We may have a mile to go to see effective immunothrarpies to occur for those with MSS

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boswind
Posts: 32
Joined: Fri Apr 11, 2014 12:04 pm

We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby boswind » Tue Nov 28, 2017 11:42 am

Before Thanksgiving day, I posted a topic about MGD007. After reading some info I found it might not be as effective as I originally thought.
The other medicine CEA-TCB (RO6958688; RG7802) by Roche in phase 1 clinical trial is based on the same principle as MGD007:
MGD007 lets T-cells targets cancer cells with gpA33 x CD3 antigen while CEA-TCB lets T-cells targets cancer cells with CEA CD3 TCB.

Below is Roche's reports of phase 1 regarding drug's efficacy and side-effects, published in May 2017.
https://www.roche.com/investors/updates ... -05-18.htm
Our forum member Julie YW got the treatment of this drug in a phase 1 clinicial trial at MSCCC. The outcome was mixed.

The makers of both drugs will present detailed results in Jun 2018 in ASCO in Chicago.

In summary, while many patients including me are eager to participate in clinical trials of these two drugs, but now I do not feel excited after reading a lot of info.
01.24.2014 Male, DX @54 Rectosigmoid Cancer, MRI: T3N0M0
03.19.2014 Completed 5-week Radia+Xeloda
05.07.2014 Had surgery to remove 13cm sigmoid-colon and rectum.
02.25.2015 PET/CT/MRI scans show liver mets and L4 Spine involvement.
MSS, KRAS wild type, BRAF wild type
Mar 2015 - Aug 2015, folfox + Avastin
Aug 2015 - Jul 2017, 5FU + leucovorin + Avastin for Maintainance
Jul 2017 - Present, folfuri + Avastin
Current CEA: 5.6
Total over 50 rounds of chemo treatment received

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Tue Nov 28, 2017 12:08 pm

A reason to be more optimistic:

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×1011 HLA-C*08:02–restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178827/

This caught my eye because it's my mutation and knowing that this has helped people already and that they are refining it is hopeful. If they can do this with G12D, then I would hope that they could do it with all of the KRAS mutations. And maybe NRAS and BRAF. It's going to take a lot of work and a decent amount of time but I think that you have a lot of researchers trying to get Immunotherapy to work.
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).

jortego128
Posts: 275
Joined: Sat Aug 15, 2015 7:47 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby jortego128 » Tue Nov 28, 2017 4:45 pm

I think the results you posted above are for the TIL (tumor infiltrating lymphocytes) therapy and specifically for our own member Sleen, who made national news because of it. She had shrinkage/obliteration of all tumors except one in her lung, which was resected.
DM 57 yrs old dx 6/8/15 T:4a N:1b M:1
KRAS G12D and TP53 C242fs mutations
Poorly Differentiated, Prominent Signet Ring Component(~50%)
Microsatellite Stable, 3 of (13)lymph nodes positive
15 Liver mets, largest 3.2 cm
Prim. Resection, Right Hemicolectomy 6/21/15
Start Chemo 7/20/15
2 rounds FOLFOX, 1 round FOLFOX +Avastin
CT 8/28/15, met growth, largest 4.5cm
4 rounds FOLFOX+Avastin
CT 11/06/15 mets stable, lungs clear
Begin FOLFIRI+Avastin 11/17/15, Stop chemo 1/26/16
Entered Paradise 3/11/2016

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Tue Nov 28, 2017 5:47 pm

jortego128 wrote:I think the results you posted above are for the TIL (tumor infiltrating lymphocytes) therapy and specifically for our own member Sleen, who made national news because of it. She had shrinkage/obliteration of all tumors except one in her lung, which was resected.


I'm not familiar with Sleen but I'm glad to see that it's worked out really well for her. It's a strange case for sure in the the NIH did a study of their approach on only one patient and it worked out really well. I'm hoping that they got the biopsy on that tumor that they removed so that they can nail those tumor cells the next time. Do you have a link to her story?
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).

User avatar
CRguy
Posts: 9323
Joined: Sun Feb 10, 2008 6:00 pm

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby CRguy » Tue Nov 28, 2017 6:12 pm

Sleen info :
https://cancerriot.blogspot.ca/ is her blog with a beautiful tribute to Tom (DK37)
and her CClub profile can be found here

DH2Sleen is her hubby who also has contributed a lot to this forum.

