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?

!!!


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

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


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


T cell based therapy


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


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


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


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


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


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


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

  • 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


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.


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?

Oncogenic blockadeFcR mediated kill?

NK

TUMOR

TUMOR


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


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


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.

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

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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