Immuno-Oncology

Question 1

are cancer cells considered to be self or non-self?

Answer 1

self

Question 2

what are 4 obstacles in eliciting effective immune responses in cancer?

Answer 2

1. cancer cells are self
2. identifying specific peptides/costimulatory signals is hard
3. tumours are heterogeneous (intra and interpatient) –> may need personalized therapy and hit multiple targets
4. cancer cells actively evade the immune system

Question 3

why is it difficult to identify specific peptides/costimulatory signals on cancer cells?

Answer 3

they are inconsistent btwn tumours and change over time

Question 4

what are 3 ways that cancer cells actively evade the immune system?

Answer 4

1. decreased antigen presentation (MHC I, antigen processing)
2. tumour cells may thrive without triggering inflammation
3. tumour cells may produce molecules to dampen the immune response

Question 5

what are the 3 strategies of antibodies for cancer?

Answer 5

1. target tumour cells
2. target immune cells
3. both

Question 6

describe 2 types of antibodies targeting tumour cells

Answer 6

1. MAb that cause cancer cell death
2. MAb that delivery anti-mitotic agents, radioisotopes to cancer cells to decrease toxicity

Question 7

what are 2 types of antibodies targeting immune cells?

Answer 7

1. agonist antibodies for costimulatory receptors (press the gas pedal)
2. checkpoint inhibitors at CTLA4, PD1 (release the brakes)

Question 8

describe antibodies that target tumour cells and immune cells

Answer 8

“BI-SPECIFIC” antibodies where 1 arm binds cancer cells, 1 arm binds T cells

this allows cancer cell and T cell to be close enough to interact

Question 9

what are 4 therapies used for cancer, besides MAb? how do they each work?

Answer 9

1. oncolytic viruses –> viruses that replicate in cancer cells and kill them
2. positive boosting signals –> cytokines that “press the gas pedal”
3. cancer vaccinations –> using cytokines, viral vectors
4. cellular therapy –> boost lymphocytes/DCs EX VIVO, then reintroduce into patient

Question 10

how does anti-CD20 antibody work? is this direct or indirect killing?

Answer 10

binds CD20 on cancer cell and recruits NK cells to kill

direct killing

Question 11

how does anti-CD30 conjugated to vedotin work? is this direct or indirect killing?

Answer 11

antibody binds CD30 on cancer cell, allow MICROTUBULE INHIBITOR called vedotin to kill the cell

direct killing

Question 12

how do immune checkpoint inhibitors work? is this direct or indirect killing?

Answer 12

bind CTLA4 or PD1 on T cell so it can kill the tumour

indirect

Question 13

what is melanoma?

Answer 13

cancer in melanocytes (skin, epithelial linings)

Question 14

describe 3 initial treatments for melanoma

Answer 14

1. surgery not feasible or advised
2. resistant to chemotherapy and radiotherapy
3. IL-2 treatment gives complete tumour regression in 5% of ppl with severe toxicity

Question 15

describe the activity of CTLA4 on T cells

what does this lead to? (2)

Answer 15

upon T cell activation, CTLA4 outcompetes CD28 for B7

1. blocks production of IFNgamma and IL-2 from signal 1/2
2. shortens the interaction of T cell with APC

Question 16

describe the activity of CTLA4 on T cells

what does this lead to?

Answer 16

CTLA4 binds B7 on DC

leads to DC making indoleamine 2,3-deoxygenase which catabolizes Trp –> T cells cannot function without Trp

Question 17

what happens to CTLA4 deficient mice?

Answer 17

massive lymphoproliferation and organ damage –> lethal

Question 18

what type of MAb is ipilimumab?

Answer 18

fully human

Question 19

describe the 5 steps of drug development

Answer 19

1. PRE-CLINICAL –> in vitro, animal studies
2. PHASE 1 –> safety, pharmacokinetics
3. PHASE 2 –> larger study on safety + efficacy
4. PHASE 3 –> compare safety + efficacy to current standard treatment
5. PHASE 4 –> on the market, continue to do tests and obtain data

Question 20

describe the graph showing ipilimumab efficacy

Answer 20

3 groups –> ipilimumab, gp100 (diff treatment), ipilimumab + gp100

gp100 alone had reduced survival: ppl died more quickly

ipilimumab +/- gp100 had increased survival that plateaued around 3years –> indicating chance of long term survival

Question 21

why did ipilimumab response change the way we look at images of tumours?

Answer 21

looking at radioactive glucose

patient had reduced tumour sites + developed more, then they all reduced but there still appeared to be tumour spots even when the patient was ok

since ipilimumab does not target the tumour itself, maybe the T cells are what is triggering the radioactive glucose bc they also have glucose

thus, the tumour sites we see may not necessarily be bad

Question 22

what is the downside of checkpoint inhibitors? what does this lead to?

Answer 22

not very specific –> immune system may attack any body system –> immune-related adverse events (irAEs)

Question 23

what organ systems does ipilimumab typically affect? (3)

Answer 23

skin, intestine, endocrine

Question 24

how can you manage the immune-boosting side effects of ipilimumab? 4 examples

Answer 24

use immune suppressants

1. corticosteroids
2. anti-TNF alpha antibodies
3. mycophenolate mofetil
4. IV immunoglobulins

Question 25

do anti-PD-1/PD-L1 have side effects?

Answer 25

yes, they are similar but not identical to anti-CTLA4

Question 26

what does anti-PD-1/PD-L1 target?

Answer 26

chronically activated T cell, tumour cells