TIL Immunotherapy at NCI

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rachel2017
Posts: 33
Joined: Tue Oct 17, 2017 9:17 pm

Re: TIL Immunotherapy at NCI

Postby rachel2017 » Mon Dec 18, 2017 1:44 pm

Which trial information did you get? Do you have the trial number?[/quote]

The trial # is 17-C-0113. That is for the G12V mutation.
DM 63. 11/16 colonoscopy (high dysplasia)
1/17 laparoscopic,6.5X4X3cm. Stage II. No chemo.
6/17 abdo pain. CEA 52. CT paracolic nodule 1.4X1.9cm
7/17 pet CT. Ascending colon 1.4X1.1cm SUV 2.4; midline scar 0.9cm SUV3.1
KRAS G12D
8/16/-9/26/17 Folfox 4 rounds
10/6/17 CT numorous perio seedings. ascending one 7cm; midline one 5.7cm.
10/16-1/5/2018 Folfox/avastin; 1/12/18 CT reviewed Slight progression
Stop chemo

NHMike
Posts: 1104
Joined: Fri Jul 21, 2017 3:43 am

Re: TIL Immunotherapy at NCI

Postby NHMike » Mon Dec 18, 2017 4:51 pm

rachel2017 wrote:Which trial information did you get? Do you have the trial number?


The trial # is 17-C-0113. That is for the G12V mutation.[/quote]

INCLUSION CRITERIA:
...
b) Confirmation of G12V mutated KRAS, NRAS or HRAS by the Laboratory of Pathology of the NCI.
c) Patients must be HLA-A 1101 positive.


https://clinicalstudies.info.nih.gov/cg ... -0113.html

Abstract LB-242: Identification of T-cell receptors targeting KRAS-mutated human tumors

KRAS is one of the most frequently mutated proto-oncogenes in human cancers, including pancreatic and colorectal cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V. The consistency, frequency, and tumor specificity of these “neo-antigens” make them attractive therapeutic targets. Recent data associates T cells targeting mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer or cholangiocarcinoma. We successfully generated T cells from HLA-A11*01 transgenic mice and subsequently isolated HLA-A11*01-resticted T cell receptors (TCRs) highly reactive with the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs can recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBL reactive with a mutated pancreatic cell line could significantly reduce its growth in NSG mice. The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers support clinical trials with these T-cells recognizing mutated KRAS in patients with a variety of common cancer types. A phase I/II clinical trial targeting KRAS G12V and G12D mutations with TCR-engineered PBL in HLA-A1101+ patients will be starting soon in the Surgery Branch NCI.


http://cancerres.aacrjournals.org/conte ... ent/LB-242

I believe that the NCI trial will work with either KRAS G12D or G12V but this is something that you should verify with them. One major note: the other trial that was only for KRAS G12D required HLA-C*0802 . HLA-C*0802 is strongest in Africa and the maximum there is 8%. Other strong areas are Spain, and France and Portugal at 5% of populations.

HLA-A*1101 is strongest in East Asia with areas of China, India, Singapore, Thailand, Bangladesh, Malaysia, Indonesia, Papa New Guinia and Northern Australia ranging from 26 to 37 percent. So descendants of people from these areas are more likely to have the required Alleles. Basically, if you're Asian, then your odds are much better with HLA-A*1102 than they are for HLA-C*0802. So they either already know that your mother has HLA-A*1102 or they will test her. If she doesn't have it, then this won't work for her but the other TIL trial might. If she does have it, then it should be full steam ahead.
6/23/17: ER rectal bleeding; Colonoscopy
7/13: Stage 3B rectal. T3N1bM0. 5.2 x 4.5 x 4.3 cm. Lymphs: 6 x 4 mm, 8 x 6, 5 x 5
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; 12/20 1.4
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 (-75%), 5 x 3 (-40%). 5.1 CM from AV
10/30: LAR, Temp Ileostomy, Path Complete Response
12/20: Started CapeOx

rachel2017
Posts: 33
Joined: Tue Oct 17, 2017 9:17 pm

Re: TIL Immunotherapy at NCI

Postby rachel2017 » Mon Dec 18, 2017 11:02 pm

INCLUSION CRITERIA:
...
b) Confirmation of G12V mutated KRAS, NRAS or HRAS by the Laboratory of Pathology of the NCI.
c) Patients must be HLA-A 1101 positive. [/i]

