Lecture 8

Question 1

What is the most effective CD4 T cell response against cancer

Answer 1

• Th1 response: CD4 cells dumping IFN gamma, this leads to the development of CD8 T cell - prime modality in which the immune system interacts with cancer
• CD8 T cells are the curative component

Question 2

Since ________ or ______ tumors are rapidly rejected, specific immunity to tumors must be studied in _______ mice

Answer 2

• Allogeneic or Xenogeneic
• Syngeneic

Question 3

Syngeneic

Answer 3

genetically identical

Question 4

Tumor specific antigens

Answer 4

are unique to each tumor and are comprised of mutant peptides

Question 5

Tumor associated antigens

Answer 5

• reactivated enbryonic genes or overexpressed tissue-specific proteins
• Tumors of a particular cellular tissue type (e.g. melanomas) sometimes express the same TAAs
• TLDR: regular cell thing that is over expressed/under expressed or weird post translational modification

Question 6

MAGE family of proteins

Answer 6

reactivated embryonic gene products ( only found in testes, only functionally expressed in a minority of other cancer)

Question 7

Antigens in the following class:
Tumor specific mutated oncogene or tumor supressor

Answer 7

• CDK 4
• beta - catenin
• Caspase B
• Surface Ig/idiotypes

Question 8

Antigens in the following class:
Germ cell

Answer 8

• MAGE 1 and 3

Question 9

Antigens in the following class:
Differentiation

Answer 9

Tyrosinase

Question 10

Antigens in the following class:
Abnormal gene expression

Answer 10

• HER-2/neu
• Wilm’s tumor (transcription factor)

Question 11

Antigens in the following class:
Abnormal PTM

Answer 11

MUC-1

Question 12

Antigens in the following class:
Abnormal Post-TRANSCRIPTIONAL Modification

Answer 12

• GP100
• TRP2

Question 13

Antigens in the following class:
Oncoviral Protein

Answer 13

• HPV type 16
• E6 and E7 proteins

Question 14

Three Es of Cancer Immunoediting

Answer 14

Cancer Immunoediting: a dynamic process composed of 3 phases, it is how the immune system’s ability to protect the host from cancer may also drive the generation of tumors better suited to survive in an immunologically intact environment.

Elimination (Cancer Immunosurveillance):
- Status quo, cell gets out of line, proliferating when it isn’t supposed, or migrating where it shouldn’t go - immune system wipes it out
- happens many times a day

Equilibrium:
- if a nascent tumor is not immediately killed, dip in the ability of immune system – or maybe immune system got a late start
- Tumor is dividing and the immune system is killing but cannot eliminate the tumor but the tumor is constantly evolving
- 2 outcomes – immune system eliminates tumor, but the longer the tumor sits around more mutations - > escape

Escape: not a process it is a moment, immune system can no longer stop the tumor, and it develops into clinically relevant disease

Question 15

Cells that make up the immunosuppressive TME

Answer 15

Tregs, MDSCs, M2 Macrophages

Question 16

Why do tumor acquire myeloid immunosuppressive microenvironment?

Answer 16

1. As tumors grow, they get good at calling immunosuppressive myeloid cells
2. This is a normal part of peripheral tolerance - body will create these myeloid cells if you have chronic inflammation

Question 17

What might be responsible for bringing immunosuppressive cells to the tumor?

Answer 17

Communication through peripheral nerves (tumor is chock full of nerves)

Question 18

What type of dendritic cell is critical for initiating a CD8 response that is anti-tumor and why?

Answer 18

CDC1 DCs because they can cross present antigens (class 1 on class 2 etc.), everything it takes up from the tumor ends up on class 1 - which allows those antigens to activate CD8 T cells

Question 18

DC Immunotherapy

Answer 18

• Makes DCs from cancer patients
• Throw tumor stuff at it
• Give inflammatory stimulus and then stick them back in the cancer patient
• Didn’t work because DCs need to see specific info at the time of maturation otherwise they don’t have all the correct info to make the correct CD8 response

Question 19

Neoepitope Vaccination

Answer 19

• Computation decides based on the patient’s HLA what the most likely neoepitope is, you put these neoepitopes on mRNA

Question 20

Using Innate Signaling Pathways for Cancer Immunotherapy

Answer 20

• TLR Signaling
• RLH Signaling
• cGAS-STING Signaling
• Use PRR agonist drugs to stimulate the immune system since all these pathways turn on interferon signaling

