Unit 5- Tumor Immunology/ Immunotherapy

Question 1

What is central T cell tolerance?

Answer 1

• immature T-cells move from bone marrow > thymus for maturation
• eliminate any autoreactive lymphocytes (discriminate self vs non-self)
• test for autoreactivity

3 outcomes- interaction of immature T cells/ self MHC antigens thymus
Non-Selection- no interaction > apoptosis
Positive Selection- binding > survival/ maturation of T cells
Negative Selection- strong affinity > apoptosis

Question 2

What is peripheral T-cell tolerance?

Answer 2

self-reactive T cells > anergy/ apoptosis/ suppression

Question 3

What is the difference between cytokines/ chemokines?

Answer 3

Cytokines- chemical messengers
Chemokines- chemoattractants

Question 4

What is the cancer immunoediting hypothesis?

Answer 4

• describes the role of the immune system in tumorigenesis
  The 3 E’s: Elimination/ Equilibrium/ Escape

Question 5

What is the elimination phase of immunoediting?

Answer 5

• cancer immunosurveillance
• innate/ adaptive immunity detects tumors before clinically visible
• tumor antigen presentation to T cells > T cell cytotoxicity

Question 6

How does tumor antigen presentation to T cells/ T cell cytotoxicity work?

Answer 6

• professional APC’S (dendritic cells/ macrophages/ B cells) take up tumor antigen/cross-present peptide via MHC
• TCR recognizes tumor antigen on APC > inflammatory cytokines

Question 7

What are the requirements of T cell-mediated killing of tumors?

Answer 7

1. ability of tumor to present tumor antigens via MHC-1
2. tumor not overexpressing T cell inhibitory ligands (PD-L1)
3. functional state of cytotoxic T cell

Question 8

What is the equilibrium phase of immunoediting?

Answer 8

• immune system holds tumor in a state of functional dormancy
• tumor cells undergo changes due to immune pressure
  > immune evasion/ induce immunosuppression
  “survival of the fittest”

Question 9

What is the escape phase of immunoediting?

Answer 9

• immune system fails to restrict tumor growth > clinically apparent disease
• tumor cells evade immune evasion/ inhibit T-cell killing

Question 10

What is the difference between hot/ cold tumors?

Answer 10

Hot tumors- immune cell infiltration/ respond well to immunotherapy
Cold tumors: do not respond to immunotherapy
-T cell Exclusion > successful antigen presentation, no killing
-T cell Desertification > no antigen presentation to T cells

Question 11

What are immunogenic cell death inducers?

Answer 11

• cell death that can activate antitumor immunity
  > chemotherapy/ radiation
• hard to measure biomarkers in patients > barrier to clinic evaluation

Question 12

What is cytokine-based cancer therapy?

Answer 12

• systemic/ intratumoral administration of a proinflammatory cytokine
• modulates entire immune response to anti-tumor
  ex) IL-2 - rapid T-cell expansion/ side effects now manageable

Question 13

What is immune checkpoint blockade (ICB)?

Answer 13

• use of immune checkpoint inhibitors (ICIs)
• immune checkpoints serve as brakes on T cells
• blocking inhibitory immune checkpoints with monoclonal antibodies unleashes T cells to exert cytotoxic effects
• combination therapy to make cold tumors hot
  > immunogenic tumor microenvironment
• off-target immune adverse effects
• any immunogenic peptide can be targeted

Question 14

What is antibody-based therapy? (non-immune checkpoint related)

Answer 14

ADC = Antibody Drug Conjugates
3 components: antibody/ linker/ payload (cytotoxic drug)
- deliver effective cytotoxic chemo drug specifically to tumor
Tumor Resistance- loss of tumor antigen/ resistance to payload
- side effects of normal chemo

Question 15

What are the 4 main types of cancer vaccines?
- fail against metastasis

Answer 15

Cell-based- 1 approved > monocyte/dendritic cells
Viral-based- tumor antigen in viral particle
Peptide-based
Nucleic acid-based- mRNA vaccines > faster/ easier to make

Question 16

What is oncolytic viral therapy?

Answer 16

• oncolytic virus exploits tumor > selective virus replication

Question 17

What is the mechanism of action of oncolytic viruses?

Answer 17

1. Direct killing of tumor cells
2. Tumor vascular shutdown (↑ hypoxia/ ↓ vasculature)
3. Activate immune response against cancer

Question 18

What is the result of oncolytic virus infection?

Answer 18

healthy cell > viral clearance/ no effect
tumor cell > lysis > inflammation/ release of viral progeny > infection of neighbouring tumor cells/ tumor antigen release > systemic anti-tumor response

Question 19

How are tumors/ oncolytic viruses a match made in heaven?

Answer 19

Tumor- ↑ virus receptor expression/ loss of innate antiviral responses
OV > selective/ unrestrained virus replication in tumor cells

Question 20

What is CARS?

Answer 20

Chimeric Antigen Receptor Based Therapy
- combination of monoclonal antibody (antigen recognition)/ TCR (signal transduction)
- chimeric antigen receptor triggers TCR signaling in cell

• patient T cells engineered with lentivirus > deliver CAR-encoding gene
• deplete bone marrow with chemo to make room for T cells
• CAR T-ells reinfused into patients blood
• CAR T cells identify cancer cells/ kill them

Question 21

What are side effects of CAR-T cell therapy?

Answer 21

On-target/off-tumor toxicity > target normal B cells > B cell aplasia
Cytokine release syndrome > neurological toxicity/ confusion/ fever

• CAR-T product can last for years after infusion/ great success in blood cancers

Question 22

What is TIL therapy?

Answer 22

Tumor Infiltrating lymphocyte therapies
- similar to CAR-T therapy but no engineering
- expansion of patients T cells, still deplete bone marrow with chemo
- ↑ success in solid tumors compared to CAR-T

• tumor harvest/ liberate TIL from TME/ select based on reactvity/ ex vivo expansion/