https://clinicalstudies.info.nih.gov/cg ... -0113.html

Thanks so much! My mom is KRAS G12D. The standard chemo (FOLFOX) didn't help her at all. On the contrary, the chemo made the seedings progressed aggressively. Since the lab doesn’t have enough tissue left, we still hesitate to do the pano genetic testing or not. We are from east Asia, so she may have HLA-A1101 alleles. I emailed the clinical coordinator today and wish she can have a chance to be screened.
DM 63. 11/16 colonoscopy (high dysplasia)
1/17 laparoscopic,6.5X4X3cm. Stage II. No chemo.
6/17 abdo pain. CEA 52. CT paracolic nodule 1.4X1.9cm
7/17 pet CT. Ascending colon 1.4X1.1cm SUV 2.4; midline scar 0.9cm SUV3.1
KRAS G12D
8/16/-9/26/17 Folfox 4 rounds
10/6/17 CT numorous perio seedings. ascending one 7cm; midline one 5.7cm.
10/16-1/5/2018 Folfox/avastin; 1/12/18 CT reviewed Slight progression
Stop chemo

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DH2Sleen
Posts: 72
Joined: Thu Jan 29, 2015 10:10 am

Re: TIL Immunotherapy at NCI

Postby DH2Sleen » Tue Dec 19, 2017 8:27 am

NHMike wrote:I believe that the NCI trial will work with either KRAS G12D or G12V but this is something that you should verify with them. One major note: the other trial that was only for KRAS G12D required HLA-C*0802 .

I would like to clarify a couple of things Mike said here.

NIH is currently recruiting for the TIL trial which Sleen did. No mutation or HLA restriction for this trial: NCT01174121

NIH is currently recruiting for NCT03190941 (also known as NIH 17-C-0113) in which only patients who have KRAS G12V and HLA-A11*01 can qualify. This is an Engineered T-Cell Receptor, Adoptive Cell Therapy (Engineered TCR ACT) immunotherapy treatment.

They have researched G12D with HLA-A11*01 in mice and think it is promising, but they are not ready to try this Engineered TCR ACT in humans yet. I think they are waiting for humans to prove the concept in NCT03190941.

They also think that Sleen's t-cells that responded to her mutation, G12D HLA-C08*02, could be developed into an Engineered TCR ACT treatment. But this is also not at the point where anyone should expect recruiting for a trial of this combination within the short-term.
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

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Sleen
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Re: TIL Immunotherapy at NCI

Postby Sleen » Tue Dec 19, 2017 10:04 am

A little about T-cells. I'm not a doctor, but I asked a lot of questions during and after the clinical trial.

Killer T-Cells (CD8+ cells) are a type of tumor-infiltrating lymphocyte. Each T-cell is designed to recognize one (and ONLY one) antigen (bad guy). The part of the T-cell doing the "recognizing" is the T-Cell receptor--each T-cell has thousands of receptors, all of them on a particular T-cell are programmed to recognize the same antigen.

T-cells become activated when they sense their target. Activated T-cells replicate themselves repeatedly, building up an army of killers that can wipe out invaders, even cancer.

An important aspect of Killer T-Cells (CD8+ cells) is that they can only recognize their target in the context of HLA. An HLA molecule has to essentially "hold onto" or "present" the T-Cell's target in order for the T-Cell to recognize it. When a doctor describes a mutation as "immunogenic" it means that the person's immune system recognizes that antigen.

Dr. Rosenberg's TIL trial (NCT01174121) requires surgery to remove a tumor. Why? Because they want to find THAT tumor's mutations, and to study THAT tumor's TIL. For trial NCT01174121 it makes no difference what HLA the patient has, nor what mutation. NCT01174121 uses the mutation and the HLA that is present in THAT patient. The key idea here is that the patient already has HLA and TIL that are fighting tumors. The trial is concerned with identifying which HLA and which mutation are already there, then go multiply that specific population of T-cells (TIL) and give it back to the patient. The patient receives their own T-cells--with their own receptors-- back.

Dr. Yang's trial (NCT03190941) does NOT require surgery to remove a tumor. Why? Because they already know what HLA and mutation worked in the mice. They intentionally studied mutations of RAS genes, and they used an HLA that they thought a high percentage of patients would carry (A*1101). Patients in this trial will get their own T-cells back, but the receptors on those T-cells will be from another source.

I hope this helps. Sneaky Tumor is a blog post I wrote that might make things more clear about how HLA works.

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 26 yrs. kids: 22, 19, 15, 10, 8
SE Michigan home schooler, unemployed mechanical engineer, and programmer.

rachel2017
Posts: 33
Joined: Tue Oct 17, 2017 9:17 pm

Re: TIL Immunotherapy at NCI

Postby rachel2017 » Tue Dec 19, 2017 10:49 pm

I hope this helps. Sneaky Tumor is a blog post I wrote that might make things more clear about how HLA works.

