Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

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DK37
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Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby DK37 » Sun Apr 19, 2015 12:50 pm

People ask me why I remain so optimistic for the chances of a Stage IV CRC cure in a significant number of patients being not that far off... It is because I read immuno-oncology scientific papers as they appear DAILY and the pace of new combinations and ever improving efficacy in pre-clinical models is simply breathtaking!! Many may fail in clinical trials but there are so many “shots on goal” rapidly coming down research pipelines I firmly believe one will “be the trick” needed for CRC.

Today’s example: a new Johns Hopkins paper in a top journal (Science Translational Medicine) combined 1.) a GM-CSF cancer vaccine 2.) adaptive immune system activation via PD-1 inhibition and 3.) Innate immune system activation via a single sc dose of a STING activator. In the poorly immunogenic CRC “CT26 model” in mice with full immune systems – they had a 100% cure rate of established tumors and when the mice were rechallenged with CT-26 tumors in the future there was immune memory & the mice refused to grow new tumors. (immunogenic means how well the immune system can recognize something as dangerous – unfortunately most CRC is poorly immunogenic which is why it hasn’t been as easy to treat with 1st generation immunotherapies as e.g. melanoma).

Best part, it appears that all of the treatment components could be combined in a clinical trial relatively quickly. I love the technique they used because they combined "both halves" of the immune system + a vaccine to teach it what to go after - this is closer & closer replicating with therapeutics how the immune system normally works.

I think it requires a subscription or purchase but here is a link to the article: http://stm.sciencemag.org/content/7/283/283ra52

-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
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Ceebo
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby Ceebo » Sun Apr 19, 2015 1:35 pm

I agree, that is such exciting news! Thanks for keeping us updated!!
DH 64 Stage 4 on 4/14 ; cecal tumor; 5+ nodes ; mets to liver; colon resection
5/14 FOLFOX
9/14 - Liver surgery aborted; peri mets
10/14 CT mult.1-2 mm lung mets; FOLFIRI & Avastin
1/15 CT -liver & lung mets shrinking
3/15 PET - ? New met. site colon; CEA rising
7/15 Chemo has failed; looking for clinical trial
9/29/15 started TAS-102 trial
KRAS mutant; MSS

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peanut_8
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby peanut_8 » Sun Apr 19, 2015 1:38 pm

That is really fascinating stuff. And we are so lucky to have you to keep us up to date.
Thanks DK
Terri aka peanut
diagnosed Jan 14, RC stage 2a, age 56
permanent colostomy
MSS
April 14, 28 chemo/rad with Xeloda
June 14 adjuvant Xeloda 6 rounds
currently NED

justAfterTEM
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby justAfterTEM » Sun Apr 19, 2015 2:20 pm

Hi DK37, already sent you private message, but I hear the pm system has problems, so just in case my msg didn't go through, I wanted to ask you here too:

Being an actual CRC researcher, what do you think are currently the most promising clinical trials/ new treatment methods? Also, I've been hearing a lot about ADAPT on this board, what do you think about ADAPT? I'm trying to help a family member who is a stage 4 CRC patient.

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Sleen
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby Sleen » Sun Apr 19, 2015 2:37 pm

Thank you for posting this--what is a STING activator?

Your enthusiasm is contagious :D

Celine
my blog: Cancer Riot

NED since April 2016!
April 2016: lower left lung lobectomy. NED
8 mo. f/u: 1 of 7 tumors progressed.
6 mo. f/u PR confirmed (Jan 2016)
Jul 2015: NIH TIL trial NCT01174121 NCI/NIH Surgery Branch FAQ
Dec 2015 stage IV w/bilateral lung mets
FOLFOX + Radiation (bladder)
KRAS G12D :: MSS
dx Sep 2013 @47yo: IIIc T4b N2b MX [bladder invasion, 17/21 lymph nodes]

Married 28 yrs. kids: 22, 19, 15, 11, 9
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Delinda2
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby Delinda2 » Sun Apr 19, 2015 3:15 pm

The only part of your post that I really understood was, "100% cure ". Happy little mice! Seriously, this is exciting stuff & I am grateful we have people like you (among others) who follow and share the changes. Won't it be amazing when it does finally happen. Soon, soon, soon!!
63 yrs,wife & mom
4/14 dx colon cancer,3C,9/22 nodes
Lymphatic,venous,&perineural invasion
<1cm margin,poorly differentiated
6/14 colostomy take down
7/14 FOLFOX w/9 Nulasta shots
2/16 dx new primary of sigmoid colon
6/16 surgery-rescection on sigmoid, total hysterectomy, temp ileo, stage 4
"I AM the storm."

