BIO 302 - Exam 3 - Systemic Treatment of Cancer PowerPoint

Question 1

What is systemic therapy? What is the delivery route?

Answer 1

Any therapy delivered to the entire body for:
* Carcinoma is known to be disseminated
* Carcinoma is likely to be disseminated but undetectable
* Adjuvant or neo-adjuvant use
* Leukemia/lymphoma

Uses the blood stream as the delivery route
* Direct intravenous injection (most common)
* Given orally, absorbed through the gut into the blood

Question 2

What are 6 normal physiological and anatomical limitations to delivery?

A
B
C

J
Pe
Pl

Answer 2

Avascular spaces
Blood-brain barrier
Cerebrospinal fluid spaces

Joint spaces
Peritoneal cavity
Pleural spaces

Question 3

What are 3 tumor-related limitations to delivery of the therapeutic agent?

Answer 3

• Tumor neovasculature is disorganized
• Dense sclerotic tumor stroma may prevent diffusion
• High interstitial fluid pressure in tumor stroma hampers diffusion.

Question 4

What are the 4 classes of Systemic therapy?

Answer 4

(1) Cytotoxic chemotherapy – most common

(2) Biological therapy – monoclonal antibodies
* The active agent in many targeted and immunotherapies
* Can also be used as a “smart bomb” to deliver an attached toxic agent.

(3) Targeted therapy - single or multiplex targeting of molecular aberrations and molecular pathways
* Antibodies (biologic therapy) or small molecules

(4) Immunotherapy
* Vaccines
* Immune stimulation (cytokines, etc.)
* Cell-based (T cell) therapies (in vitro manipulations of various sorts including genetic engineering)
* Checkpoint inhibition

Question 5

Biggest challenge with finding a cure are related to limited effectiveness due to?

Answer 5

TUMOR CELL HETEROGENEITY WITH THERAPY-RESISTANCE in advanced stage disease.

Question 6

Other 4 problems limiting success of treatment include:

Answer 6

Treatment toxicities and complex clinical care
Treatment cost (can be VERY high)
Quality-of-life in-treatment and post-treatment.
Secondary cancers

Question 7

Systemic therapy is often used in the face of ______ or ______ disease when the chances of benefit are very low.

Sometimes ______ therapy makes no sense - offers no upside, only a downside.

Issue of timing of recommendation for palliative care (versus interventional care) is difficult and signals an end to hope for any positive effect.

This is end of life reality.
In an effort to “buy time”, the quality of remaining life may be sacrificed.

Answer 7

advanced / recurrent / anti-cancer

Question 8

(1) All forms of systemic therapy have adverse systemic effects on normal cells and tissue.
(2) Side effects can be severe and debilitating, even life-threatening
(3) Patient’s ability to tolerate the therapy may require modifying or stopping the therapy before the treatment goal can be reached

(4) 10 Examples of common side effects of cytotoxic systemic therapy:

Bl
Bl
Bo
D
F

E
H
N
M
S

Answer 8

• Bleeding or clotting
• Blood disorders (bone marrow suppression): infection; anemia.
• Bone density loss
• Diarrhea, nausea and vomiting
• Fatigue, pain
• Emotional distress
• Heart damage
• Nervous system effects (e.g., neuropathies)
• Memory loss
• Skin and hair changes

Question 9

Successful therapies must address what 3 things? Are these challenges met?

Answer 9

(1) Complexity of the cancer
(2) Adaptive evolution
(3) Rx escape

THESE CHALLENGES ARE NOT YET MET!

Question 10

Types of Systemic Therapy: Chemotherapy

What does the treatment Cytotoxic chemotherapies do?

Toxicity is i______ and p______.

Answer 10

kill dividing cells (cancer or normal) / inevitable / predictable

Question 11

What is the action of Alkylating agents in Cytotoxic chemotherapy?
What part of the cell cycle does this affect?
What are they used to treat?
What could they cause?

