Why did science rank immunotherapy as 1
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Why did Science rank immunotherapy as #1? PowerPoint PPT Presentation


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Why did Science rank immunotherapy as #1?. !!!. Specific immunotherapy Active immunotherapy Antibody therapy Adoptive transfer of T cells Vaccine-based immunotherapy Tumour-based vaccines Virus-based vaccines Peptide-based vaccines others. Immunotherapy.

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Why did Science rank immunotherapy as #1?

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Why did science rank immunotherapy as 1

Why did Science rank immunotherapy as #1?

!!!


Immunotherapy

Specific immunotherapy

Active immunotherapy

Antibody therapy

Adoptive transfer of T cells

Vaccine-based immunotherapy

Tumour-based vaccines

Virus-based vaccines

Peptide-based vaccines

others

Immunotherapy


Abridged history of cancer immunotherapy

Abridged history of cancer immunotherapy

Lesterhuis et al, Nature Reviews 2011

2011: Ipiliumumab shows overall survival benefit in melanoma (2011)

2012-2013: PD1 and PD-L1 blockade has benefit in melanoma, NSCLC, renal cell

(4 NEJM papers)

2011-2013: CAR-modified T cells show durable remissions in B cell ALL and CLL


Why did science rank immunotherapy as 1

Can we combine local RT, antibodies to oncogenic receptors , selected chemo, hormones to alter tumor microenvironment that allow immunotherapy to optimize host immune response for tumor regression?

Major barriers in immunotherapy

  • Difficult to break tolerance

  • Poor recruitment to tumor site

  • Strong suppressive environment within the tumor site

  • Fast growing tumor in mouse model

  • Lack of defined antigens and adjuvant for CTL


Why did science rank immunotherapy as 1

T cell based therapy


Why did science rank immunotherapy as 1

Human CD19 expression by hematopoietic cells within the spleen and lymphoid tissues

Tedder, T. F. (2009) CD19: a promising B cell target for rheumatoid arthritis

Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2009.184


Why did science rank immunotherapy as 1

Using CAR to Overcome Tolerance

Creation of Bi-specific T cells

TCR heterodimer approach “CAR” or T body approach

TCR

Chimeric Protein

- off the shelf

- MHC independent

Tumor binding domain

CD3

Extracellular

Intracellular

Signaling domain

- ITAM


Why did science rank immunotherapy as 1

Design of CART19: Choice of 4-1BB Signaling Domain

Promotes CAR T Cell Proliferation/Survival


New strategies that target tumor microenvironment and generate local and systemic immune protection

New strategies that target tumor microenvironment and generate local and systemic immune protection


Improved targeting of x rays

TUMOR

Lead Cover

Lead Cover

Lead Cover

Improved Targeting of X-rays

tumor

Lead Plate

X-ray

Transparent

Plexiglass

X-Rays

11

Backscatter

Lead Cover


Local ablative rt mediates tumor regression

Nude

Wt

7500

6000

Control

Control

6000

RT

RT

4000

4500

Tumor volume (mm3)

Tumor volume (mm3)

3000

2000

1500

0

0

0

10

20

30

40

0

10

20

30

40

Days post RT

Days post RT

***

Local Ablative RT mediates tumor regression

B16-SIY: 20Gy or B16: 20Gy x 2

die

RT-mediated tumor regression depends on T cells

Traditional low dose and hyper-fractionated RT can not control tumor

Cure all die

Blood 2009, Cancer Res. 2011, JI 2013, JCI in press


Why did science rank immunotherapy as 1

100

Control

75

a

RT+

CD8

Percent survival

RT

50

25

0

0

10

20

30

40

50

60

70

Days post tumor injection

Which immune cells controls tumor growth

CD8+ T cells are required for therapeutic response to RTIncrease of PDL-1 induces resistance and allows relapse

B16 RT on day 14: 15Gy x day 14, 15, ad 16

2000

***

)

3

Control

1500

a

RT+

CD8

RT

1000

Tumor volume (mm

500

**

0

0

3

6

9

12

15

Days post RT


Can rt increase cross priming of tumor ag by intratumor dcs

25000

***

20000

cpm

15000

10000

5000

0

RT-DC+T

RT-DC only

No RT-DC+T

No RT-DC only

Which cytokines?

can RT increase cross-priming of tumor Ag by intratumor DCs?