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vilca11
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby vilca11 » Sun Apr 19, 2015 4:41 pm

DK, great find, thank you for posting! I just emailed my Onc in Hopkins, Dr. Nilo Azad, will post what she responds about that study and possibility of clinical trial to be held soon.
Hugs, vilca
11/2005 CC stage 1, F,50yo@dx
Mod dif adenocar, MSS, APC, TP53, CEAs1.6-4.8
1/12 1met liver@Vena Cava, RFA, 3oxi,11 5FU
8/13 2 mets same place,SBRT
4/14 2 Xeliri+Avastin
5/14 Nano Knife liver same 2 mets
6/14 2 Xeliri, ADAPT
4/15 PET, 2 same mets,Cryo Liver
5/15 MJ Oil, Herbs, Suppl, ADAPT
10/15 PET, same area, doubled in size, high SUV
10/15 RH, HAI, visceral involv., no LN
2/16 red FF, 50% red dose FUDR, CEA trends up
3/16 CT, PET, MRI L.Lobe all in small tumors
4/16 No acceptable options, going home

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lilacbreastedroller
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby lilacbreastedroller » Sun Apr 19, 2015 5:32 pm

Could someone please explain what the science means? I clicked the link and read the article abstract- only thing I got out of it is that "dithio diastereomer" would be a great name for a Harry Potter character...

- Karin
dx 6/1/12@45yo
RT, 4 liv, 5 lung
7/12 FOLFOX
2/13 Xeloda 4k mg/d
7/13 DC VAX,1k mg/d metro Xel
11/13 Erbi, Irino
6/14 clinical trial lirilumab, nivolumab
9/14 Stivarga
1/15 clinical trial immunotherapy (young TILs)
RT, mets to liv, lung, adrenal, lns

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vilca11
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby vilca11 » Sun Apr 19, 2015 8:44 pm

Got response from Dr. Azad. She wrote "Not ready for prime time yet".... kind of very brief... well, it is a Sunday night... I was expecting some time estimate for clinical trial availability...
11/2005 CC stage 1, F,50yo@dx
Mod dif adenocar, MSS, APC, TP53, CEAs1.6-4.8
1/12 1met liver@Vena Cava, RFA, 3oxi,11 5FU
8/13 2 mets same place,SBRT
4/14 2 Xeliri+Avastin
5/14 Nano Knife liver same 2 mets
6/14 2 Xeliri, ADAPT
4/15 PET, 2 same mets,Cryo Liver
5/15 MJ Oil, Herbs, Suppl, ADAPT
10/15 PET, same area, doubled in size, high SUV
10/15 RH, HAI, visceral involv., no LN
2/16 red FF, 50% red dose FUDR, CEA trends up
3/16 CT, PET, MRI L.Lobe all in small tumors
4/16 No acceptable options, going home

lpas
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby lpas » Sun Apr 19, 2015 11:46 pm

Wow, that sounds really encouraging. Thanks so much for posting!
11/14 Dx sigmoid CC @ 45yo
12/14 Colectomy + hysterectomy
Stage IIIB, T3N1bM0, 2/20 nodes, MSS, G2, KRAS(A146T), TP53, SMAD4, ERBB2, CEA 1.0
2/15-7/15 XELOX & Celebrex
3/16 Ovarian mass removed. Benign fibroid
9/16 clean scope
4/18 clean CT
Ongoing Celebrex, Tagamet & other carefully-targeted supplements
Post-chemo CEA 3.0, 2.5, 2.3, 2.0, 1.6, 1.3, 1.8, 2.1, 1.8, 2.0, 1.8, 1.9, 1.7, 1.5, 1.6, 1.5, 1.4, 1.4, 1.3, 1.3, 1.6, 1.6, 1.3, 1.4, 1.6, 2.2, 2.4, 2.1
Mom to a 4 & 6yo

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DK37
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby DK37 » Mon Apr 20, 2015 1:03 am

Hi Everyone,

Sorry I was out all day so couldn't post any responses sooner...

Vilca11: Thanks for getting feedback from the Johns Hopkins clinician! That kind of info is so useful for the board! I did hope to stress in the post that this study was in mice but on the good side, the "components" used in the study are either already in the clinic (PD-1) or being researched by numerous places (not just Johns Hopkins) - so if the science & basic strategy of the paper is confirmed by other organizations (which they will be attempting asap after last week's publication), it is the kind of thing that is potentially not super far away from clinical testing. I don't think a trial in 2015 is possible but after that all bets are off - I have never seen research & translation to clinical trials happen as fast as it is right now. The beauty of science is that one of the other labs doing follow-up could potentially figure out their own tricks to improve even further... that is the beauty of scientific progress, it feeds & builds on itself and upon each new step forward.

There were a couple of questions asked in the comments today. I'll address them within the next few days with another post reply - I need to get to sleep... it's a work day tomorrow :)

-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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vilca11
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby vilca11 » Mon Apr 20, 2015 6:16 am

DK, do you know what would be (at least approximately) the probability of mice experiment results translating into the same or close to results in human trial ?

