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PHRM 864 > Immunotherapy > Flashcards

Immunotherapy Flashcards

1
Q

Humanization of Antibodies

A

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

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2
Q

B cells

A

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

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3
Q

Nomenclature of Monoclonal antibodies (mab)

A

Mouse: -o
Chimeric: -xi
Humanized: -zu
Fully humanized: -u

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4
Q

Effects of antibodies in cancer

A
  1. Binding of antibodies to cell surface receptors can inhibit their function
  2. 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
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5
Q

Cetuximab (Erbitux)

A

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

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6
Q

Trastuzumab (Herceptin)

A

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

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7
Q

Pertuzumab (Perjeta)

A

MOA: binds to HER2 receptor and inhibits dimerization

CLEOPATRA Trial: showed efficacy of Trast;Pert;Taxane

OFTEN USED IN COMINATION WITH TRASTUZUMAB

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8
Q

Bevacizumab (Avastin)

A

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

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9
Q

Ramucirumab

A

MOA: Binds to VEGFR

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10
Q

Trastuzumab Emtansine (TDM1)

A

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)

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11
Q

Trastuzumab Deruxtecan

A

MOA: Trastuzumab binds to HER2: induces internalization and degradation, induces ADCC

Deruxtecan inhibits topoisomerase 1

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12
Q

Overview of B-cells

A

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

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13
Q

Rituximab

A

B-cell antibody

MOA: Binds to CD20 that inhibits B cell proliferation and induces ADCC

Treatment of B-cell lymphomas

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14
Q

Daratumumab

A

B-cell antibody

MOA: Binds to CD38 that eliminates natural killer cells and induces ADCC

Treatment of multiple myeloma

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15
Q

Blinatumomab

A

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

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16
Q

Mosunetuzumab

A

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

17
Q

Teclistamab

A

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

18
Q

Taquetamab

A

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

19
Q

CTLA-4 and PD1 act as brakes on the immune system

A

When inhibited, can reactivate T-cells

20
Q

Ipilimumab

A

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

21
Q

Pembrolizumab

A

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

22
Q

Atezolizumab

A

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

23
Q

Sipulcel-T (Provenge)

A

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

24
Q

CAR-T Cell therapy

A

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

25
Q

T cell activation

A
  1. Naive T cell encounters antigen in combination with MHC
  2. If TCR recognized the antigen, it will become activated–> a cytolytic T-cell will kill and proliferate creating a population of specific T-cells
  3. Once tumor is cleared, T-cell population will die down to memory population that will combat antigen when presented again
26
Q

How do we direct the immune system to the cancer cell?

A

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

27
Q

What is the solution to central tolerance?

A
  1. Redirect T cells to cancer using genetic means
  2. Redirect T cells to cancer using recombination proteins
  3. Lower the threshold too for targeting neo-antigens
28
Q

Types of selection

A

Non-selection: no binding occurs–>apoptosis

Negative selection: binding too tight–> apoptosis

Positive selection: perfect binding–>survival

PHRM 864 (9 decks)

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