Celine[/quote]

Thank you so much! Celine! Wish you stay NED forever!
DM 63. 11/16 colonoscopy (high dysplasia)
1/17 laparoscopic,6.5X4X3cm. Stage II. No chemo.
6/17 abdo pain. CEA 52. CT paracolic nodule 1.4X1.9cm
7/17 pet CT. Ascending colon 1.4X1.1cm SUV 2.4; midline scar 0.9cm SUV3.1
KRAS G12D
8/16/-9/26/17 Folfox 4 rounds
10/6/17 CT numorous perio seedings. ascending one 7cm; midline one 5.7cm.
10/16-1/5/2018 Folfox/avastin; 1/12/18 CT reviewed Slight progression
Stop chemo

sdino
Posts: 52
Joined: Tue Mar 28, 2017 5:32 pm

Re: TIL Immunotherapy at NCI

Postby sdino » Thu Jan 11, 2018 12:19 pm

My Wife had lung wedge resection surgery this week 1/8/18 at NCI/NIH to harvest her TILs. Everything went well and today we will go home after she completes Aspheresis. Now we wait and see for 3 months if the harvested cells grow with the proper mutations. Incredible stuff going on down here in Bethesda, MD.
Caregiver for Wife 52 yrs old
DX:11/16-CC sigmoid colon
Lung Mets: Bilateral ranging 4mm-1.5cm
MSS, KRAS-mut G12D; TP53;
Completed 12 rounds Folfox/Avastin + Oxi 11/16 to 5/17, 8/17 Start Xeloda + Avastin
CT Scans: 5/17 colon & lung met shrinkage,11/17 and 1/18 slight progression lungs/colon
NCI YOUNGER TIL Trial NCT03412877 - 1/18 VATs lung surgery 2 mets wedge resect
CEA: 16 - 11/16; 0.6 - 5/17; 3.0 - 11/17; 4.4 - 1/18; 5.7 - 2/18; 4.9 - 3/18

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Sleen
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Re: TIL Immunotherapy at NCI

Postby Sleen » Thu Jan 11, 2018 1:29 pm

wooHOO! Glad to hear from you :)
Praying for good news from the lab!
Hope your wife's surgery recovery is quick and complication-free.

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 26 yrs. kids: 22, 19, 15, 10, 8
SE Michigan home schooler, unemployed mechanical engineer, and programmer.

Lee
Posts: 5506
Joined: Sun Apr 16, 2006 4:09 pm

Re: TIL Immunotherapy at NCI

Postby Lee » Thu Jan 11, 2018 3:30 pm

AWESOME! Here's hoping those harvested tumors give the medical team a lot of information to kick her cancer into the next universe.

Lee
rectal cancer - April 2004
46 yrs old at diagnoses
stage III C - 6/13 lymph positive
radiation - 6 weeks
surgery - August 2004/hernia repair 2014
permanent colostomy
chemo - FOLFOX
NED - 10 years and counting!

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Sleen
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Joined: Tue Jan 14, 2014 7:41 am
Location: Detroit
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Re: TIL Immunotherapy at NCI

Postby Sleen » Wed Jan 31, 2018 3:09 pm

I'm back to report on Follow-up #13. Lucky 13 :)

My scans show no signs of cancer! Bloodwork is good. Still NED.

They asked me to consent to a new study where they will do research on my T-cells. They'd like to figure out how to "turn back the clock" and revert them to a previous state, when they were stem cells. They want to know how/why my cells are behaving differently than some other patients' cells. I signed the papers--Patrick (DH2Sleen) signed as witness. I was assured that no apheresis would be necessary!

I got to meet another mCRC patient who will be starting the trial this week! Not sure if this person posts here or not.

The attending told us that they're working on changing the trial to use "young TIL" from the patients. They hope the young TIL will be more reactive. My understanding is that they'd use the patient's own T-cell receptors for this. I don't know the timeline for when this change is going to happen.

I'm due back in six months for follow-up 14.

Pro Tip: If you haven't yet tried Crystal Light powder in your iohexol, I highly recommend it. A very kind fellow-patient saved me from tossing my cookies in the CT waiting area on Monday by adding some flavor to my final cup of "juice". I know that some institutions use flavored slurries for their contrast, but NIH uses a clear, nasty-tasting (to me) watery contrast instead. It gets more and more difficult for me to swallow each time. I'll be packing Crystal Light from now on!

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 26 yrs. kids: 22, 19, 15, 10, 8
SE Michigan home schooler, unemployed mechanical engineer, and programmer.

