17 - Immunity to Tumors

Question 1

3 Parts to
Cancer ImmunoEditing

Answer 1

ELIMINATION
Innate + Adaptive system recognize transformed cells –> destroy

EQUILIBRUM
Surviving tumor variants may persist, but immune cells/molecules PREVENT TUMOR GROWTH

ESCAPE
Mutations result in evasion of recognition, killing, or control by immune system
–> progression to detectable malignancy
Where Immunotherapy seeks to treat cancer

Question 2

Cancer ImmunoEditing:
ELIMINATION

Answer 2

Innate + Adaptive immune cells + cytokines recognize cells and destroy them

LOTS OF KILLING CELLS // FEW REGULATORY CELLS

Evidence:
Mice w/ defective immune system cells
VVVV
More susceptible to Carcinogen-induced tumors
More likely to develop Spontaneous Tumors
Earlier & More Aggresive ONSET of cancer

Question 3

Cancer ImmunoEditing:
EQUILIBRIUM

Answer 3

PERSISTS

Immune cells & molecules prevent tumor out growth

EQUAL AMOUNTS OF KILLING & REGULATORY CELLS

Proposed explanation for:
latency periods that seperate transformation & Malignancy

Question 4

Cancer ImmunoEditing
ESCAPE

Answer 4

FEW KILLING CELLS // LOTS OF REGULATORY CELLS

WHERE IMMUNOTHERAPY TREATS

Additional Mutations
may result in evasion of killing / recognition / control by immune system
VVVV
permit progression to malignancy

Immunosuppressive Tumor Microenvironment
Tumor cells inhibit function of effector immne cells

Question 5

Immune Checkpoint

Answer 5

Molecules on certain immune cells that
need to be activated / inactivated
to START an immune resposnse

Cancer cells can use these checkpoints to
avoid being attacked by the immune system

Immune Checkpoint Therapy:
Drugs that target these checkpoints to unmask cancer cells & target them for destruction

Question 6

Programmed Death 1
Important Inhibitory Checkpoint Molecules

Answer 6

DIRECT REGULATION –> PD-1 / PD-L1

Normal Binding of PD-1 –> PD-L1:

• LIMITS* T-cell activity, PREVENTS excessive stimulation
• *maintains immune tolerance to self-antigen**

Blocks TCR & CD28 SIGNAL

Question 7

Cancer Therapy for
PD-1/PD-L1

Answer 7

NORMALLY
Tumor Cell’s PD-L1 –> T-cell’s PD-1
resulting in INHIBITION of the T-Cell Activity

Anti PD-1** or **Anti PD-L1
BLOCKS the intraction –> allows for TCR Signaling Cascade
T-cell Proliferation / differentiation / Cytokines / CELL KILLING
VVV
T-Cell can KILL the cancer cell

Question 8

CTLA-4
Important Inhibitory Checkpoint Molecules

Answer 8

INDIRECT REGULATION:

Normally:
B7 –> CD28 = +COSTIMSIGNAL for T-CELL
Active T-cell –> Kill Tumor

COMPETETIVE INHIBITION by CTLA-4
T-cell’s CTLA-4 –> Binds B7 with MORE AFFINITY than CD28
–> LIMITS downstream signaling –> Attenuates T-cell Activation

Question 9

Cancer Therapy for
CTLA4

Answer 9

ANTI-CTLA-1 ANTIBODIES
–> Binds to CTLA-4 (on T-cell)
VVVV
Allows for B7-CD28 to produce COSTIM SIGNALING
VVV
ACTIVE T-CELLS
VV
KILLING OF TUMOR CELLS

Question 10

CAR T-Cell Therapy

Answer 10

Cell-Based Gene therapy that directs patient’s immune system to fight cancer

Kymriah
First gene therapy in US for ALL & some non-hodgkin Lymphoma

Yscarta
approved for treatment for Diffuse Large B-cell Lymphoma

Question 11

What is CAR?

Answer 11

Chimeric Antigen Receptor

Copies the CYTOPLASMIC SIGNALING DOMAIN of TCR
+
scFv = single chain veriable fragment
ANTIBODY EXTRAcellular domain

Newer Generations of CAR
have COSTIMULATORY ENDODOMAINS = CD28 + 4-1BB
VV
MORE POTENT T-CELL SIGNALING

Question 12

How does CAR recognize Cancer cells?

Answer 12

TAA = Tumor Associated Antigen
proteins that are abundant on tumor cells, & differ on the type of tumor

• *Kymriah / Yescarta** target CD19
• *High Expression of CD19 = Likely to be cancerous**
• *B-Cell Cancers**

Alteration of CD19 antigenicity or expression through MUTATION:
can allow cancer cells to evade CD19 targeted CAR Therapy:
CD22 / CD123
future targets

Question 13

• *Kymriah & Yescarta**
• *Target What?**

Answer 13

CD19
used to diagnose B-cell Cancers

CD22 / CD123 are newer targets

Kymriah –> ALL / non-hodgkins lymphoma

Yescarta –> diffuse Large B-cell Lymphoma

Question 14

CAR Targets for OTHER Cancers:

Answer 14

HER2
Over expression shown to play role in Aggresive Breast Cancer
Biomarker & target of therapy for breast cancer patients

MSLN = Mesothelin
Differentiation Antigen that is HIGHLY expressed in human cancers:
All Mesotheliomas / Pancreatic Adenocarcinomas
70% of ovarian cancers // 50% of lung carcinomas

Question 15

What is meant by “ENGINEERED to express CARs?”

Answer 15

LENTIVIRAL TRANDUCTION

Lentivirus w/ RNA genome
VVV
Regular VIRAL INFECTION but WITHOUT KILLING THE CELL

Integrates the GENOME into the host cell (T-cell)
VV
PRODUCE CAR on the T-cell

Question 16

What is NEXT for CAR T-cell Therapy?

Answer 16

Make the therapy
MORE SPECIFIC
VVV
>1 CAR molecule TARGET = CD19 + CD22 + CD123 etc

CD4- Based CARs for HIV

We have the killing DEVICE, but we
NEED A TARGETTING MECHANISM