Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... post)

Please feel free to read, share your thoughts, your stories and connect with others!
User avatar
DK37
Posts: 510
Joined: Tue Sep 17, 2013 8:31 am
Location: San Diego

Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... post)

Postby DK37 » Fri Aug 21, 2015 8:23 am

Thanks Jortego128 for posting the Bavituximab Rectal cancer information yesterday.

Although it remains to be seen if anti-phosphatidylserine therapy will be "the winner" co-therapy with anti-PD-1 for CRC, this is EXACTLY the "general strategy" I think will be at least one of the ways that CRC gets over the finish line in terms of successful immunotherapies. As mentioned in my Currently Incurable post ( http://fightcolorectalcancer.org/resear ... ot-part-1/ )- the problem with CRC and checkpoint inhibition is that the tumor microenvironment (the "neighborhood" surrounding the tumor) is so damn immunosuppressive in MSS CRC, simple checkpoint inhibition just can't break through. My favorite analogy is in that post, there are just piles of signals coming off the tumor like the raging current of a river pushing away immune cells from doing their job. I believe what MSS CRC is going to need (at least to get high response rates) is a cocktail of drugs - adding in a drug(s) that stop that immunosuppression to allow PD-1 inhibitors to do their job. Another example strategy along these lines is anti-CSF1 e.g. the trial NCT02526017.

This broad class of anti-immunosuppresion drugs (anti-PS is one example) is probably the single largest area of immunooncology research right now. Every company is working on them. What is envisioned is that anti-PD1 drugs will be the future "backbone" therapy for an incredibly wide assortment of cancers - then individual cancer types will have other drugs added on to either allow success (e.g. in the case of MSS CRC) or in the case of the relatively easy cancers for immunotherapies (which see responses from PD-1 monotherapy - e.g. lung, melanoma, rectal, MSI CRC etc) - these combinations hopefully will allow an even larger majority of patients to respond with durable responses.

In addition to 1.) anti-PD-1 and 2.) anti-immunosuppression, a third component will likely be a drug which teaches the immune system what to look for. This could be a cancer vaccine, an oncolytic virus, or something that causes the cancer cell to die in a fashion which spills its guts in a way the immune system easily sees them - radiotherapy killing is one example of that kind of killing in addition to some types of old fashioned chemo & targetted therapies. That is the scientific rationale behind Peregrine's rectal cancer radiotherapy study. It could really go either way why they haven't announced results yet - but fingers crossed.

There is a good chance that a fourth key component to really do a wide based knock-out punch of cancer will involve activation of the innate immune system - but instead of confusing things, I'll post about that some other time ;)

This is behind the HUNDREDS of PD-1 co-therapy trials going on right now in parallel with the entire industry working together (I have never seen anything like it!). A lot of combos work great in mice, it takes clinical trials to see what works in humans. Not all will work but there are so many "shots on goal" I am sure at least one will for MSS CRC!

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

Ceebo
Posts: 132
Joined: Sat Feb 14, 2015 9:15 am
Location: Southwest Michigan

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby Ceebo » Fri Aug 21, 2015 9:02 am

Great information! Thanks for continuing to take time to share this valuable information!!
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

User avatar
Nik Colon
Posts: 5210
Joined: Thu Jan 08, 2015 3:35 pm
Location: MN

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby Nik Colon » Fri Aug 21, 2015 10:43 am

Thanks again 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

JENNJ
Posts: 115
Joined: Tue Feb 17, 2015 8:00 pm

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby JENNJ » Fri Aug 21, 2015 11:44 am

Thank you so much for the info. As soon as any results are released, could you please share them? My Dad is MSS and we are already looking for more treatments/clinical trials.
Katy

jortego128
Posts: 284
Joined: Sat Aug 15, 2015 7:47 am

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby jortego128 » Fri Aug 21, 2015 3:27 pm

Thanks for the response DK. It really does seem like almost every biotech/pharma out there are going all out in pursuit of a magic bullet for solid-tumor cancers. Like you, I also think its just a matter of time before we have our own "Gleevec". I just hope it comes sooner rather than later.

On that note--have you heard about the vaccine ETBX-011 that Etubics Corporation in Seattle has used to "more than DOUBLE the lifespan of advanced stage colorectal cancer patients"? Not only that, but they are now partnering with NCI who is giving them two more drugs to use with their vaccine that they expect to make it even more effective.