Answer 11

• Crosslink and/or damage DNA; work at all phases of the cell cycle.
• Used to treat lymphoma, leukemia, Hodgkin lymphoma, multiple myeloma, and sarcoma, as well as carcinomas of the lung, breast, ovary
• Alkylating agents may cause leukemia later

Question 12

What are Platinum drugs in Cytotoxic chemotherapy?

What part of the cell cycle does this affect?

Answer 12

Directly damage DNA and work at all phases of the cell cycle but are less likely to cause post-Rx leukemias

Question 13

What is the action of Anti-metabolites in Cytotoxic chemotherapy? BCDbIDS

What part of the cell cycle does this affect?

What cancers does this treatment affect?

Answer 13

Block cell division by interfering with DNA synthesis (the “anti-metabolite” is inserted instead of the normal nucleotide)
Cells damaged during the S (synthesis) phase, when the cell’s chromosomes are being copied
Commonly used to treat leukemias, cancers of the breast, ovary, and the intestinal tract.

Question 14

What is the action of Topoisomerase inhibitors in Cytotoxic chemotherapy?

What part of the cell cycle does this affect?

Answer 14

Topoisomerases are enzymes that relax the supercoiling of DNA to allow the enzyme helicase to separate the strands of DNA so they can be copied during S phase.

When topoisomerases are inhibited, helicase can’t separate the strands.

Question 15

What is the action of Anti-neoplastic antibiotics?

What part of the cell cycle does this affect?

Answer 15

• Either break up DNA strands or stop DNA synthesis
• May work in any of the phases of the cell cycle
• Made by micro-organisms
• Do not act like the antibiotics used to treat infections

Question 16

What does Plant alkaloids and naturally occurring products
in Cytotoxic chemotherapy do? BCDbDMF

What part of the cell cycle does this affect?

Answer 16

• Block cell division (mitotic inhibitors) by disrupting microtubule formation.
• The spindle that is required for separation of the chromosomes into two cells during mitosis is made of microtubules
• Stop mitosis in M phase

Question 17

Drug resistance: major challenges for systemic therapies

Most resistance mechanisms accomplished through ______ ______.
Compensatory modifications of an existing mechanism also may occur.

Answer 17

new mutation

Question 18

Hormone therapy ______ ______ kill cancer cells: used in combination with other chemotherapies that do kill cancer cells.

Answer 18

does not

Question 19

What are the two types of hormonal agents? What reasons are they used for?

Answer 19

(1) Antagonists of sex hormones are anti-tumor.
* Artificial sex hormones block hormone receptors (if present) and control growth of tumors driven by hormone stimulation.
* Prostate cancer: androgen deprivation therapy (“ADT”).
* Breast cancer: block estrogen .

(2) Corticosteroids (prednisone, dexamethasone) –are not tumor-directed.
* Used to reduce inflammation, reduce swelling, boost appetite, help relieve side effects of other chemotherapies.

Question 20

Surgical removal of natural sources of sex hormone
______ (remove testes)
______ (remove ovaries)
______ (remove adrenal glands)

Answer 20

Orchiectomy (remove testes)
Oophorectomy (remove ovaries)
Adrenalectomy (remove adrenal glands)

Question 21

Other systemic therapies

What are Proteasome inhibitors?

Answer 21

Block the action of proteasomes, cellular complexes that break down (degrade) proteins

Build-up of unwanted proteins causes the cancer cell to die

Question 22

Other systemic therapies

What are Cell differentiation agents?

Answer 22

Induce terminal differentiation to non-replicating state (leukemias/lymphomas but not solid tumors to date)

Question 23

Customized, “targeted”, and precise

Answer 23

Molecular profiling of tumors to facilitate the right Rx choice for right disease subtype or to identify futile Rx choices (increase efficacy)
Molecular profiling of the patient to facilitate the right Rx choice for right patient (pharmacogenomics to increase efficacy and decrease toxicity)
Concept of “precision medicine” matches the biology of the tumor and the biology of patient to the most rationale treatment approach

Question 24

What are targeted therapies?

Answer 24

Targeted therapy is a type of cancer treatment that targets proteins that control how cancer cells grow, divide, and spread.

