Big New MSS-CRC Immmunotherapy Trial: anti-CD47

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DK37
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Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby DK37 » Fri Nov 04, 2016 6:22 am

BIG new immunotherapy clinical trial just announced for MSS CRC! We'll actually be a lead solid tumor indication for one of the hottest immunotherapy targets: anti-CD47 (if you google it you'll see many hits). CD47 is a "don't eat me" signal sent to macrophages - the drug blocks it from doing this. An issue with anti-CD47 drugs is a small safety window but they are working to address that.

CD47 made a huge splash in the scientific world a few years ago with its preclinical data. People have been anxiously watching to see how it behaves in the clinic. The initial clinical focus was on blood cancers but they are now ready to start solid tumor testing - and MSS CRC is being chosen as an early test case!

Trial: NCT02953782
Drug name: Hu5F9-G4
Both KRAS WT and Mut
Combination with cetuximab
Locations: TX, MI, TN
Pretty loose inclusion/exclusion criteria

https://clinicaltrials.gov/ct2/show/NCT ... 016&rank=2

A link to a news story about the company "Forty Seven":
http://www.fiercebiotech.com/special-report/forty-seven

Preclinical papers:

http://www.pnas.org/content/109/17/6662.long

http://www.tandfonline.com/doi/full/10. ... 15.1011450

Cheers,
-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

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Nik Colon
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Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby Nik Colon » Fri Nov 04, 2016 6:46 am

Thanks DK :)
KRAS-mut G12V,MSS
Stage IVa Sig CC 2 lvr mets 1/12 Ln
(3, =<3 lng spots at dx til 5/16)
=T3N1aM1a 4cmX4mm (lng not included)
dx 12/2014 at age 39
CEA 1/15-4.9, 12/16-4.9 again
neoadj FOLFOX 1/15-3/15 (4tx, 3w/1wo oxi)
Col/Lvr surg 4/23/15 NED
adj FOLFIRI start 6/15-9/15 (8tx, 5w/3wo iri)
1 sml lvr spot/cyst
12/6/16 multi lung spots/mets?
No longer NED :(
My tx ongoing-start 1/20/15
Adding your SIGNATURE, etc

dudette
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Joined: Sat Oct 17, 2015 10:04 am

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby dudette » Fri Nov 04, 2016 2:22 pm

Thanks muchly for sharing!

Could you briefly expand on the limited safety window, please? Is it because all cells have/express CD47 and the trial drug will also go after the healthy cells?
Temi
Dx 03/2015 @ age 41 - CC stage IV - pT3 N2b (14/29) cM1 (hep) L1 V1 Pn1 R1
Wild K-RAS, N-RAS, BRAF / MSS
unresectable mets liver 60% + lungs
Surgery
04/15 - sigmoid resect.
07/16 - hysterectomy (ovaries)
Chemo
05-06/15 - 4 x Folfirinox
12/15 - 02/16 4 x Xeliri + Avastin
03-05/16 9 x Xeloda
09-12/16 Folfiri + Cetuximab
01/2017 - metronomic chemo + methadone
July 20, 2107 - Temi has passed away.

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DK37
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Location: San Diego

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby DK37 » Sun Nov 06, 2016 10:15 am

dudette wrote:Thanks muchly for sharing!

Could you briefly expand on the limited safety window, please? Is it because all cells have/express CD47 and the trial drug will also go after the healthy cells?


CD47 is expressed by normal cells as well although it is up-regulated by tumors which is hoped to present a safety window. In particular, clinical investigators have been keeping a very close eye on impacts on blood counts, e.g. platelets. Different anti-CD47 drugs (there is more than one in clinical trials) and for example different dose amounts and schedules are hoped to maximize the safety window.

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

KElizabeth
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Location: Omaha

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby KElizabeth » Sun Nov 06, 2016 11:59 am

I'm confused about the use of Cetuximab with KRAS mutant CRC in this trial. Is the thought that the CD47 will circumvent the process that causes the poor prognosis that is associated with the use of Cetuximab with KRAS?
Female age 38- ,2 teens.
Colon Cancer - DX March 2013
Age 34 at DX - Stage III B
Resection surgery -May 2013
FOLFOX - June, 2013 to Sept, 2013
5FU plus leukavorin Sept, 2013 to Dec, 2013
METs liver and lungs discovered Sept, 2015
KRAS - MSS
FOLFIRI plus Avastin - Sept, 2015 - July 2017
Durvalumab and Cediranib Sept 2017 -current
CEA at recurrence:10.1/august, 2015
CEA: 1.9 February, 2016
CEA: 16.4 March 2017
CEA: 90.1 October 2017

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DK37
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Location: San Diego

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby DK37 » Tue Nov 08, 2016 4:10 am

KElizabeth wrote:I'm confused about the use of Cetuximab with KRAS mutant CRC in this trial. Is the thought that the CD47 will circumvent the process that causes the poor prognosis that is associated with the use of Cetuximab with KRAS?


Hi KElizabeth,

KRAS-mutant tumors still have EGFR receptors for Erbitux to bind to - but the mutant status gives it a way to grow irrespective of blocking the EGFR signal. In this case however, Erbitux is being used not to block a EGFR signal but instead to facilitate cancer cell killing via macrophages. The therapy may work better for KRAS-wild type (since it is getting a double-whammy) but in theory should have activity against KRAS-mutant as well.