For such an incredible claim, you would think there would be more buzz about this. I had seen the posting a while back in mid-July, then I could not find it again, but I just found it today, and an even newer August 5 update from Etubics. There seems to have been a recent flurry of press releases and activity since June of this year. According to their press releases, their Phase 2b randomized clinical trial is slated to be initiated in the first half of 2016 (Contract#: HHSN261201100097C).

http://etubics.com/news-press-releases/ ... -patients/

http://www.statesman.com/news/news/nati ... cy-/nmrFz/
http://www.kirotv.com/news/news/seattle ... cy-/nmqtp/

What do you make of this? Is this the real deal? On paper, it sounds like the biggest breakthrough since Avastin(much bigger, even)-- one can only hope this is not just more hype than substance.
Last edited by jortego128 on Fri Aug 21, 2015 3:49 pm, edited 1 time in total.
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

User avatar
DK37
Posts: 510
Joined: Tue Sep 17, 2013 8:31 am
Location: San Diego

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby DK37 » Fri Aug 21, 2015 3:47 pm

KMSGJP wrote:As soon as any results are released, could you please share them? My Dad is MSS and we are already looking for more treatments/clinical trials.
Katy


Most definitely Katy, Colon Talk is the first place I post new publications I see that I think could be of interest :)

-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

rp1954
Posts: 1379
Joined: Mon Jun 13, 2011 1:13 am

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby rp1954 » Tue Aug 25, 2015 10:46 am

DK37 wrote: ...the problem with CRC and checkpoint inhibition is that the tumor microenvironment (the "neighborhood" surrounding the tumor) is so damn immunosuppressive in MSS CRC, simple checkpoint inhibition just can't break through.


I don't see much directly published about linkage/correlation between histamine and MSS and immunosuppression since Eaton's comment in Nature (2002).

At our house, we assume excess histamine or H2 receptor expression associates with immunosuppression or other unfavorable modulations associated with CRC positive for both CA19-9 and CSLEX1, as seem to be common co-occurrences for advanced CRC, and nuke them with cimetidine and IV vitamin C + C metabolites. Mixed along with other integrative practices for molecular inhibition and immunomodulation.
watchful, active caregiver for stage IVb CC since early 2010. immuno"Chemo forever," for mCRC

jortego128
Posts: 284
Joined: Sat Aug 15, 2015 7:47 am

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby jortego128 » Tue Aug 25, 2015 3:38 pm

Peregrine and AstraZeneca have announced they are collaborating on an Immuno-Oncology combination clinical trial for solid-tumor cancers using Peregrines PS inhibitor Bavituximab in combination with AZ's anti-PD-L1 immune checkpoint inhibitor, durvalumab. No word on trial dates/enrollment yet.

The buzz around these combination therapies is that they are the next step towards finding more effective treatments.

http://ir.peregrineinc.com/releasedetai ... eID=928488
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

User avatar
DK37
Posts: 510
Joined: Tue Sep 17, 2013 8:31 am
Location: San Diego

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby DK37 » Tue Aug 25, 2015 4:28 pm

jortego128 wrote:Peregrine and AstraZeneca have announced they are collaborating on an Immuno-Oncology combination clinical trial for solid-tumor cancers using Peregrines PS inhibitor Bavituximab in combination with AZ's anti-PD-L1 immune checkpoint inhibitor, durvalumab. No word on trial dates/enrollment yet.

The buzz around these combination therapies is that they are the next step towards finding more effective treatments.

http://ir.peregrineinc.com/releasedetai ... eID=928488


Awesome news Jortego! Fingers crossed......

-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

User avatar
DK37
Posts: 510
Joined: Tue Sep 17, 2013 8:31 am
Location: San Diego

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby DK37 » Fri Aug 28, 2015 1:38 pm

No mention of CRC specifically (in the news release, I haven't seen the actual presentation) but as an addition to the anti-PS (Bavituximab) thread initiated by Jortego128 - this scientific presentation was made this week, news release pasted below. Explains the timing of the combo therapy development deal earlier in the week...

-DK

http://ir.peregrineinc.com/releasedetai ... eID=928906

August 26, 2015

Peregrine Pharmaceuticals Presents Data at Annual Immunotherapy and Vaccine Summit (ImVacS) Supporting Ability of Bavituximab to Mediate Anti-Tumor T Cell Responses Across Multiple Tumor Types

- Increasing Activated T Cells in Tumors Demonstrates Potential Complement to anti-PD-1 and anti-PD-L1 Checkpoint Inhibitors -
- Clinical and Preclinical Studies Demonstrate Estimated Survival Curves that Plateau -

TUSTIN, Calif., Aug. 26, 2015 (GLOBE NEWSWIRE) -- Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company focused on developing therapeutics to stimulate the body's immune system to fight cancer, today announced the presentation of a range of clinical, translational and pre-clinical study results highlighting the ability of bavituximab, Peregrine's investigational phosphatidylserine (PS)-signaling pathway inhibitor, to promote anti-tumor T cell mediated activity in several tumor types. The data were presented today by Jeff T. Hutchins, Ph.D., vice president, preclinical research at Peregrine Pharmaceuticals and chairperson of the Combination Immunotherapy Strategies session at the 10th Annual Immunotherapy and Vaccine Summit (ImVacS), being held August 24-28, 2015 in Boston, Massachusetts.

