tumour immunology and immunotherapy of cancer

Question 1

4 different tumour immunotherapy types

Answer 1

antibody-based therapy, therapeutic vaccination, immune checkpoint blockade, adoptive transfer of immune cells, (combination of all 4)

Question 2

3 types of monoclonal antibody-based therapy, and major problem

Answer 2

naked, conjugated, bi-specific; hugely expensive

Question 3

example of naked monoclonal antibody-based therapy

Answer 3

Herceptin (anti-HER2); also naked monoclonal antibody-based therapywhich are anti CD20, anti CD52, anti EGFR

Question 4

example of radioactive particle conjugated monoclonal antibody-based therapy

Answer 4

Zevalin (anti CD20 linked to yttrium-90)

Question 5

example of drug conjugated monoclonal antibody-based therapy

Answer 5

Kadcyla (anti-HER2 linked to cytotoxic drug)

Question 6

what are bi-specific monoclonal antibodies

Answer 6

genetically engineered to combine 2 specificities (2 arms bind to 2 different antigens)

Question 7

example of bi-specific monoclonal antibodies

Answer 7

Blinatumomab, which combines anti CD3 and anti CD19, and used for some B cell tumours

Question 8

what therapeutic cancer vaccination is used for advanced prostate cancer

Answer 8

provenge

Question 9

what does provenge vaccination use

Answer 9

patient’s own WBC treated with fusion protein between prostatic acid phosphatase (PAP) expressed in prostate, and cytokine GM-CSF

Question 10

what does provenge vaccination do

Answer 10

stimulate dendritic cell maturation to enhances PAP-specific T cell responses (put back into patient)

Question 11

basis of personalised tumour-specific cancer vaccines

Answer 11

different mutations, so ideally would make individualised vaccines, which is possible

Question 12

process of personalised tumour-specific cancer vaccines

Answer 12

extract DNA from tumour and normal cells -> whole exome sequencing to get HLA type -> identify mutations in tumour cell -> use computer programming to determine which peptides would bind to those antigens -> production of candidate neoantigens and add adjuvant for personalised vaccine

Question 13

describe immune checkpoint blockade approach

Answer 13

rather than directly stimulate responses, it reduces/removes negative regulatory controls of existing T cell responses

Question 14

immune checkpoint blockade: targeted CTLA-4 pathway

Answer 14

CTLA-4 expressed on activated and regulatory T cells, binds to CD80/86 (on APC), so CTLA-4 targeted with antagonist

Question 15

immune checkpoint blockade: targeted PD-1 pathway

Answer 15

PD-1 expressed on activated T cells, binds to PD-L1.2 (may be upregulated by tumours), so PD-1 targeted with antagonist

Question 16

disadvanatge of immune checkpoint blockade

Answer 16

if self-reactive T lymphocytes, can lead to auto-immune disease

Question 17

advantage immune checkpoint blockade

Answer 17

general (just removing negative influencers), so not tumour specific

Question 18

adoptive immunotherapy: adoptive transfer of cells

Answer 18

T cell source -> T-cells removed -> non-specific TIL expansion, as well as antigen-specific expantion (make more T cells which target cancer) -> grown in culture -> expansion -> re-infusion

Question 19

adoptive immunotherapy: what is there an opportunity for in adoptive transfer of cells

Answer 19

genetic engineering

Question 20

adoptive immunotherapy: adoptive transfer of cells: chimaeric antigen receptors (CAR) as example of genetic engineering

Answer 20

single CAR antibody fragment (specific to tumour antigen) added onto T cell, so altered specificity to target cancer cells