Cheers
CR
Caregiver x 3
Stage IV A rectal cancer/lung met
10 Year survivor
my life is an ongoing totally randomized UNcontrolled experiment with N=1 !
Review of my Journey so far

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Tue Nov 28, 2017 9:43 pm

CRguy wrote:Sleen info :
https://cancerriot.blogspot.ca/ is her blog with a beautiful tribute to Tom (DK37)
and her CClub profile can be found here

DH2Sleen is her hubby who also has contributed a lot to this forum.

Cheers
CR


That's a fascinating blog and she provided a great description of the conditions required for the cure. My son explained the HLAs (his manager alluded to these in an email to me but I didn't know what an HLA was). My son told me that the problem with KRAS mutations is that the mutation is inside the cell and that there isn't a way for Immunotherapy approaches because they can't see inside the cell. The HLAs allow that but it looks like there are lots of these things and that each person only has a few so the question is: which HLAs match up with being able to identify KRAS (and NRAS and HRAS) mutations to the cell surface? We know that the particular HLA in this case aligns with KRAS G12D. When we do Genomic Tumor testing, we should have a test: if you have KRAS G12D and the right HLA, then this particular solution should work. At any rate, is looks like a healthy channel for research.
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).

User avatar
DH2Sleen
Posts: 68
Joined: Thu Jan 29, 2015 10:10 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby DH2Sleen » Wed Nov 29, 2017 9:20 am

NHMike wrote:
CRguy wrote:Sleen info :
https://cancerriot.blogspot.ca/ is her blog with a beautiful tribute to Tom (DK37)
and her CClub profile can be found here

DH2Sleen is her hubby who also has contributed a lot to this forum.

Cheers
CR


That's a fascinating blog and she provided a great description of the conditions required for the cure. My son explained the HLAs (his manager alluded to these in an email to me but I didn't know what an HLA was). My son told me that the problem with KRAS mutations is that the mutation is inside the cell and that there isn't a way for Immunotherapy approaches because they can't see inside the cell. The HLAs allow that but it looks like there are lots of these things and that each person only has a few so the question is: which HLAs match up with being able to identify KRAS (and NRAS and HRAS) mutations to the cell surface? We know that the particular HLA in this case aligns with KRAS G12D. When we do Genomic Tumor testing, we should have a test: if you have KRAS G12D and the right HLA, then this particular solution should work. At any rate, is looks like a healthy channel for research.


Thanks for the mention CRguy. We have been trying to get back to "normal" life lately, so we haven't been posting as much. Tom's passing was pretty hard on both of us.
HLA is the key to activation of a normal immune system in response to an abnormality in cells in the body, and there are hundreds of HLAs. But each person has six distinct HLAs in their "self" cells. The HLA-C*08:02 that they found in Sleen, which presented the mutation to the immune system as a "foreign" presence, is one of the HLAs that are known to be able to present the mutation Kras G12D. That particular HLA is present in about 11% of the population of European decent, and higher for some other ethnic groups. They have also proven that Kras G12D is presented by HLA-A*11:01 (a more common HLA) and they have an active trial for that combination ongoing at NIH now. And HLA-A*11:01 has also been proven to present Kras G12V, but that has not reached the trial stage yet.
The strategy for targeting a known mutation/HLA combination is called Engineered T-cell Adoptive Cell Therapy (ACT). With hundreds of HLAs and thousands of mutations, you can imagine the complexity of creating Engineered T-cell ACT for every combination. But at least progress is being made, and more trail participants means that more effective combinations will be found. I hope that everyone who reads this will plan to apply for a trial at NIH.
DW, Sleen dx 9/2013 @47yo: IIIc T4b N2b MX
09/2013 colectomy
10/2013 - 3/2014 FOLFOX
04/2014 - 6/2014 Rad to bladder
12/2014 +'ve for lung mets, MX becomes M1
03/2015 enter TIL trial @ NIH
07/01/15 Receive 148E9 cells to target K-ras G12D mutation
08/11/15 Reduction=18%, no new tumors
09/15/15 25%
10/20/15 27%; PET -> one hot met
11/24/15 30% all mets shrinking
01/26/16 46% but one suspicious met
03/24/16 46% but one growing
04/07/16 Lung lobectomy NED for the first time

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Wed Nov 29, 2017 7:44 pm

DH2Sleen wrote:
NHMike wrote:
CRguy wrote:Sleen info :
https://cancerriot.blogspot.ca/ is her blog with a beautiful tribute to Tom (DK37)
and her CClub profile can be found here

DH2Sleen is her hubby who also has contributed a lot to this forum.

