Cancer Targeted Therapy I

Question 1

What are some types of monoclonal antibodies used in cancer treatment?

Answer 1

1) Naked monoclonal antibodies2) Conjugated monoclonal antibodies3) Bispecific antibodies

Question 2

What is the basis of naked monoclonal antibodies?

Answer 2

Most attach to cancer cell antigens to block proliferation, others work by boosting the patient’s immune response against the cancer

Question 3

What is the basis of conjugated monoclonal antibodies?

Answer 3

antibodies conjugated to another compound to deliver it to a tumor for cytotoxic effect usually

Question 4

What is Rituximab used to treat?

Answer 4

CLL, NHL

Question 5

How does Rituximab work?

Answer 5

The binding of naked antibody drugs to the target cell can elicit one of a number of effects leading to the death of the cell. Overall clinical activity is derived from a combination of the following mechanisms.“1) CD20 has an associated intracellular signal transduction mechanism following external receptor stimulation. It has been found that binding of Rituximab to CD20 induces the B lymphocyte to enter the apoptotic pathway.2) Rituximab is an IgG class antibody that has an Fc portion. After binding to CD20 on B lymphocytes, the Fc portion is able to be bound by complement C1 protein. Binding of C1 activates the classical complement cascade which leads to the formation of the membrane attack complex and cell lysis.”“3. After binding of Rituximab to CD20 on B lymphocytes, complement C1 protein binds to the Fc portion and activates the classical complement cascade. The classical complement cascade generates complement C3b proteins from soluble complement C3 proteins. C3b covalently attaches to the surface of cells and opsonises them. C3b opsonised cells are detectable by complement receptors on phagocytes such as neutrophils, dendritic cells and macrophages. 4. Binding of Rituximab to CD20 on B lymphocyte opsonises them with IgG. The Fc portion of the IgG is detectable by Fc receptors on phagocytes. Recognition of IgG opsonised cells by phagocytes induces phagocytosis and destruction of the cell.5.Binding of Rituximab to CD20 on B lymphocytes can also initiate ADCC since it is an IgG antibody.

Question 6

What is Trastuzumab used to treat?

Answer 6

Breast Cancer

Question 7

How does Trastuzumab work? Side-effect?

Answer 7

With trastuzumab, binding leads to immediate inhibition of a stimulatory signal and, in consequence, the HER-2 receptor is downregulated, p27 accumulates, and cell cycle arrest occurs. big unintended side effect is cardiotoxicity

Question 8

A monoclonal drug called Pertuzumab also to treat breast cancer. How does it work?

Answer 8

In the case of HER2 signaling, a functional and physical association with a second related receptor, HER-3, is often important. HER-2 kinase phosphorylatesthe HER-3 cytoplasmic domain, activating it as a scaffold to promote the PI3-kinase cascade. Pertuzumab’s likely mechanism of action is to block heterodimerization of HER-2 and HER-3.

Question 9

Which anticancer drugs bind and block the EGFR pathway?

Answer 9

Cetuximab and Panitumumab

Question 10

Cetuximab and Panitumumab are used primarily to treat what?

Answer 10

colorectal cancer

Question 11

Adverse effects with Cetuximab and Panitumumab?

Answer 11

skin rash with sun

Question 12

Which monoclonal drugs works by binding to free VEGF and preventing its association with its cell surface receptor, thus blocking angiogenesis in tumors?

Answer 12

Bevacizumab (used to treat colon cancer)

Question 13

How are Mabs given?

Answer 13

IV, SC, or IM only. Size limitations require multiple injectionsthey tend distribute via lymphatics

Question 14

Why are Mabs mostly IgGs?

Answer 14

because this offers the best characteristics in terms of duration or persistence in the body following administration.

Question 15

How are Mabs eliminated?

Answer 15

Rather than being modified structurally to yield water soluble and thus more readily eliminated metabolites (like small molecule drugs), Mabs are degraded in lysosomal or cytosolic processes. these are often conjugated to polyethylglycol to prevent GF and renal excretion

Question 16

Are drug-drug interactions with Mabs common?

Answer 16

Drug-drug interactions, at least in the conventional sense, have not been reported. However, indirect effects may impact CYPs

Question 17

What role does the neonatal immunoglobulin Fc receptor (FcRn) play in Mabs?

Answer 17

plays a critical role in the transfer of maternal IgG to the fetus or neonate. It is also the homeostatic receptor responsible for extending the serum half-life of IgG in adults.

Question 18

Which tissues express FcRn?

Answer 18

both endothelial cells and bone-marrow-derived cells can extend the serum persistence of IgG. FcRn is also expressed in other tissues, including the blood–brain interface, the glomerular filter in the kidneys and the intestinal epithelium. By extending native IgG, this receptor is responsible for the long persistence of antibody-based drugs after administration.

Question 19

How does the FcRn receptor work?

Answer 19

Cells internalize serum IgG, which binds to FcRn in an acidic endosomal compartment. FcRn then recycles IgG back into circulation, thus extending its serum half-life. Serum proteins without a recycling receptor are destined for lysosomal degradation.

Question 20

What are the major side effects of Mabs?

Answer 20

one of the issues with these so-called “targeted” drugs is the fact that the target, while it may be overexpressed in tumor cells, is also expressed and has an essential role in normal non-tumorous tissue. Emerging issues with the monoclonal antibody drugs include cardiovascular problems such as congestive heart failure,Studies have revealed the essential nature of homeostatic pathways being impacted by these drugs. It may be impossible to completely eradicate this issue of adverse drug effect.

