L3: ICIs with Other Approaches (K. Khan)

Question 1

PD-1/ PD-L1 pathway

Answer 1

PD-1 on CD8 T cell
PD-L1 on tumor cell
binding results in T cell inhibition (no antitumor response)

Question 2

how is PD-1 upregulated/ downregulated

Answer 2

signaling cascade regularly upregulated
with PD-L1 binding - downregulated with SHP2 blocking the cascade

Question 3

PD-1 upregulation leads to

Answer 3

T cell proliferation, activation, effector function, survival

Question 4

ICI of PD-1 / PD-L1 pathway

Answer 4

either anti-PD1 or anti-PDL1 antibody to block the interaction

Question 5

why are combinations with ICIs needed?

Answer 5

increase portions of patients that respond
improve responses in those that do respond - i.e. complete responses
open up ICIs for other more difficult to treat cancer types such as pancreatic cancer

Question 6

additive combination

Answer 6

just sum of effect

Question 7

synergistic combination

Answer 7

A futher enhances B

Question 8

dual synergistic combination

Answer 8

both enhance each other

Question 9

are all synergistic effects good

Answer 9

no, can also lead to harmful toxicities

Question 10

what combinations are being used in the clinic

Answer 10

regular FDA approvals with PD-1 or PD-L1 antibody (most chemo) or CTLA-4 antibody

Question 11

what is VEGF

Answer 11

vascular endothelial growth factor-A
secreted by tumor
VEGF stimulates angiogenesis and vessel movement to tumor
tumor increases blood supply –> tumor can enter vasculature and lead to metastasis

Question 12

tumor angiogenesis

Answer 12

formation of new blood vessels
(cell survival and proliferation of tumors through VEGF can lead to angiogenesis)

Question 13

anti-VEGF therapeutics

Answer 13

1- specific inhibition of VEGF with antibodies: Bevacizumab
2- less specific inhibition with tyrosine kinase inhibitors (TKIs) - less specific, may also inhibit others, can increase toxicity

Question 14

why does VEGF therapies fail

Answer 14

patients can gain resistance
also patients can be intrinsically resistant to angiogenesis inhibition (non-angiogenic tumors - acquire supply by vessel co-option)

Question 15

what can be done if patient develops resistance?

Answer 15

other angiogenic growth factors can be used: FGF2, HGF

Question 16

3 main ways angiogenic growth factors or anti-angiogenic molecules have effects on immune system

Answer 16

1 - direct immunosuppressive effects
2- indirect immunosuppressive effects
3 - indirect physical effects

Question 17

Direct immunosuppressive effects on immune cells of VEGF

Answer 17

increased tumor proliferation and homing
less DC maturation
CD8 T cell: increased IC molecules (exhaustion), less proliferation and function, upregulated TIM-3, PD-1, LAG3
Macrophage: increased PD-L1 expression
Monocyte: increased IL-10 secretion and tumor homing

Question 18

Indirect immunosuppressive effects on immune cells of VEGF

Answer 18

immunosuppressive properties of tumor endothelium
ICAM1 adhesion molecule reduction = less effector immune cell infiltration
PD-L1 expression by tumor vessels = exhausted T cells
Stabilin 1 = selective recruitment of Tregs
Tumor vessel expression of FasL = CD8 apoptosis

Question 19

Indirect physical effects on immune cells of VEGF

Answer 19

colorectal carcinoma: leaky, areas of low or no flow, blind ends
this leads to hypoxia and less immune cell infiltration

Question 20

the impact of VEGF inhibition on various steps in the cancer immunity cycle

Answer 20

during cancer antigen presentation or priming/activation of T cells: helps relieve inhibition of DC maturation and function
also later: vessel normalization and relieving T cell exhaustion

Question 21

PFS

Answer 21

Progression free survival
duration of time a patient lives with disease but doesn’t get worse

Question 22

OS

Answer 22

Overall survival
duration of time patient is alive for

Question 23

Kaplan Meier plots each downward step

Answer 23

death

Question 24

Hazard Ratio: 1

Answer 24

drug and control same effect

Question 25

Hazard Ratio: 0.5

Answer 25

favors drug/experimental over control

Question 26

Hazard Ratio: 2

Answer 26

favors control

Question 27

MSI-Hi (microsatellite instability) vs MSI-Lo (misrosatelite stable: MSS)

Answer 27

MSI-Hi: mismatch repair deficient, increased mutations, increased chance that CD8 recognizes, leading to cytotoxicity, more neoantigens
MSI-Lo: mismatch repair proficient, tumor cells can repair damage, less reponsive to PD-1 therapy
therefore, anti-PD-1 approved by FDA for MSI-Hi tumors

Question 28

biosimilar

Answer 28

exact same sequence but different company, has the same function

Question 29

neoadjuvant therapy

Answer 29

given before surgery to shrink tumor

Question 30

HCC neoadjuvant VEGFR inhibitor + PD-1 antibody

Answer 30

expansion of T cells, B cells
memory cells in circulation?

Question 31

Biological rationale for combining ICI’s with anti-angiogenic drugs

Answer 31

VEGF is immunosuppressive
Relieve immunosuppressive vessel barrier
Vascular normalization and increase T-cell infiltration

Question 32

chemotherapy 4 “poisons”

Answer 32

1- alkylating agents and platinum based
2- anti-microtubule agents (inhibit cell division)
3- anti-metabolites
4- topoisomerase inhibitors

Question 33

ICD (Immunogenic cell death)

Answer 33

find me signals (dying cells empty cellular content)
eat me signals (pre-apoptotic cell expresses calreticulin)

Question 34

antibody drug conjugates

Answer 34

a targeted way of delivering effectively a chemotherapy drug
3 main components:
the antibody, linker, payload (drug)