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Foundations 9 > Immunotherapy > Flashcards

Immunotherapy Flashcards

1
Q

Surgery

A

Remove as much of bulk as possible

If benign, may not need follow up

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2
Q

Surgery cannot do anything for

A

Micro-metastatic disease

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3
Q

Radiation therapy

A

Disrupts DNA of proliferating cells and disrupts ability to make new DNA
Bone marrow, lining of gut, hair follicles might also be damaged
Destroys residual tumor in surgical field

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4
Q

Chemotherapy

A

Us of cytoreductive compounds to reduce tumor burden and destroy micro-metastatic tumor deposits
Can be used for both metastatic and micro-metastatic dz
Disrupts metabolic paths like cytoskeleton, etc.
Bone marrow particularly sensitivr

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5
Q

Limitations of conventional therapies

A

Resistance (like DNA repair mechanisms)

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6
Q

Solution for limitations of conventional therapies

A

Need less toxic therapies (maintain BM)
Need to address residual dz, mets, and micro-mets
Need to personalize
Need therapies where chemo lacking or unresectable

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7
Q

Immunotherapy

A

Biologic therapy
Specific
Good for micrometastatic
Some can have memory

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8
Q

Passive immunotherapy

A

Generate therapeutic reagenet large scale in labs

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9
Q

Active immunities

A

Inject antigen and let paitents immune system do work

Therapeutic vaccines

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10
Q

Cytokine administration

A

Can be toxic, have a short half life, can be combined

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11
Q

Renal cell cancer and melanoma

A

IL-2 and alpha IFN

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12
Q

CML and hairy cell leukemia

A

Alpha IFN

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13
Q

Too toxic cytokines

A

4,6,12, TNF

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14
Q

Currently being explored cytokines

A

7, 15

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15
Q

Is cytokine therapy durable?

A

No, about 4.1 months

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16
Q

-omab

A

Fully mouse, most immunogenic

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17
Q

-ximab

A

VR - mouse, CR - human…chimeric

Less immune response against Fc region

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18
Q

-zumab

A

Humanized

CDR-mouse…everything else human

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19
Q

-umab

A

Fully human…least immunoigenic

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20
Q

Things ABs can do

A

ADCC
CDC
Growht inhibition
Prevent metastasis
Monoclonal-AB toxin conjugate (like chemo or toxin)
Radiolabeled monoclonal AB (or radio-nuclide that kills_

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21
Q

Examples of ADCC

A

NK, macro, granulocytes

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22
Q

Infliximab used for

A

Rheumatoid arthritis

Against TNF

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23
Q

Nataliuizimab used for

A

MS…reduced number of lesions

24
Q

Cellular nonspecific immunotherapies

A

Macrophages, NK cells, LAK

25
Q

Cellular specific immunotherapies

A

TILs

26
Q

LAKs with pros and cons

A

IL-2 infusions with NK cells
Need Leukapheresis
Pros - worked for advanced, 25-30% response
Cons - required ICU, expensive, not durable

27
Q

TILs with pros and cons

A

T cells from solid tumor biopsies expanded in IL-2
Pros - autologous and personalized, de-bulked, evidence mounted that infusion with specific anti tumor specificity (MHC restricted) resulted in tumor regression
Cons - sterility, equipment and staff, time to tx, expensive

28
Q

TIL protocol

A

Resect lesions
Enzyme digest
Culture in IL-2
Reinfuse TIL with Il-2

29
Q

GP100

A

Found in melanocytes…can be target

30
Q

Tyrosinase

A

Melanocytes
Expressed higher when dividing
CD4 and CD8s have receptors for tyrosinase
Need to break tolerance

31
Q

Autologous T cell immunotherapy

A

Excise tumor and take T cells needed…select the MHC restricted ones and only proliferate those

32
Q

Tx with fluberivine and cyclophosphamide

A

Decrease T cell counts…used with T cell immunotherapy to “make room” for new T cells

33
Q

One advantage of TIL

A

Can tailor it to act just on tumor cells

34
Q

Other cellular immunotherapies

A

Make tumor cells act as APCs
Modify antigen spceificity of T cells - isolate specific TCR clone, and put back in (PBMC)
CART cells - AB variable regions attached to T cell signaling domains to recognize a single tumor antigen

35
Q

Genetic mods of tumor cells

A

Insert therapeutic gene to enhance response
Insert costimulator gene
Insert cytokine gene

36
Q

CART cells effectively

A

Bypass the T cell specificty and allow AB binding region to activate T cell…only works against B cell tumors

37
Q

What is critical for T cell memory?

A

IL-7 receptors on T cells

38
Q

Splicing of memory and naive T cells

A

Memory/effector - excludes A,B, C exons (CD45RO)

Naive - includes A,B, C exons (CD45RA)

39
Q

Types of memory T cells

A

Central, effector, resident

40
Q

B cells primary

A

M, G, A, E…low affinity and hypermutation

41
Q

B cells secondary

A

G, A, E

high affinity and hypermutation

42
Q

MART

A

Melanoma antigen recognized by T cells

43
Q

Vaccine requirement for cancer

A

Must be inactivated

44
Q

Inactivation process

A

Infect human cultured cells, transfect monkey cells, take back out and then inject into humns

45
Q

Adjuvants

A

Alum - aluminum hydroxide/ohosphate formulations

46
Q

Depot effect of adjuvants

A

Concentrate antigen in one place os it does not dilute out too quikcly

47
Q

Bystander effect of adjuvants

A

Induce cytokine release…due to immune response to adjuvant

48
Q

How does alum work?

A

Stimulates clusters of proteins called inflammasomes inside certain cells…release cytokines
Operate in parallel with TLRs

49
Q

Admin of vaccines

A

Inoculation - most feared but most common
Ingestion - preferred
Nasal prep- occassional

50
Q

Provenge vaccine

A

Against prostate cancer
Induces equilibrium (4.1 months)
Isolate CD14 positive monocytes and culture to make dendritic cells…pulse cells to prostate attached to GM-CSF…this signals BM to release granulocytes and monocytes and increase APC precursors

Downside is that MDSCs are also released which are suppressive

51
Q

Autologous dendritic cell vaccine

A

Non-resectable non small cell lung cancer
Autologous CD14+ derived DCs
Used GM-CSF

52
Q

ELISPOT analysis for

A

Gamma-IFN…key in anti-tumor response

53
Q

IL-6, IL-10, and IFN-gamma importance

A

IL-6 higher in non-responders (inflammatory)
IL-10 - higher in some non-responders (Th2)
IFN-gamma - important for anti-tumor

54
Q

Cytokine levels with stage in disease

A

Th1 wont change

Th2 will increase with stage

55
Q

Checkpoint inhibitors

A

CD80/86;CTLA4 (ipilimumab/Yervoy)

PD1:PDL1

56
Q

Mech of CTLA4 checkpoint inibitor

A

Use AB for CTLA4 which prevents inhibition of T cell and therefore allows it to live…induces equilibirium (14.8 months)…works only in lymph node between dendritic and T cell

57
Q

Mech of PD1:PDL1 inhibitor

A

PDL1/PD1 AB works on T cell (PD1) or cancer cell/dendritic cell with PDL1…cancer cells can express this sometimes
Used in lymph node AND at tumor site

Foundations 9 (6 decks)

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