Question 21

Again, note that most Mabs are directed against epitopes that are over-expressed in cancer, but are NOT uniquely expressed in cancer

Answer 21

Thus, toxicities are common

Question 22

What is a major side effect of Trastuzumab?

Answer 22

blocks HER2 activity in cardiac myocytes, leading to an increase in cardiotoxicity

Question 23

What is a major side effect of Bevacizumab?

Answer 23

upsets renal homeostasis, causing HTN, proteinuria, thrombotic microangiopathy

Question 24

What is a major side effect of Cetuximab?

Answer 24

hypomagnesemia via effects in the distal convoluted tubules

Question 25

Some Mab drugs work to amplify (or de-repress) immune response to tumor cells. Which Mab targets upregulated CTLA-4 on tumor cells?

Answer 25

Ipilumumab.

Question 26

Describe the timing of CTLA-4 expression on T cells in relation to the amplitude of the signal.

Answer 26

The CTLA4-mediated immune checkpoint is induced in T cells at the time of their initial response to antigen. The level of CTLA4 induction depends on the amplitude of the initial T cell receptor (TCR)-mediated signalling. High-affinity ligands induce higher levels of CTLA4, which dampens the amplitude of the initial response.

Question 27

Another way to look at the mechanics of CTLA-4 expression.

Answer 27

The key to the regulation of T cell activation levels by the CD28–CTLA4 system is the timing of surface expression. Naive and memory T cells express high levels of cell surface CD28 but do not express CTLA4 on their surface. Instead, CTLA4 is sequestered in intracellular vesicles. After the TCR is triggered by antigen encounter, CTLA4 is transported to the cell surface. The stronger the stimulation through the TCR (and CD28), the greater the amount of CTLA4 that is deposited on the T cell surface. Therefore, CTLA4 functions as a signal dampener to maintain a consistent level of T cell activation in the face of widely varying concentrations and affinities of ligand for the TCR.

Question 28

How is PD-1 different from CTLA-4?

Answer 28

By contrast, the major role of the programmed cell death protein 1 (PD1) pathway is not at the initial T cell activation stage but rather to regulate inflammatory responses in tissues by effector T cells recognizing antigen in peripheral tissues. Activated T cells upregulate PD1 and continue to express it in tissues. Inflammatory signals in the tissues induce the expression of PD1 ligands, which downregulate the activity of T cells and thus limit collateral tissue damage in response to a microorganism infection in that tissue.

Question 29

What is the best ligand for PD1 ligand 1 up regulation?

Answer 29

The best characterized signal for PD1 ligand 1 (PDL1; also known as B7-H1) induction is interferon-γ (IFNγ), which is predominantly produced by T helper 1 (TH1) cells, although many of the signals have not yet been defined completely. Excessive induction of PD1 on T cells in the setting of chronic antigen exposure can induce an exhausted or anergic state in T cells.

Question 30

Which Mabs target PD-1?

Answer 30

Nivolumb and Pemboizumab

Question 31

What are some of the main symptoms caused by overstimulating T cell proliferation (such as with CTLA-4 inhibitors like Ipilumumab or PD-1 inhibitors)?

Answer 31

dermatitis including toxic epidermal necrolysisBBW: endocrinopathies, diarrhea, pregnancy toxicity, neuropathyNOTE: The adverse effects of CTLA-4 inhibitors are more intense than those of PD-1 inhibitors

Question 32

What is aldesleukin?

Answer 32

an IL-2 agonist whose effects are essentially identical to those of endogenous interleukin-2

Question 33

Side effects of aldesleukin?

Answer 33

CNS, cardiac (VLS-capillary leak syndrome), pulmonary, and renal obstruction- all BBW. Thus, limited use.IL-2 also stimulates TReg cells which can diminish the beneficial effects of stimulating tumor- or virus-specific T cell responses.

Question 34

Notes on application and monitoring of aldesleukin.

Answer 34

Aldesleukin use should be restricted to patients with normal cardiac and pulmonary function as defined by thallium stress testing and by formal pulmonary function testing. A baseline and daily on-treatment chest X-ray are also recommended.

Question 35

What is capillary leak syndrome caused by?

Answer 35

due either to stimulation of CD122hi NK cells, leading to the release of TNF and the production of vasoactive mediators, or to the direct binding of IL-2 to CD25+ endothelial cells rather than to NK cells or other CD25−CD122+ cells.

Question 36

What is intron alpha?

Answer 36

acts like endogenous interferons, which overall result in increased ability to activate both CD8+ T cells and to promote the ability of NK to directly lyse tumor cells utilizing various mechanisms which include perforin, granzyme, and FasL.

Question 37

BBW for intron alpha?

Answer 37

The potential for a worsening of pre-existing autoimmune disease, cardiac dysfunction and with a worsening of depression, possibly leading to increased risk of suicidal ideation. Although flu and flu-like symptoms are the most common adverse effect, the drug is also associated with toxicity towards components of the blood, with elevation of hepatic enzymes, and with pulmonary toxicity. For these several resons, routine tests for CBC, pulmonary X-ray, ECG and LFTs are indicated.

Question 38

How does the drug Sipuleucel-T work?

Answer 38

autologous cellular immunotherapy designed to stimulate T-cell immunity against prostatic acid phosphatase (PAP)

Question 39

How does Sipuleucel-T tailer its therapy?

Answer 39

A patients APCs are cultured with recombinant PAP-GM-CSF. By producing expression of the prostatic acid phosphatase on components of the immune system, the CD8+ T-cells (killer T-cells) are primed to seek out prostatic tumor cells anywhere in the body to eradicate them.

Question 40

Adverse effects of Sipuleucel-T?

Answer 40

N/V, GI pain, paresthesias and citrate toxicity