Cheers
CR


That's a fascinating blog and she provided a great description of the conditions required for the cure. My son explained the HLAs (his manager alluded to these in an email to me but I didn't know what an HLA was). My son told me that the problem with KRAS mutations is that the mutation is inside the cell and that there isn't a way for Immunotherapy approaches because they can't see inside the cell. The HLAs allow that but it looks like there are lots of these things and that each person only has a few so the question is: which HLAs match up with being able to identify KRAS (and NRAS and HRAS) mutations to the cell surface? We know that the particular HLA in this case aligns with KRAS G12D. When we do Genomic Tumor testing, we should have a test: if you have KRAS G12D and the right HLA, then this particular solution should work. At any rate, is looks like a healthy channel for research.


Thanks for the mention CRguy. We have been trying to get back to "normal" life lately, so we haven't been posting as much. Tom's passing was pretty hard on both of us.
HLA is the key to activation of a normal immune system in response to an abnormality in cells in the body, and there are hundreds of HLAs. But each person has six distinct HLAs in their "self" cells. The HLA-C*08:02 that they found in Sleen, which presented the mutation to the immune system as a "foreign" presence, is one of the HLAs that are known to be able to present the mutation Kras G12D. That particular HLA is present in about 11% of the population of European decent, and higher for some other ethnic groups. They have also proven that Kras G12D is presented by HLA-A*11:01 (a more common HLA) and they have an active trial for that combination ongoing at NIH now. And HLA-A*11:01 has also been proven to present Kras G12V, but that has not reached the trial stage yet.
The strategy for targeting a known mutation/HLA combination is called Engineered T-cell Adoptive Cell Therapy (ACT). With hundreds of HLAs and thousands of mutations, you can imagine the complexity of creating Engineered T-cell ACT for every combination. But at least progress is being made, and more trail participants means that more effective combinations will be found. I hope that everyone who reads this will plan to apply for a trial at NIH.


Here's a paper on it for the curious:

http://www.nejm.org/doi/pdf/10.1056/NEJMc1616637
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Sat Dec 02, 2017 10:46 pm

DH2Sleen wrote:
Thanks for the mention CRguy. We have been trying to get back to "normal" life lately, so we haven't been posting as much. Tom's passing was pretty hard on both of us.
HLA is the key to activation of a normal immune system in response to an abnormality in cells in the body, and there are hundreds of HLAs. But each person has six distinct HLAs in their "self" cells. The HLA-C*08:02 that they found in Sleen, which presented the mutation to the immune system as a "foreign" presence, is one of the HLAs that are known to be able to present the mutation Kras G12D. That particular HLA is present in about 11% of the population of European decent, and higher for some other ethnic groups. They have also proven that Kras G12D is presented by HLA-A*11:01 (a more common HLA) and they have an active trial for that combination ongoing at NIH now. And HLA-A*11:01 has also been proven to present Kras G12V, but that has not reached the trial stage yet.
The strategy for targeting a known mutation/HLA combination is called Engineered T-cell Adoptive Cell Therapy (ACT). With hundreds of HLAs and thousands of mutations, you can imagine the complexity of creating Engineered T-cell ACT for every combination. But at least progress is being made, and more trail participants means that more effective combinations will be found. I hope that everyone who reads this will plan to apply for a trial at NIH.


There's a nice HLA-A*1101 frequency table by ethnic group and location at https://en.wikipedia.org/wiki/HLA-A11

It looks like it's most common in East Asia.