B16-SIY

20 Gy

14 days

3 days

CD11c+ from tumor

2C T cells

Proliferation Assay


Why is cross priming increased

Why is cross-priming increased

  • It is known that IFNs can be induced by viral DNA for cross priming of CTL.

  • Hypothesis: RT-induce DNA damage leads to excessive DNA fragments, like viral infection, which trigger IFNs that induce DC maturation and cross priming

  • RT induces IFN inside tumor tissues


The therapeutic response to rt is dependent on type i ifns

5000

IFNAR KO Control

)

IFNAR KO RT

3

4000

WT Control

WT RT

3000

Tumor Volume (mm

2000

1000

**

0

0

5

10

15

Days post RT

The therapeutic response to RT is dependent on type I IFNs

RT induced tumor regression depends on STING but not MyD88 and TRIF

While anti-Her2/neu uses MyD88.


Why did science rank immunotherapy as 1

RT and anti-PD-L1 reduces MDSC through CTL

harvest

A

Ctrl RT+αPD-L1 RT+αPD-L1+αCD8

19.9% 0.55% 10.2%

Gr-1

CD11b

Re-activated CTL kills Ag+ cells

Including MDSC and tumor

B

RT

TUMOR

αB7-H1 mAb (but not anti-PD-1)

Day 0 14 17 20


Anti her2 neu antibody reduces tumor burden how

anti-HER2/neu antibody reduces tumor burden: how?

Oncogenic blockadeFcR mediated kill?

NK

TUMOR

TUMOR


Why did science rank immunotherapy as 1

WT mIgG

Wt -neu

Rag-/- mIgG

Rag-/--neu

Tumor model that depends on oncogenic signals and FcR dependent in immunocompetent host

1250

TUBO derived from

MMTV-Rat neu Tg

FcR and NK dep.

1000

750

Tumor volume (mm3)

500

**

Rag-1 +Ab

Wt + Ab

250

*

0

0

10

20

30

40

50

Days after tumor inoculation

Are T cells essential for Ab-mediated tumor regression?

Cancer Cell, 2010


Why did science rank immunotherapy as 1

Ab-mediated tumor regression is CD8 dependent: wt and Tg mice

A)

B)

Ctrl

Ctrl

-neu

-neu

Neu Tg mice

-neu + -CD8

-neu + -CD8

Tumor volume(mm3)

Tumor volume(mm3)

**

*

*

Naive

2000

-neu

1500

Days after tumor inoculation

Days after tumor inoculation

1250

1000

700

1000

1250

600

C)

D)

500

750

500

1000

**

Ctrl

400

0

500

750

-neu

3T3 KB

TUBO

300

250

IFN + reactive cells

/ 106 splenocytes

200

500

memory

Tumor volume (mm3)

100

0

250

0

10

20

30

40

50

0

0

10

20

30

40

50

60

0

0

10

20

30

40

50

60

70

80

Days after tumor

re-challenge

Cancer Cell, 2010, MT, 2013, CCR 2013


Why did science rank immunotherapy as 1

How can antibody trigger immune responses?

CD8

IFN

cytokines

Increased

Cross-priming

ADCC

Stress protein or DNA TLRs?

MyD88


Type i interferons are induced and necessary during antibody mediated tumor regression

Type I interferons are induced and necessary during antibody-mediated tumor regression.

A

TUBO

Ab or adenovirus-IFN

*

WT mice

*

0 1 2 3 4 5 6 wk

B

Ab can induce IFN for tumor regression but antibody can not induce IFN in Ab-resistant tumor

Could exogenous IFN be potent for targeting tumor?

*


How to target tumor with ifn armed ab with ifn for ab resistant tumor

How to target tumor with IFN: armed Ab with IFN for Ab-resistant tumor

B16-EGFR

25ug Ab or Ab-IFN

WT mice

0 1 2 3 4 5 6 wk

Anti-EGFR

Linker

IFNb

Anti-EGFR-IFNb is effective for controlling Ab resistant tumor


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