• Agents that target specific molecular aberrations or pathways.
• Requires the presence of the molecular “target” in the tumor.
• A “companion diagnostic” test may be required to demonstrate that the target of a therapy is present before administering that therapy.

Question 25

Drug-resistance through use of by-pass pathways requires?

MSBoCSP

Answer 25

multi-site blockade of connected signaling pathways

Question 26

Treating cancers with drugs: the ugly reality

(1) Tumor heterogeneity virtually guarantees that no SINGLE drug will affect (kill) all tumor cells (pre-existing drug resistance).

(2) New mutations will confer Rx resistance.

(3) In most cancers the efficacy of single therapies is either short-lived or completely ineffective.

Combination therapies with different mechanisms of action help to increase therapeutic efficacy BUT……..
*
*
*
*

Answer 26

The increased toxicity limits patient tolerance
The cost is increased
The dosing schedules are complicated
The probability is high that Rx-resistant variants WILL eventually emerge

Question 27

What are 2 the challenges of immunotherapy?

Answer 27

Must hit multiple tumor clones at multiple sites of metastatic disease.

Must hit each new variant clone that may emerge.

Question 28

The immune system is engineered to address what 3 things?

DRD

Answer 28

Detection - Reaction - Destruction of foreign antigens.

• Cognate capacity – recognizes new foreign (mutated) antigens
• Adaptive (reacts as new mutant proteins appear)
• Destructive capacity – killing of cells with foreign antigens

Question 29

Immunotherapy: Harnessing the detection and destruction capabilities of the body’s immune system

Ask about developing a question: how does it fit into the hallmarks?

Answer 29

Immuno-modulators (stimulate the immune system generally)
Anti-tumor monoclonal antibodies
Cell-based (T cell , NK cell, or dendritic “antigen-presenting” cell) therapies = “Living drugs”:
Tumor-infiltrating lymphocytes (TILs) extracted from tumor, expanded in the lab and reintroduced to patient
Genetically engineered killer T cells with artificial anti-tumor receptors (CAR-T cells)
NK cells lyse tumor cells in an antigen-independent manner
Blockade of tumor inhibition of cytotoxic T cells

Question 30

What are Monoclonal antibodies?

What is the function of monoclonal antibodies?
* T
* B
* B
What are the Challenges?
* Ph
* An

Answer 30

Direct destruction of tumor cells with or without a “Rx warhead” (a cytotoxic molecule, for example)

• Tagging tumor cells for destruction by immune cells
• Blocking tumor cell signaling pathways \
• Blocking host tissue stroma signaling pathways that promote tumor proliferation (anti-angiogenesis mAbs)

Challenges
Physical access to target tumor cells
Antigen-deletion clones that escape destruction

Question 31

What is Activated (immune) cell therapy (ACT)?

Answer 31

Also called “T cell transfer therapy” or “Living drugs.”

Capture, expand and re-infuse unmodified tumor-infiltrating lymphocytes (TILs), which are cytotoxic lymphocytes (killer T cells) that target cancer cells.

Question 32

What is Genetically Engineered Killer T Cells:CAR-T therapy?

Answer 32

Killer T cells harvested from cancer patients are genetically engineered in vitro to express chimeric antigen receptors (CARs) that recognize tumor antigen(s)
These receptors don’t exist in nature
Called “chimeric” because they combine both an antigen-binding (extracellular) and T-cell activating domain (intracellular) into a single receptor.

Question 33

What is a cytokine storm?

Answer 33

Cytokine release syndrome (“cytokine storm”):As CAR T cells multiply, they can release large amounts cytokinesinto the blood, which can ramp up the immune system.

Question 34

Advantages of Engineering Natural Killer (NK) Cells against Cancer

NK cells are part of the INNATE immune system, perform immune surveillance, and circulate in the blood ready to react to virally infected or cancer cells that lack inhibitory MHC1 (self) surface proteins, release perforins and granzymes that cause apoptosis of the target cell.
Unlike cytotoxic T cells, part of the ADAPTIVE immune system, NK cells have the reduced risk for prolonged immune attack against normal cells because they are short-lived.
Possibility to produce “off-the-shelf” allogeneic cell therapy products, which can be prepared in advance and readily available for multiple patients on demand.

