principles of treatment 3- immunotherapy

Question 1

who does th host immune response not fight against cancer?

Answer 1

The immune system can recognise and react against cancers
BUT…
The immune response against tumours is often dominated by regulation or tolerance
Remember, tumours are “self”
Evasion of host immunity is one of the hallmarks of cancer

Question 2

what are the 4 different possible immune responses to cancer?

Answer 2

1. macrophages recognising he specific tumour antigen and engulfing the cell
2. B cell recognising antigen with the help of CD4- launching a humour antibody response
3. CD8 T cell recognising the tumour antigen
4. natural killer cells recognising a reduced class 1 MHC expression

Question 3

what are neoantigens?

Answer 3

Most tumour antigens that elicit immune responses are neoantigens

Question 4

what are 2 ways that neoantigens can be produced?

Answer 4

1. Produced by mutated genes that may be involved in oncogenesis (driver mutations)
2. markers that reflect genomic instability (passenger mutations)
3. In tumours caused by oncogenic viruses (HPV, EBV), neoantigens are encoded by viral DNA
4. derepression of some unmated proteins by epigenetic changes can also cause them to be neoantigens- cancer testis antigens

Question 5

what are 3 ways that tumour neoantigens can be identified?

Answer 5

• Next gen sequencing and/or RNA-seq
• Identification of HLA-binding peptides
• MHC-peptide multimer and/or functional assays

Question 6

why identify tumour neoantigens?

Answer 6

Potential to generate neoantigen-specific antibodies

Identify and expand neoantigen-recognising T cells (TILs)

Question 7

what are 3 ways of harnessing the immune system to combat cancer?

Answer 7

1. vaccines- mostly prophylactic like HPV against cervical cancer
2. adoptive cellular therapy- CART
3. blockade of checkpoint molecules

Question 8

why do vaccines work prophylactically but not once the actual tumour is there?

Answer 8

• because if a tumour is forming then it is already being recognised as self and is being tolerated by the body

Question 9

how are checkpoint molecules involved in cancer?

Answer 9

tumour cells up regulate molecules that inhibit T cell response- these are called checkpoint molecules

developing checkpoint inhibitors is useful for tx of some types of cancer

Question 10

what are 2 different checkpoint molecules?

Answer 10

• PDL1 which binds to PD1 on the surface of T cells
• CTLA4 which competes for costimulation of T cell with CD80/686
  resulting in activation of inhibition

Question 11

what is the checkpoint blocker for PDL1?

Answer 11

• pembrolizumab

- nivolumab

Question 12

what is the checkpoint blocker for CTLA4?

Answer 12

• ipilimumab

Question 13

what are 2 major risk factors of CART therapy?

Answer 13

• cytokine storm, requires anti-inflammatory therapy- anti IL6R - risk of long term tissue damage especially to brain
• increased risk of autoimmune reactions from endogenous TCRs

Question 14

what happens in CART therapy?

Answer 14

e.g. patient with leukaemia

• isolate lymphocytes from blood
• expand in culture with anti CD3, anti CD28 and CAR gene
• transfer back into patient

Question 15

what are limitations of CARTtherapy?

Answer 15

• unclear how well it works against solid tumours
• tumours may lose target antigen and develop resistance
• risk of exhaustion of transferred T cells

Question 16

what are immune responses to promote tumour growth?

Answer 16

• TH2 CD4 T cells release il4 and IL13
• IL4/13 both activate M2 macrophages
• M2 macrophages release iNOS and Arg1 = repress cytotoxic T cells
• M2 macrophages activate EGF, E=VEGF, TGFB these are antigenic and antiapoptotic