Dr. Nilofer Azad is presently a Director of Clinical Trial on CRC, I am expecting to hear about the possibility of that trial from her as soon as it is ready for prime time. So, will keep my fingers on the pulse non-stop.
Hugs, Vilca
11/2005 CC stage 1, F,50yo@dx
Mod dif adenocar, MSS, APC, TP53, CEAs1.6-4.8
1/12 1met liver@Vena Cava, RFA, 3oxi,11 5FU
8/13 2 mets same place,SBRT
4/14 2 Xeliri+Avastin
5/14 Nano Knife liver same 2 mets
6/14 2 Xeliri, ADAPT
4/15 PET, 2 same mets,Cryo Liver
5/15 MJ Oil, Herbs, Suppl, ADAPT
10/15 PET, same area, doubled in size, high SUV
10/15 RH, HAI, visceral involv., no LN
2/16 red FF, 50% red dose FUDR, CEA trends up
3/16 CT, PET, MRI L.Lobe all in small tumors
4/16 No acceptable options, going home

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DK37
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Location: San Diego

Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby DK37 » Tue Apr 21, 2015 5:10 pm

Hi All,

I’m back to briefly answer some of the questions posed on this thread last weekend. I’ll do them in order given…

justAfterTEM: I’m not a MD so I can’t give medical advice but I do give scientific opinions on clinical trial drugs. There are so many variables (e.g. genetic) in cancer patients that it is impossible to make a blanket statement of what specific current trials I think are scientifically most interesting for all patients. As a general statement, along with many on this forum, I am particularly hopeful that one of the upcoming/in progress immunotherapy trials will identify the trick needed to work for CRC. It is a tough nut to crack (CRC is usually poorly immunogenic) but I am hopeful since there are “so many shots on goal” being taken within the next few years, that at least one will work. Immunotherapy as a “concept” has been the Holy Grail of oncology for many many years but it is much easier said than done – research is finally catching up to the much easier to make “concept”. Every major company/research university/cancer center & countless small biotechs are simultaneously working very hard on immunotherapies right now ever since the CTLA-4 inhibitor Yervoy first showed proof-of-principle in melanoma a few years ago. In the non-immunotherapy space, I think RRx-001 is a very scientifically intriguing molecule with an unique preliminary clinical profile. Likewise, I am intrigued by ADAPT although I wish they would publish more data or at least case studies in oncology journals…

Sleen: STING is the acronym name of the protein “Stimulator of interferon genes” http://en.wikipedia.org/wiki/Stimulator ... eron_genes Keeping things simple, it is one of the main regulators of half of your immune system called the “innate immune system”. This is an extremely powerful (but historically tough to control) side of the immune system that is an area of intense oncology immunotherapy research right now. The famous PD-1 inhibitors impact the other half of the immune system (the adaptive immune system). They are just now finding new tricks to activate the innate immune system, e.g. with STING activators as well as other targets. There is hope that by activating BOTH sides of your immune system, a broader list of cancer types (e.g. hopefully CRC :) ) will respond to immunotherapy…

Lilacbreastedroller: See above. In the paper, they also added an immune-activating tumor vaccine called STINGVAX. Historically cancer vaccines have not worked very well because e.g. a vaccine won’t do its job if the associated tumor is shooting out immunosuppresive signals turning off the immune system. In this study they combined 3 things: 1.) a vaccine to teach the immune system/activate it 2.) a STING agonist to activate the innate half of the immune system and 3.) a PD-1 inhibitor to stop the tumor from suppressing the adaptive half of the immune system. Their goal was to impact three different major aspects of immune response simultaneously as a cocktail. And... (in mice at least!) it worked…

Vilca11: I wouldn’t hazard a guess... In broad terms: 1.) many many things work in mice but fail in the clinic. 2.) Even if this strategy ends up working in the clinic, I can’t imagine ever getting a 100% response rate (human cancers are very heterogeneous, the mouse model used was not) 3.) On the positive side, compared to most mouse studies – this one had abnormally excellent results/high activity (in one of the best mouse models) – which is why it was published in a top journal and will generate a lot of attention for follow-up...

-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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lilacbreastedroller
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Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby lilacbreastedroller » Tue Apr 21, 2015 6:50 pm

DK37 - Thank you so much for taking the time to explain the study. I think I kind of get it...! :shock:

atb

Karin
dx 6/1/12@45yo
RT, 4 liv, 5 lung
7/12 FOLFOX
2/13 Xeloda 4k mg/d
7/13 DC VAX,1k mg/d metro Xel
11/13 Erbi, Irino
6/14 clinical trial lirilumab, nivolumab
9/14 Stivarga
1/15 clinical trial immunotherapy (young TILs)
RT, mets to liv, lung, adrenal, lns

Delinda2
Posts: 483
Joined: Fri Jan 16, 2015 6:28 pm
Location: Washington state

Re: Johns Hopkins Immunotherapy Paper: 100% CRC cure rate in a poorly immunogenic CRC Mouse Model

Postby Delinda2 » Wed Apr 22, 2015 5:06 am

Thanks so much for explaining. We are lucky to have so many members that are really knowledgeable. My dunce cap is very uncomfortable. :shock: :roll:
63 yrs,wife & mom
4/14 dx colon cancer,3C,9/22 nodes
Lymphatic,venous,&perineural invasion
<1cm margin,poorly differentiated
6/14 colostomy take down
7/14 FOLFOX w/9 Nulasta shots
2/16 dx new primary of sigmoid colon
6/16 surgery-rescection on sigmoid, total hysterectomy, temp ileo, stage 4
"I AM the storm."


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