antibodies to cell surface receptor can lead to complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity and eliminate tumor cell via immune system
Cetuximab (Erbitux)
EGFR/VEGF/HER2 Antibodies
MOA: Binds to the extracellular domain of EGFR: competitively inhibits binding of EGF and TGF-alpha and blocks phosphorylation and activation of kinases
Treatment of colorectal and head/neck cancers
SE:severe infusion reaction from 1st dose, rash, fever
Trastuzumab (Herceptin)
Binds to HER2 receptor and:
- Induces receptor internalization and degradation
-Induced antibody-dependent cellular cytotoxicity
Treatment of HER2+ breast cancer
SE: flu-like symptoms, hypersensitivity reactions, risk of cardiomyopathy/CHF
Pertuzumab (Perjeta)
MOA: binds to HER2 receptor and inhibits dimerization
CLEOPATRA Trial: showed efficacy of Trast;Pert;Taxane
OFTEN USED IN COMINATION WITH TRASTUZUMAB
Bevacizumab (Avastin)
MOA: Binds to VEGF:
-Blocks interaction of VEGF with receptors
-Blocks endothelial cell proliferation and new blood vessel formation
Treatment of metastatic colorectal cancer in combination with 5-FU
CANNOT BE USED AS MONOTHERAPY
Ramucirumab
MOA: Binds to VEGFR
Trastuzumab Emtansine (TDM1)
Antibody-drug conjugates
MOA: Trastuzumab binds to HER2: induces receptor internalization and degradation, induces ADCC
Emtansine inhibits microtubule assembly
2nd line treatment for HER2+ metastatic breast cancer
SE: Flu-like symptoms, hypersensitive reactions, risk of cardiomyopathy/CHF, hepatotoxicity (emtansine), thrombocytopenia (emtansine)
Trastuzumab Deruxtecan
MOA: Trastuzumab binds to HER2: induces internalization and degradation, induces ADCC
Deruxtecan inhibits topoisomerase 1
Overview of B-cells
CD antigens are cell surface markers that can be used as biomarkers to identify various phases of B-cell maturation or activation
CD20: Expressed on normal B lymphocytes and immature pre B-cells
CD20 works with the B cell receptor to drive proliferation of B cells
Over-expressed B cell lymphoma
CD38 is expressed on plasma B cells
Multiple myeloma
Rituximab
B-cell antibody
MOA: Binds to CD20 that inhibits B cell proliferation and induces ADCC
Treatment of B-cell lymphomas
Daratumumab
B-cell antibody
MOA: Binds to CD38 that eliminates natural killer cells and induces ADCC
Treatment of multiple myeloma
Blinatumomab
Bispecific T-cell Engager (BiTE)–> serves as steering wheel to steer T-cell to tumor cell
MOA: Bind simultaneously to CD19 on B cell lymphomas and CD3 on all T-cells that bring T-cell to the cancer–> T cell lyses tumor cell
Treatment of acute lymphoblastic leukemia (ALL)
SE: Cytokine storm
Mosunetuzumab
MOA: Binds simultaneously to CD20 on B cell lymphomas and CD3 on all T-cells that bring T-cell to the cancer–> T cell lyses tumor cell
Treatment of non-Hodgkin lymphomas (NHL)
SE: Cytokine storm
Teclistamab
BiTE
MOA: Binds simultaneously to B-cell maturation antigen (BCMA) and CD3 on all T-cells that bring T-cell to the cancer–> T-cell lyses tumor cell
Treatment of multiple myeloma
SE: Cytokine storm
Taquetamab
BiTE
MOA: Binds simultaneously to human G-protein coupled receptor family C group 5 member D (GPRC5D) and CD3 on all T-cells that bring T cell to the cancer–> T -cell lyses tumor cells
Treatment of multiple myeloma
SE:Cytokine storm
CTLA-4 and PD1 act as brakes on the immune system
When inhibited, can reactivate T-cells
Ipilimumab
MOA: Tumor cell antigens are recognized by dendritic cells, which present the antigen to the CTLs
Cytotoxic T lymphocytes (CTL) recognizes and destroy malignant tumor cells
Dendritic cells also deliver an inhibitory signal to CTLs via CTLA-4 receptor
Ipilimumab binds to the CTLA-4 receptor and blocks inhibition
Treatment of advanced metastatic lymphoma
SE: enterocolitis, hepatitis, dermatitis, neuropathy, endocrinopathy
Pembrolizumab
MOA: Binds to PD-1 and blocks interaction with PDL-1 AND PDL-2
PD-1 is expressed on T-cells
PDL-1/2 is expressed on tumor cells/macrophages
Treatment of advanced metastatic melanoma after Ipilimumab +/- BRAF inhibitor
Treatment of PDL-1 + NCSLC
When to avoid? Autoimmune disease, immunosuppression
Atezolizumab
MOA: Bind to PDL-1 and blocks interaction with PD-1
PD-1 is expressed on T cells
PDL-1/2 is expressed on tumor cells
When to avoid?
Autoimmune disease
Immunosuppression
Sipulcel-T (Provenge)
MOA: APCs are collected from patient via leukapheresis
APCs are activated by ex vivo treatment with PAP-GM-CSF and rein-fused into patient
STIMULATE PATIENT’S OWN IMMUNE SYSTEM TO ATTACK THE CANCER
Treatment of metastatic prostate cancer
SE: Flu-like symptoms, Risk of stroke
CAR-T Cell therapy
MOA: T-cells are isolated from patient
Grown in lab where the CAR is to target CD19
CAR-T cells are engrafted back into patient
Patient becomes immunized against CD19
All immature B-cells are eliminated
T-cells lives indefinitely
T cell activation
- Naive T cell encounters antigen in combination with MHC
- If TCR recognized the antigen, it will become activated–> a cytolytic T-cell will kill and proliferate creating a population of specific T-cells
- Once tumor is cleared, T-cell population will die down to memory population that will combat antigen when presented again
How do we direct the immune system to the cancer cell?
Central tolerance: negative selection (deletion) of T-cells that bind to “self” peptides in the thymus
Peripheral tolerance (safety net): self-reactive T cells that escape the thymus into peripheral tissues are inactivated to an unresponsive stage by Tregs or fail to be properly stimulated APCs
What is the solution to central tolerance?
- Redirect T cells to cancer using genetic means
- Redirect T cells to cancer using recombination proteins
- Lower the threshold too for targeting neo-antigens
Types of selection
Non-selection: no binding occurs–>apoptosis
Negative selection: binding too tight–> apoptosis
Positive selection: perfect binding–>survival
