Anti Tumour Immunity And Immunotherapy For Cancer

Question 1

How are cancer cells different from normal cells?

Answer 1

Rapid uncontrolled growth

Increase mobility

Invade tissue

Evade immune system

Metastasize

Question 2

How does the immune system play a integral role in cancer?

Answer 2

Immunodeficiency lead to tumour formation

Inflammatory conditions lead to cancers too

Tumours infiltrated with lymphocytes have better prognosis

Question 3

Can the body defend against cancer?

Answer 3

Antibody responses can kill the tumour cells

Production of immune memory cells

Question 4

Describe the experiment using mice to demonstrate the immune response t tumour cells

Answer 4

Mice were induced with sarcoma and methylholanthrene

The tumour cells were then surgically removed and cultured

They were then transplanted Into three different mice

Syngeneic (genetically similar mouse) - tumour growth

Tumour bearing mouse - no tumour growth

Syngeneic + CD8 cells from original mouse - no tumour growth

Question 5

What is meant by tumour immunosurveilance?

Answer 5

A process where the immune system continually recognise cancerous and pre-cancerous cells leading to their elimination before they can cause damage

Question 6

What are the 3 E’s of immunoediting?

Answer 6

Elimination

Equilibrium

Escape

Question 7

What is tumouigenesis?

Answer 7

Normal cells that develop abnormal tumour antigens

Danger signals such as extra-cellular matrix products

• inflammation
• radiation
• viral infection

Start to become cancer

Question 8

What occurs during ELIMINATION?

Answer 8

NKs NKTs, MCs and DCs - innate immunity takes place to destroy tumour cells

INFy and chemokine lead to tumour death

Tumour specific DCs activate adaptive immunity in draining lymph nodes

Tumour specific CD4 and CD8 T cells join response to tumour cells.

Question 9

What occurs during EQUILIBRIUM?

Answer 9

Elimination phase incomplete

Tumour cells lie dormant and may modulate tumour antigen expression and stress signals

Immune syste eliminated susceptible tumour clones when possible, preventing tumour expansion

Tumour heterogeneity resulting in “Darwinian” selection

Question 10

What occurs during ESCAPE?

Answer 10

The immune system is unable to suppress the tumour cell growth, easing to tumour progression

Question 11

How can cytokines (INTERFERON) be used as a immunotherapy for cancer?

Answer 11

Interferon type 1 (A and B)

Produced by virally infected cells

Most cells have a a viral detection pathways - upregulation of MHC 1, tumour antigen expression and adhesion molecules

Activated T cells, B cells and DC.

Used successful in metastatic melanoma

Nasty side effects (flu like symptoms)

Question 12

How can cytokines (INTERLEUKIN-2) be used as a immunotherapy for cancer?

Answer 12

T cell growth factor

Success in RCC and melanoma

Toxicity

LAK cells treated with IL-2 and re infused into patients reduces toxicity

Question 13

How can cytokines (GM-CSF) be used as a immunotherapy for cancer?

Answer 13

GM-CSF stimulates APC

Trilled in melanoma, evidence of some success

May be of benefit if used with IL-2

Question 14

What are 3 ways antibodies can prevent tumour growth?

Answer 14

1. Direct tumour cell killing - antibodies can block receptors ,or can be conjugated to toxins, or act as a cell agonist to lead to apoptosis
2. Immune educated tumour cell killing
   - antibodies binding will expose the macrophage Fc receptors allowing macrophages to destroy the cell
   - antibody binding allows T cell to recognise tumour cell without MHC restriction
   - antibody binding to CTLA4 prevents T cell from switching off
   - antibodies bind to tumour material, and tumour material is taken up and presented by dendritic cells
3. Vascular and stromal cell abiation — antibodies binds attract T cell, ultimately destroying the blood vessel supply tumours need to grow

Question 15

Give two examples of drugs used to block growth factors on tumour cells

Answer 15

Tastuzumab targets ERBB2 on breast cancer cells

Bevacizymab targets VEGF and blocks signalling, used on colon cancer and kidney cancer

Question 16

What drugs can be used to induce apoptosis?

Answer 16

Rituximab: anti-CD20, used for CD20 positive B cell non-Hodgkin’s lymphoma and chronic lymphocytic lymphoma

Alemtusuma: anti CD52, used for B-CLL

Question 17

What drugs are used in immunomodulation?

Answer 17

Ipilimumab (anti-CTLA-4) blocks the inhibition due to CTLA-4 signalling

Used in metastatic melanoma

Question 18

How can checkpoint inhibition be used?

Answer 18

Ipilimumab (anti-CTLA-4) combined with Nivolumab and pembrolizumab

Blocked of effector cell death

Antibody against Programmed cell death protein 1 (PDL-1)

Expressed on T cells and can induce apoptosis when bound by PDL-1

PDL-1 can be found on tumour cells

Question 19

What are the cell based therapies for cancer?

