281. Tumor Immunology

Question 1

What are the 7 steps of the cancer-immunity cycle and what drugs act on what steps?

Answer 1

1. Cancer cell death = release of cancer antigens: Chemotx, RT, targeted tx (kills cancer cells)
2. Cancer Antigen Presentation (DCs/APCs): Vaccines, GM-CSF, IFN-a
3. T cell priming/activation: anti-CTLA4, IL-2 (boost T cell fx)
4. T cell trafficking to tumor
5. T cell infiltration into tumor (anti-VEGF)
6. T cell recognition of cancer cells
7. Cancer cell killing (anti-PDL1, anti-PD1)

Question 2

What cells take part in antibody-dependent cell-mediated cytotoxicity?

What cells recognize tumor specific antigens?

What cells are a critical link between innate and adaptive immunity?

How do tumor cells avoid the immune system?

Answer 2

1. ADCC - NK cells
2. CD8 cytotoxic T cells recognize tumor antigens
3. DCs are link b/w innate and adaptive immunity (pick up neo-antigens and take to LNs to prime and activate T cells)

Avoid immune system by downregulating APC-T Cell interaction (MHCI downregulation and more), or increasing inhibitory signals (more Tregs and suppression)

Question 3

What are 6 broad classes of immunotherapy?

Answer 3

1. Cytokines/immune stimulants
2. mAb’s (most common)
3. Vaccines
4. Oncolytic Virus (TVEC)
5. Gene/Cellular Therapy - none approved yet
6. Chimeric Antigen Receptor (CAR) T cells

Question 4

Anti-PD-1 and Anti-CTLA-4 antibodies

• names
• mechanisms, locations

Answer 4

Anti-PD-1 (Nivolumab, Pembrolizumab, Cemiplimab)

• block PD1-PDL1 interaction in tumor microenvironment = keep T cells active (prevent tumor PDL1 from shutting down T cells)
• TUMOR microenviro
• retains T cell effector fx

Anti-CTLA-4 (Ipilimumab)

• binds CTLA-4 to keep T cell active
• CTLA4 binds B7 20x more potently than CD28 does, causing shutdown of T cell interaction
• blocking CTLA4 causes T cell ACTIVATION (prevents suppression) in LN (when APC presents neo-antigen to TCR in LN)
• Lymph node
• retains T cell priming

USE IN COMBO = SYNERGY
(but anti-PD-1 better than anti-CTLA-4 alone)

Question 5

What is the name and mechanism of using oncolytic viruses in melanoma?

Answer 5

TVEC: modified HSV1 to only infect tumor cells - modified to express GM-CSF = makes “cold” tumor “hot” or inflamed = attracts immune cells = anti-tumor response

Question 6

What are key side effects of immunotherapy?

Answer 6

AUTOIMMUNITY (any organ)

• immune mediated dermatologic toxicity (rash, psoriasis, lichen planus, dermatomyositis, subacute cutaneous lupus erythematosus)
• immune mediated colitis
• hypophysitis (irreversible endocrinopathy due to pit damage)
• pneumonitis (treatable)
• transverse myelitis (immune rxn in spine)
• encephalitis

Question 7

What tumor factors make it difficult for immunotherapy to work? (3)

Answer 7

(1) “Cold” tumors with (2) low immune infiltration and (3) low expression of immune signaling mLcs