New CRC Immunotherapy Paper: PD-L1 + ITK Inhibitors

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DK37
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New CRC Immunotherapy Paper: PD-L1 + ITK Inhibitors

Postby DK37 » Fri Feb 20, 2015 6:49 pm

Even though this is a pre-clinical paper and has not been tested in clinical trials yet, I wanted to let you know about a very interesting CRC immunotherapy paper published in the Proceedings of the National Academy of Sciences this week that I think has a decent chance of translating into a CRC clinical trial.

As most of you know, PD1 monotherapy has unfortunately not shown much success against CRC in the clinic although these inhibitors are immunotherapy miracle drugs for some other types of cancer, producing very long remissions in some patients.

I won’t go into all of the scientific details (the paper’s abstract is pasted below, PM if you have questions) but basically what the paper did was co-dose a FDA-approved drug (ibrutinib) along with a PD-L1 inhibitor. Ibrutinib was designed to be a “BTK inhibitor” and is FDA-approved for mantle cell lymphoma and chronic lymphocytic leukemia (http://en.wikipedia.org/wiki/Ibrutinib). Although it was designed to be a “BTK inhibitor”, like most drugs it is not completely selective for a single target and it also hits the “ITK” target. “ITK” is a target whose inhibition has impacts on immune system T-cells.

The paper shows that by co-dosing ibrutinib along with a PD-L1 checkpoint inhibitor, significant activity is seen not only in lymphomas but also in two solid tumor models (triple negative breast and CRC). In the case of the CRC model, dosing with the co-therapy was synergistic and about 30% of the mice were cured. At a later time point, the authors attempted to regrown the tumor lines in the cured mice and they were resistant – indicating successful immune memory.
Of course, cancer is easier to cure in mice than humans but I do believe this is potentially a step forward in CRC immunotherapy research and worth keeping an eye on in terms of potential future clinical trials!

I honestly believe eventually checkpoint inhibitor therapy will be successful in CRC as it has been in other cancers, it will just require the identification of a proper co-dosing drug cocktail – perhaps an ITK inhibitor is the trick needed, perhaps not… – only clinical trials will tell. A nice aspect of this current research is that it involves 2 drugs which are either FDA-approved or almost FDA-approved – so an almost ideal situation for a potential quick start of clinical testing.

Take care everyone,
-DK

http://www.pnas.org/content/early/2015/02/09/1500712112.abstract

Abstract
Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti–PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.

Significance
Antibodies that block the negative signals between PD1-Ligand on tumor cells and PD-1 on T cells are effective therapies against several types of cancer. Ibrutinib, a covalent inhibitor of BTK is an approved therapy for B-cell leukemia and lymphoma. But ibrutinib also inactivates ITK, an enzyme required for certain subsets of T lymphocytes (Th2 T cells). We found that the combination of anti–PD-L1 antibodies and ibrutinib led to impressive therapeutic effects not only in animal models of lymphoma but, surprisingly, also in models of breast cancer and colon cancer. Based on these preclinical results, we suggest that the combination of PD-1/PD-L1 blockade and ibrutinib be tested broadly in patients with lymphoma and also in other hematologic malignancies and solid tumors.
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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GrouseMan
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Re: New CRC Immunotherapy Paper: PD-L1 + ITK Inhibitors

Postby GrouseMan » Sat Feb 21, 2015 12:26 am

Very interesting indeed! I find the experiment, where in they try to implant and grow up tumors again in the "cured" mice to be a very significant experiment. I agree, this by all rights should be fast tracked. Drug supplies are available. The individual drugs safety and PK/PD profile is known, so an abbreviated Phase I trial quickly into a well designed Phase II one could likely be put together rather quickly if funding could be found. I hope so.

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

User avatar
DK37
Posts: 510
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Location: San Diego

Re: New CRC Immunotherapy Paper: PD-L1 + ITK Inhibitors

Postby DK37 » Sat Feb 21, 2015 1:18 am

GrouseMan wrote:Very interesting indeed! I find the experiment, where in they try to implant and grow up tumors again in the "cured" mice to be a very significant experiment. I agree, this by all rights should be fast tracked. Drug supplies are available. The individual drugs safety and PK/PD profile is known, so an abbreviated Phase I trial quickly into a well designed Phase II one could likely be put together rather quickly if funding could be found. I hope so.

GrouseMan


I agree GrouseMan! In terms of funding, this is a potential large market expansion of both on-patent ibrutinib and checkpoint inhibitors, so from a financial point of view I am sure money will not be a bottleneck for this particular clinical trial!
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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