I looked for something similar for HLA-C*0801 and didn't find anything. There are small studies of various regions but I couldn't find something that's rolled up.
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Sat Dec 02, 2017 11:18 pm

I found a paper with percentages by racial group for the United States at http://www.academia.edu/24748549/Analys ... opulations

HLA-A*1101:
African-Americans 2.3%
Caucasions 7%
Hispanics 5.8%
Native Americans 2.7%
Asians 23%

HLA-C*0802
African-Americans 3.2%
Caucasions 3.8%
Hispanics 5.1%
Native Americans 1.9%
Asians 0.1%
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).

rp1954
Posts: 1205
Joined: Mon Jun 13, 2011 1:13 am

Re: We may have a mile to go to see effective immunotherapies to occur for those with MSS

Postby rp1954 » Sun Dec 03, 2017 11:12 pm

In the meantime, a lot of people are missing important immunotherapy opportunities that they've had since day 1, and those that they have even while waiting for a good trial.

Some generic drugs and supplements have easy companion tests that should help (y)our choices and doses. Other materials will probably be best guided by serial blood panels and markers. The problem we have here is that we are too hesitant, hoping a few small changes will do heavy lifting, when success beyond what's commercially offered (e.g. -oxi, -iri, BEV, CET ) takes several well aimed steps, but without the incredible side effects and high costs.

We do these things because they are cheaper, more effective and mostly more convenient than "standard" or someone's experiment, on us.
watchful, active caregiver for stage IVb CC since early 2010. immuno"Chemo forever," for mCRC

Stewsbetty
Posts: 101
Joined: Thu Jul 14, 2016 7:08 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby Stewsbetty » Mon Dec 04, 2017 2:10 am

boswind wrote:Before Thanksgiving day, I posted a topic about MGD007. After reading some info I found it might not be as effective as I originally thought.
The other medicine CEA-TCB (RO6958688; RG7802) by Roche in phase 1 clinical trial is based on the same principle as MGD007:
MGD007 lets T-cells targets cancer cells with gpA33 x CD3 antigen while CEA-TCB lets T-cells targets cancer cells with CEA CD3 TCB.

Below is Roche's reports of phase 1 regarding drug's efficacy and side-effects, published in May 2017.
https://www.roche.com/investors/updates ... -05-18.htm
Our forum member Julie YW got the treatment of this drug in a phase 1 clinicial trial at MSCCC. The outcome was mixed.

The makers of both drugs will present detailed results in Jun 2018 in ASCO in Chicago.

In summary, while many patients including me are eager to participate in clinical trials of these two drugs, but now I do not feel excited after reading a lot of info.


I didn’t read the whole report but I wanted to encourage you a bit. I read several study reports on immunotherapy for MSI high (which I am) and the numbers weren’t always the most encouraging but if you do respond (which I have ) it is the most amazing thing in the world. So don’t necessarily write off a trial because there aren’t high percentages of Complete or partial response. For many even stable disease sounds like a win.

Beth
42yo At diagnosis. Female in BC, Canada
Dx: CC ascending
Right Hemi colectomy 06/16 clear margins
Adenocarcinoma 6cm High Grade
pT3 pN2a Stage 3
10 out of 16 lymph involved
MSI-h, Kras mut, Braf wild
Finished chemo Feb. 2017
PET scan showing active area April 2017
July 2017 CT showing LN mass and spread to other LN
Stage 4

NHMike
Posts: 690
Joined: Fri Jul 21, 2017 3:43 am

Re: We may have a mile to go to see effective immunothrarpies to occur for those with MSS

Postby NHMike » Wed Dec 06, 2017 12:45 pm

Image
6/23/17: ER rectal bleeding; Colonoscopy+Biopsy
7/13: Stage 3B rectal cancer. T3, N1b, M0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6 mm, 5 x 5 mm
7/31-9/8: Xeloda 3,400 mg/day+radiation
7/5: CEA 2.7; 8/16: 1.9; 9/8: 1.8. 11/30: 0.6
MSS, KRAS G12D
10/6: 2.7 x 2.2 x 1.6 cm (-90%). Lymphs: 3 x 3 mm (-62.5%), 4 x 3 mm (-75%), 5 x 3 mm (-40%). 5.1 CM from AV
10/30: Surgery: LAR, Temp Ileostomy
Path report: Tumor regression grade: 0 (complete response).


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