Answer 19

LAK
NK-T cells
Gd T cells
DC
TIL
CAR

Question 20

How can LAK cells be used to treat cancer?

Answer 20

Lymphokine activated killers - mad by PBMC taken from patients and cultured with IL-2 in vitro

NK, NKT and CD25 T cells (Predominantly NK cells)

Higher then normal anti-tumour activity

Can target NK resistant tumour cells

Question 21

How can natural killer cells be used to treat cancer?

Answer 21

Recognise lack of MHC1

About 5-10% of human peripheral blood lymphocytes

Majority are CD3 - CD56+

Primarily found in blood, BM, spleen and liver

Main type in LAK populations

Question 22

How can NK-T immunotherapy be used in cancer treatment?

Answer 22

A galactosyl ceramide

Used for in vitro expanded NKT based vaccines

Used a-gal cer pulsed DCs

Well tolerated

Induce expansions of NKTs in vivo

some stable disease in a variety of cancers

Question 23

How can the gd T cell be used in cancer treatment?

Answer 23

TCR tructurally similar to alpha-beta

May not need normal antigen presentation mechanisms

May not recognise peptides and therefore no need for protein processing

May detect stress or small organic molecules which signify infection

Can respond to MICA and MICB expressed on stressed cells

Can recognise small organic molecules secreted by bacteria

Question 24

What Is a therapeutic vaccination?

Answer 24

Induces a long lasting response against tumour

Stimulate the adaptive arm of the immune response

Use professional APC such as Dendritic

Question 25

What are the principles of DC vaccination?

Answer 25

1. Isolation of monocytes from peripheral blood of patients
2. Generation of immature dendritic cells
3. Isolation of patient tumour cells
4. Lysate preparation from tumour cells
5. Loading of dendritic cells with whole cell tumour-Lysate
6. Mature antigen presenting dendritic cells are vaccinated into the patient

Question 26

Why do we think TILs are important?

Answer 26

Presence of lymphocytes has prognostic significance

Large numbers of TILs in many tumours

High number of CD8 cells also has prognostic significance

High CD8/Treg ratio

Pre-existing antigen specificity of TILs has been correlated with outcome in immunotherapy of melanoma

Question 27

Describe what occurs in adoptive therapy with TILS

Answer 27

1. Tumour biopsy
2. In vitro polyclonal stimulation (IL-2 and nit CD3 antibody)
3. Lymphodepletion of patient (enhances persistence of transferred T cells)
4. Stimulated T cells reintroduced into the patient

Question 28

What are the results expected to be seen after adoptive cellular therapy with TILS?

Answer 28

Cytotoxicity against tumour cells in culture

> 50% response rate

Best results when patients are pre-treated with peripheral lymphodepletion regimen of total body irradiation

Question 29

What are the disadvantages of adoptive cell therapy with TILs?

Answer 29

Need enough tumour to generate sufficient CTLs

TILs may be refractory to stimulation

Time consuming and labour intensive

Culture time may be too long

Culture time MAY influence quality of T cells

High failure rate of culture

Question 30

What is the use of peripheral blood derived T cells in local expansion?

Answer 30

1. Isolate peripheral blood PBMCs/PBLs
2. Simulate in vitro with autologous DC + antigen
3. Grow out tumour reactive clones

Question 31

When is clonal expansion against a known antigen used?

Answer 31

Used extensively for treatment of pos-transplant lymphoproliferative diseases

Used in haemolytic malignancies with some success

Question 32

What is a advantage of clonal expansion against a known antigen to treat cancer?

Answer 32

Easy availability of large numbers of T cells

Question 33

What is a disadvantage of clonal expansion against a known antigen to treat cancer?

Answer 33

Cloning and culture takes a long time

Question 34

What occurs during high finite TCR transduction?

Answer 34

TCRs reactive to TAAs characterised and cloned

1. Alpha and beta chains oof TCR are engineered into a retroviral vector

2 Patients CD8 T cells from peripheral blood are removed and transducer with TCR virus

3. Adoptive transfer back into patients

Question 35

What are the limitations of high finite TCR transduction?

Answer 35

2/15 patients with. Clinical response

T cells remain in peripheral blood for up to one year

Epitopes need to be characterised and matched to HLA

Must be present in tumour

Becomes a patient specific therapy

Autoimmunity? Off-target hits, have lead to death

Question 36

What are chimeric antigen receptors (CARs)?

Answer 36

Similar in nature to TCR transgenics

Composed of
- antibody recognition domains
- cytoplasmic til with multiple signalling domains that activate T cells

Advantages of specificity and high affinity

Not yet extensively studied

Question 37

Does immunotherapy work?

Answer 37

CPI now in regular use for some cancers

Much improved survival

We keep improving