Question 21

TILs Therapy for Melanoma and Other Solid Tumors

Answer 21

• Biopsy to extract tumor and then chop up into fragments
• Let TILs extravasate out of the tumor (propagate them on the tumor fragments)
• Melanoma reactive TILs are expanded and then jazzed up with inflammatory cytokines and are then injected back into the patients

Question 22

CAR-T Cell Therapy

Answer 22

• Remove blood from patient to get T cells
• Make CAR T cells in the labs by inserting gene for CAR
• Grow millions of CAR T Cells
• Infuse CAR T cells into patient
• CAR T cells bind to cancer cells and kill them
• Doesn’t work well for solid tumors
• Works really well for B cell tumors because it is made with B Cell surface Antibodies

Question 23

CAR Mechanism of Action
- Add to this, info at the bottom of the definition

Answer 23

• Know the figure on Slide 33 (print out)
• CAR allows T cell to bypass MHC restriction
• Take a single chain of the variable region of an antibody (scFv) and attach it T cell signaling domains and put that into retrovirus and then infect patient T cells

Question 24

Transgenic TCR vs CAR

Answer 24

- Transgenic has 2 chains whereas CAR has 1 chain - Transgenic only recognizes antigen on MHC whereas CAR can recognize antigen directly - Transgenic gives better memory (but not great) since the MHC requirement means you will get more t cell help - This is why CAR T sometimes needs multiple infusions - since cells will get exhausted

Question 25

Anti-CTLA-4 Mechanism of Action

Answer 25

- CTLA-4 blocks stimulation by binding to B7 on APC - mAb binds to CTLA-4 on T cells - Is non-specific so it has a mortality rate (1%)

Question 26

Anti-PD-1/L1 Mechanism of Action

Answer 26

- PD-L1 on cancer cell binds PD-1 on T cell, inhibiting T cell killing of cancer cell - mAb binds to either one of these - A lot of PD-1 T cells are cancer specific - so this is a more specific than anti-CTLA-4

Question 27

Anti-LAG3 Mechanism of Action

Answer 27

- Another checkpoint inhibitor in melanoma because of how dangerous anti-CTLA 4 is - LAG3 is expressed by T−cells and binds to MHC class II with higher affinity than does CD4. It downregulates T−cell function by a) outcompeting CD4 for MHC class II binding, thereby abrogating initiation of TCR signaling b) initiating negative regulatory signaling upon MHC class II engagement

Question 28

When do T cells upregulate PD-1

Answer 28

When they think may be killing something that is self ????

Question 29

If tissues are attacked again and again they will ...

Answer 29

upregulate PD-L1

Question 30

mAbs for Cancer Immunotherapy

Answer 30

- binds to antigen that is over expressed or specific the target cancer cell - This can lead to killing via the complement cascade or ADCC (NK/neutrophils) - Tends to work in liquid tumors

Question 31

Bispecific T cell Engagers

Answer 31

- IgG like bispecific antibody brings together CD3+ T cell and Tumor cell, and the idea is that this close proximity will enable the T cell to kill the cancer cell - Works in hematopoietic indications

Question 32

Name all the different Cancer immunotherapies

Answer 32

- Cytokines (IL-2, IFN-alpha) and cytokine antagonists (anti-TGF-beta) - mAbs and BiTEs - Innate signaling agonists - Cell infusions: CAR T, Transgenic TCR, TILs, NK cells - Vaccine Immunotherapies: Neoepitope Vaccination, DCs - Checkpoint Inhibitors: Anti CTLA 4, PD-1/L1, LAG-3 etc.

Question 33

1. a mouse is immunized with irradiated tumor cells (cannot grow) 2. Two other syngeneic mice are injected with 1) viable cells of the same tumor and 2) viable cells of a different tumor. What happens to each mouse and what does this show?

Answer 33

- The mouse injected with viable cells of the same tumor will clear the tumor whereas the other mouse will die - These observations indicate that the tumors express antigens that can become targets of a tumor-specific T-cell response that rejects the tumor - because tumors express a lot of stuff that is different from regular cells.

Question 34

How do MDSCs help tumors escape immune surveillance?

Answer 34

- Downregulate Ag presentation of DCs - Downregulate cytotoxicity of NK Cells - Downregulate activation of CD8 T cells - Recruit M2 Macrophages - Turn CD4 T cells into T regs