L3: ICIs with Other Approaches (K. Khan) Flashcards

1
Q

PD-1/ PD-L1 pathway

A

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

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2
Q

how is PD-1 upregulated/ downregulated

A

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

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3
Q

PD-1 upregulation leads to

A

T cell proliferation, activation, effector function, survival

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4
Q

ICI of PD-1 / PD-L1 pathway

A

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

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5
Q

why are combinations with ICIs needed?

A

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

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6
Q

additive combination

A

just sum of effect

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7
Q

synergistic combination

A

A futher enhances B

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8
Q

dual synergistic combination

A

both enhance each other

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9
Q

are all synergistic effects good

A

no, can also lead to harmful toxicities

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10
Q

what combinations are being used in the clinic

A

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

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11
Q

what is VEGF

A

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

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12
Q

tumor angiogenesis

A

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

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13
Q

anti-VEGF therapeutics

A

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

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14
Q

why does VEGF therapies fail

A

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

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15
Q

what can be done if patient develops resistance?

A

other angiogenic growth factors can be used: FGF2, HGF

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16
Q

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

A

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

17
Q

Direct immunosuppressive effects on immune cells of VEGF

A

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

18
Q

Indirect immunosuppressive effects on immune cells of VEGF

A

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

19
Q

Indirect physical effects on immune cells of VEGF

A

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

20
Q

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

A

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

21
Q

PFS

A

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

22
Q

OS

A

Overall survival
duration of time patient is alive for

23
Q

Kaplan Meier plots each downward step

24
Q

Hazard Ratio: 1

A

drug and control same effect

25
Hazard Ratio: 0.5
favors drug/experimental over control
26
Hazard Ratio: 2
favors control
27
MSI-Hi (microsatellite instability) vs MSI-Lo (misrosatelite stable: MSS)
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
28
biosimilar
exact same sequence but different company, has the same function
29
neoadjuvant therapy
given before surgery to shrink tumor
30
HCC neoadjuvant VEGFR inhibitor + PD-1 antibody
expansion of T cells, B cells memory cells in circulation?
31
Biological rationale for combining ICI's with anti-angiogenic drugs
VEGF is immunosuppressive Relieve immunosuppressive vessel barrier Vascular normalization and increase T-cell infiltration
32
chemotherapy 4 "poisons"
1- alkylating agents and platinum based 2- anti-microtubule agents (inhibit cell division) 3- anti-metabolites 4- topoisomerase inhibitors
33
ICD (Immunogenic cell death)
find me signals (dying cells empty cellular content) eat me signals (pre-apoptotic cell expresses calreticulin)
34
antibody drug conjugates
a targeted way of delivering effectively a chemotherapy drug 3 main components: the antibody, linker, payload (drug)