DebZ
Posts: 78
Joined: Fri Nov 14, 2014 9:01 pm
Facebook Username: Bulc

Re: TIL Immunotherapy at NCI

Postby DebZ » Wed Jan 31, 2018 10:44 pm

I'm so happy to hear of your continued good health! You're very inspiring to those of us still in the trenches. It's been a pretty rough year with all our losses on this board, so good news and celebrations are a bright light!
48 @ diagnosis Sept 2014
MSS; Kras mutant G12D
Oct 2014: right hemicolectomy
Dec 2014: Folfox 12 treatments (lots of reductions in oxaliplatin and ceased before end)
June 2015: clean scans
Sept 2015: scans reveal ovarian mass and liver met; Folfiri
Jan 2016: liver wedge resection and complete hysterectomy
April 2016: multiple lung mets; Folfiri+Avastin
June 2017: lung mets growing; switching to Folfox+Avastin

sdino
Posts: 52
Joined: Tue Mar 28, 2017 5:32 pm

Re: TIL Immunotherapy at NCI

Postby sdino » Fri Feb 02, 2018 7:51 am

What I found on "Young" TILs -
This led to the development by Dudley et al in 2010 of a streamlined “Young TIL” protocol that pools lymphocytes from multiple tumor fragments, without additional selection, to obtain the cell number needed prior to rapid expansion, shortening the time compared with that of growing cells from individual microcultures to sufficient numbers [15]. By minimizing the time in culture, this new method enriched for TIL with an earlier differentiation stage with higher expression of CD27 and CD28 and longer telomeres. Svane and colleagues in Denmark performed a side-by-side comparison of ‘standard’ TIL and ‘young’ TIL in 2011 and also found a higher expression of CD27 and longer telomeres [29]. Their average time to establishment of TIL culture, prior to the 14-day rapid expansion step, was approximately 25 days for ‘young’ TIL vs 45 days for standard TIL. This faster production time also carries significant clinical impact by decreasing the numbers of patients who become ineligible for treatment due to rapid disease progression and clinical decline during the period of TIL generation.

So...
1. So they want to grow Cells in a faster pace.
2. Since they do # 1 ABOVE, do they also accelerate the introduction of these Cells in a quicker timetable back into the patient ? - or is it mutually exclusive of lab cell growth ?
Caregiver for Wife 52 yrs old
DX:11/16-CC sigmoid colon
Lung Mets: Bilateral ranging 4mm-1.5cm
MSS, KRAS-mut G12D; TP53;
Completed 12 rounds Folfox/Avastin + Oxi 11/16 to 5/17, 8/17 Start Xeloda + Avastin
CT Scans: 5/17 colon & lung met shrinkage,11/17 and 1/18 slight progression lungs/colon
NCI YOUNGER TIL Trial NCT03412877 - 1/18 VATs lung surgery 2 mets wedge resect
CEA: 16 - 11/16; 0.6 - 5/17; 3.0 - 11/17; 4.4 - 1/18; 5.7 - 2/18; 4.9 - 3/18

Lee
Posts: 5506
Joined: Sun Apr 16, 2006 4:09 pm

Re: TIL Immunotherapy at NCI

Postby Lee » Fri Feb 02, 2018 5:33 pm

Celine,

CONGRATULATIONS on your continued NED status.

May you always reside in NEDville,

Lee
rectal cancer - April 2004
46 yrs old at diagnoses
stage III C - 6/13 lymph positive
radiation - 6 weeks
surgery - August 2004/hernia repair 2014
permanent colostomy
chemo - FOLFOX
NED - 10 years and counting!

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Sleen
Posts: 307
Joined: Tue Jan 14, 2014 7:41 am
Location: Detroit
Contact:

Re: TIL Immunotherapy at NCI

Postby Sleen » Sat Feb 03, 2018 7:31 am

Thanks, Lee!

c.
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 26 yrs. kids: 22, 19, 15, 10, 8
SE Michigan home schooler, unemployed mechanical engineer, and programmer.

DAS43
Posts: 44
Joined: Thu Aug 18, 2016 8:10 pm

Re: TIL Immunotherapy at NCI

Postby DAS43 » Sat Feb 03, 2018 9:15 am

Great news Celine!
Have you heard any news/reports on number of successes with the trail? I believe more people would try it if they would publish some results.
11/13 total blockage DX colon cancer IV, colostomy
1/14 folfox
3/14 liver resection NED
8/14 last chemo
12/14 colostomy reversal
8/16 3mets to lungs
10/16 trial at NIH TIL
9/17 partial responder to TIL protocol


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