Question 35

Immuno-evasion by tumor cells involves ______ ______ by immune cells or ______ ______ by immune cells (or both).

How does it accomplish this?

(1) A

(2) S

Answer 35

reducing detection / inhibiting killing

(1) Avoidance of detection (stealth – immuno-editing):
* Loss or masking of abnormal tumor cell surface proteins recognized by antibodies, natural killer (NK) cells and/or killer T cells.

(2) Suppression of the host immune system (hijacking):
* Tumor signaling to inactivate killer T cells that would attack them.
* Tumor signaling to activate regulatory T cells (Treg) that inhibit killer T cells
* Secretion of immunosuppressive cytokines or induction of cells in the micro-environment to secrete immunosuppressive cytokines.

Question 36

Which cancers are more responsive / less responsive to immunotherapy?

More:
* B
* H
* M
* N
* R

Less:
* C
* P
* O

Answer 36

More:
* Bladder
* Head & Neck
* Melanoma
* NSCLC
* Renal

Less:
* Colorectal
* Pancreatic
* Ovarian

Question 37

Immunogenic Versus Non-Immunogenic: Tumor Microenvironments

Predicts the outcome for immunotherapy.

Immunogenic: Non-immunogenic:
* H * C
* I * N
* S * S
* HMB * LMB
* HTNE * LTNE

Answer 37

Immunogenic:
‘Hot’
‘Inflamed’
‘Stimulatory’
High Mutation Burden
High Tumor Neoantigen Expression

Non-immunogenic:
‘Cold’
‘Non-inflamed’
‘Silent’
Low Mutation Burden
Low Tumor Neoantigen Expression

Question 38

Classifying responses to systemic Rx

Terms to describe different effect / outcomes of a patient.

(1) No

(2) OS

(3) PFS

(4) C

(5) Pr

(6) Re

Answer 38

(1) No response, partial response, or complete response

(2) Overall survival (OS)Important
* does not tell you about the quality of life afterward.

(3) Progression-free survival (interval) (PFS)
* The tumor wasn’t progressing during that time.

(4) Chronic, stable disease
* aim is to keep the disease stable until the individual dies of something else.

(5) Progressive disease
* growth of tumor in the face of therapy

(6) Recurrent disease in patients previously viewed as having no or minimal residual disease.
* You look like to have achieved getting rid of the tumor before it comes back and kills the patients.
*Tumor cells went into dormancy.

(7) Terminal disease
* Patient is going to die and there is no treatment.

Question 39

What is RECIST?

Answer 39

Response Evaluation Criteria In Solid Tumors (RECIST)
Imaging of size and volume of tumor metastases
Not sufficiently sensitive to detect emergence of treatment-resistant tumor cell clones in solid tumors

Question 40

What is the difference between a standard biopsy and a liquid biopsy?

Standard:
* T
* L
* N
* S
* I

Liquid:
* Q
* C
* E
* M
* M

Answer 40

Standard:
* Time intensive procedure
* Localized sampling of tissue
* Not easily obtained
* Some pain / risk
* Invasive

Liquid:
* Quick
* Comprehensive tissue profile
* Easily obtained
* Minimal pain / risk
* Minimally evasive

Question 41

Take home messages

• Systemic therapy is first line treatment for most advanced (metastatic) cancers.
• Systemic therapy is unlikely to be curative in metastatic disease that has evolved to have a high degree of heterogeneity of response to therapy.
• All systemic therapies have adverse effects on normal cells as well as tumor cells.
• Therapeutic resistance my be an intrinsic feature of the tumor before treatment is given.
• Therapy puts additional evolutionary pressure on the tumor to evolve Rx-resistance.

Question 42

Take home messages

Successful therapy needs to address:

• Emergent properties (Drug resistance & Immuno-evasion).
• The dynamic nature of tumor evolution creating greater and greater heterogeneity within a tumor nodule/mass and
  among different tumor nodules/masses.
• Faster detection of drug-resistant clones and more agile, anticipatory shifts in Rx regimen are needed.