-DK
6/4/2012 Dx Stage 3C CRC @ 40 yo. MSS, KRAS-WT, BRAF-WT, p53-mut
7/12 FOLFOX/FOLFIRI
2/13 NED!
8/13 Enlarged lymphs - Stable
10/14 Stage IV. Lung & Lymph mets. 5-FU+bev
3/15 Cetuximab
11/15 FOLFIRI + bev
11/16 Signs of FOLFIRI resistance (Lymph mets)
1/17 Palliative radiation for resistant mets
2/17 FOLFIRI + bev + Maraviroc (off-label)
3/17 FOLFIRI + Erbitux + Maraviroc (off-label)
MSS-CRC Clinical Trial Finder: http://trialfinder.fightcrc.org/
2016 Colondar 2.0 Model
DK37 Science Posts List

dudette
Posts: 106
Joined: Sat Oct 17, 2015 10:04 am

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby dudette » Wed Nov 09, 2016 8:22 am

Damn, I wish I had your brain, DK37!

Thanks again for sharing your knowledge.
Temi
Dx 03/2015 @ age 41 - CC stage IV - pT3 N2b (14/29) cM1 (hep) L1 V1 Pn1 R1
Wild K-RAS, N-RAS, BRAF / MSS
unresectable mets liver 60% + lungs
Surgery
04/15 - sigmoid resect.
07/16 - hysterectomy (ovaries)
Chemo
05-06/15 - 4 x Folfirinox
12/15 - 02/16 4 x Xeliri + Avastin
03-05/16 9 x Xeloda
09-12/16 Folfiri + Cetuximab
01/2017 - metronomic chemo + methadone
July 20, 2107 - Temi has passed away.

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GrouseMan
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Joined: Mon Aug 12, 2013 12:30 pm
Location: SE Michigan USA

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby GrouseMan » Thu Nov 10, 2016 12:45 pm

As DK says - Ebritux will still bind to EGFr in Mutant KRAS tumors, it just doesn't reduce the always on KRAS signaling cascade in the tumor very much. BUT as DK says the EGFr it binds to basically alerts the immune system that this tumor cell needs some attention so to speak. Cetuximab is a monoclonal antibodies (MAB) of the IgG1 isotype and as a result may activate a complement pathway and mediate antibody-dependent cellular cytotoxicity (ADCC) of immune effector cells, thanks to the activation of the Fc receptors on their membranes by the Fc regions of the MAB's of this IgG1 isoform.

See section of this Wki article about Panitumab (Vectibix) vs Cetuximab (Erbitux):

https://en.wikipedia.org/wiki/Panitumumab

and

http://www.healthvalue.net/IgG1_IgG2.html

Regards,

GrouseMan
DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

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Maia
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Joined: Fri Aug 24, 2012 8:00 am

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby Maia » Fri Nov 11, 2016 7:32 am

.
Last edited by Maia on Fri Nov 11, 2016 7:37 am, edited 1 time in total.

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Maia
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Joined: Fri Aug 24, 2012 8:00 am

Re: Big New MSS-CRC Immmunotherapy Trial: anti-CD47

Postby Maia » Fri Nov 11, 2016 7:35 am

DK37 wrote: CD47 is a "don't eat me" signal sent to macrophages - the drug blocks it from doing this. An issue with anti-CD47 drugs is a small safety window but they are working to address that.

CD47 made a huge splash in the scientific world a few years ago with its preclinical data. People have been anxiously watching to see how it behaves in the clinic.


Yes! Very promising --personally, I think it might be specially interesting for the 'cold' cancers, like CRC. Here it is a clear and recent article about the subject, for those interested:

CD47 Studies Take Immunotherapy in New Direction
October 31, 2016
(...) The dominant strategy thus far has been to activate T cells, the central mediators of the adaptive immune response. This approach is antigen specific, involves memory recall, and could in theory have long-lasting therapeutic benefit.

Yet there are 2 arms to the immune system that act in concert with one another and evidence is building that the second arm—the innate immune response—is also likely to be important.

As a result, researchers and pharmaceutical companies, seeking to carve out new niches in the immuno-oncology field, are looking to the major player in the innate immune response: the macrophages.

A particularly promising therapeutic target in this area is the CD47 protein, dubbed the “don’t eat me” signal for its role in inhibiting the phagocytic activity of macrophages and seemingly exploited by cancer cells to make them appear as normal cells to the innate immune response. -

Full article: here


In the same issue, an brief article by Dr Allison, an insight pertinent for CRC (cold tumour):

James Allison Says Rational Combinations Key to Immunotherapy Success in "Cold" Tumors
Oct 31, 2016

(...) “There is enough progress being made across the board that I think we can start thinking about some of the colder tumors responding if we just keep studying and making rational combination decisions,” said Allison, professor and chair of Immunology at MD Anderson Cancer Center. “As we understand this better, we can rationally put two things together that won’t just duplicate or cancel each other out, but will do different things that can at least be additive, if not synergistic.”

Full article: here


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