Chemotherapy Drugs: Immunotherapy

Question 1

See slide 3

Also link to the original article:
https://cancerres.aacrjournals.org/content/72/13/3125#sec-2

Answer 1

Immune cells in tumor
T cells, macrophages, dendritic
Can drive progression of cancer
	- Chemokines, cytokines
	- Allow for disintegration fo matrix proteins

some stay dormant in tumor
immunotherapy

Figure caption from article:
Cellular infiltrates within the tumor microenvironment. Established cancers consist of a wide array of immune cells that contribute to the tumor stroma of a growing malignancy. Tumors possess infiltrating cells of both innate and acquired immunity, such as MDSCs, macrophages, DCs, mast cells, eosinophils, neutrophils, NK cells, and lymphocytes. These cells coordinately form a complex regulatory network that fosters tumor growth by creating an environment that enables cancers to evade immune surveillance and destruction. G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; NO, nitric oxide; ROS, reactive oxygen species.

Question 2

What are the 2 inhibitory receptors for immunotherapy?

Answer 2

CLTA-4:
- down-regulates T-cell activation when bound to B7
proteins on antigen-presenting cells.

PD-1:
- down-regulates T-cell activation when bound to PD-L1 or PD-L2 ligand on tumor cells.

Makes the cells dormant
Uses them to progress cancer
Suppresses killer T cells
If we can inhibit ability of tumor cells to negatively regulate receptors, it may be advantageous

Question 3

PD-1 blockade
effects

see slide 5 - articles

see slide 6 - article

Answer 3

50% regression
Benefit to cause T cell activation

Side fx: by hyperactivating t cells (immune system)

- Attack normal cells
- Liver toxicity,  nephritis

Question 4

What are the Immune Checkpoint Inhibitors?

2 types

Answer 4

• PD-1/PD-L1 Inhibitors
  – Nivolumab (Lung)
  – Pembrolizumab (Lung)
  – Atezolizumab (Lung)
  – Durvalumab (Several)

• CTLA Inhibitors
– Ipilimumab (Several)

Question 5

See slide 8 - Vaccination

See slide 9 - Neoantigens
- summarize the concept

see slide 10 - article

• pts tested after neoantigen vaccination
• some did not have recurrence, some did
• for pt with recurrence, they gave them PD1 inhibitor (immuno) because they thought T cells were not activated (due to suppression) so they can’t kill tumors
• strong clinical response after

see slide 11 - graph

• response is seen only with the mutant forms opf protein containing the new antigen but not wild type (normal cells)
• specificity**

Answer 5

Administration of antigenic material antigen triggers antibody production in the body

simulate individual’s immune system to develop adaptive immunity

NEOANTIGENS

• sequence your DNA and find antigens with new mutations that encode for functional pts of protein expressed on cell membrane
• can either activate cells outside the body to attack the neoantigens or other ways to present immune cells
• must find a specific sequence only expressed on tumor to selectively trigger immune cells to attack cancer cells with neo antigens
• most cancers will have neo antigens, problematic if can’t find surface expressing mutation that T cell can attack

Question 6

What is CRISPR?

- ideal to sequence genome when you are born

Answer 6

• acronym for Clustered Regularly Interspaced Short
  Palindromic Repeats
• a family of DNA sequences found in the genomes of
  prokaryotic organisms such as bacteria and archaea.
• Cas 9 cleaves DNA in specific manner to cut out and fix mutation

Question 7

What is CRISPR-Cas9?

Answer 7

CRISPR gene editing is a genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. It is based on a simplified version of the bacterial CRISPR-Cas9 antiviral defense system. By delivering the Cas9 (enzyme) nuclease complexed with a synthetic guide RNA (gRNA) into a cell, the cell’s genome can be cut at a desired location, allowing existing genes to be removed and/or new ones added in vivo (in living organisms).

Question 8

See slide 14:

CRISPR-Cas9 has also been used in “correction of a pathogenic gene mutation in human embryos”

Answer 8

ok

many ethical considerations

Question 9

what is currently the most attractive strategy for personalized therapy

what to do with how heterogenous cancer is evolving to in order to eradicate this condition

Answer 9

tumor specific antigens

multiple treatment regimes