Bavituximab is an investigational immunotherapy designed to assist the body's immune system by targeting and modulating the activity of phosphatidylserine (PS), a highly immune-suppressive signaling molecule expressed broadly on the surface of cells in the tumor microenvironment. Peregrine's PS signaling pathway inhibitor candidates, including bavituximab, reverse the immunosuppressive environment that many tumors establish in order to proliferate and fight cancer by activating macrophages and cytotoxic T cells in tumors. Preclinical data demonstrate that combining the enhanced T cell anti-tumor activity of bavituximab-like antibodies with checkpoint inhibitors, such as anti-PD-1 antibodies, results in significantly improved tumor control in multiple models of cancer.

Dr. Hutchins' presentation highlighted key findings from several recent bavituximab-focused studies including:
The potential of bavituximab to shift the tumor microenvironment from immuno-suppressive in which tumors evade immune detection to a state of immune activation in which the immune system recognizes and fights the tumor. Presented findings demonstrate that bavituximab-like antibodies significantly increase the prevalence of tumor infiltrating CD8+ T-cells and immune-activating cytokines, while decreasing macrophages and myeloid cells that allow the tumor to evade immune detection. This elucidation and confirmation of bavituximab's mechanism of action highlights the potential of bavituximab to enhance the anti-tumor effects of both chemotherapy and immune checkpoint inhibitors.

Bavituximab increases the number of activated CD8+ cells in the tumor, which stimulates PD-1 expression, thereby upregulating the target for checkpoint inhibitors such as anti-PD-1 and anti-PD-L1.

Importantly, translational study data across multiple cancers indicated that tumors with low PD-L1 or PD-1 expression on tumor infiltrating T cells showed promising signs of immune activation after treatment with bavituximab. This suggests the potential for bavituximab to activate a tumor specific immune response in patients with PD-L1 negative tumors that generally do not respond as well to PD-1 and PD-L1 inhibitors. By doing so, it is believed that bavituximab may hold potential to increase the number of patients able to respond to PD-1 and PD-L1 targeting immunotherapies.

Furthermore, the combination of bavituximab-like antibodies and anti-PD-1 antibodies resulted in enhanced, synergistic anti-tumor activity in animal models of multiple tumor types, as compared to either agent alone. In some cases, complete tumor regressions were achieved, highlighting the anti-tumor potential of bavituximab in combination with checkpoint inhibitors such as anti-PD-1 antibodies.

Results from several clinical and preclinical studies in a range of tumor types show that bavituximab and bavituximab-like antibodies, in combination with conventional therapy, have consistently demonstrated estimated survival curves that plateau.

"We continue to generate a broad collection of pre-clinical, translational and clinical data highlighting bavituximab's novel mechanism of action and synergistic activity for a range of combination treatments. These study results, particularly as they relate to the potential synergies between bavituximab and checkpoint inhibitors, create great excitement for us as we begin work with our new collaborators at Memorial Sloan Kettering Cancer Center and AstraZeneca, while continuing our long-standing relationship with the University of Texas Southwestern Medical Center where this technology was originally developed," said Dr. Hutchins. "By aligning with these world leaders in cancer immunotherapy to study novel immuno-oncology combination therapies, we are best positioning ourselves to maximize the potential role that bavituximab can play in this new era of innovative cancer treatments."
About Bavituximab: A Targeted Investigational Immunotherapy

Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab, the lead compound in Peregrine's immuno-oncology development program, blocks PS to alter this immunosuppressive signal and sends an immune activating signal. Targeting PS with bavituximab has been shown to shift the functions of immune cells in tumors, resulting in anti-tumor immune responses.

About Peregrine Pharmaceuticals, Inc.
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a pipeline of novel drug candidates in clinical trials focused on the treatment of cancer. The company's lead immunotherapy candidate, bavituximab, is in Phase III development for the treatment of second-line non-small lung cancer (the "SUNRISE trial") along with several investigator-sponsored trials evaluating other treatment combinations and additional oncology indications. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (http://www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and third-party customers. For more information, please visit http://www.peregrineinc.com.
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

jortego128
Posts: 284
Joined: Sat Aug 15, 2015 7:47 am

Re: Anti-Immunosuppression PD-1 Co-therapies for CRC (Reply to Jortego128’s Bavituximab for Rectal Adenocarcinoma... pos

Postby jortego128 » Fri Aug 28, 2015 3:32 pm

Yeah, saw that a few days ago, but never got around to posting.

Sounds promising, at least on the surface. They are saying they believe using Bavituximab in combination with Keytruda or Opdivo -type PD-L1 antibodies may trigger an immune response to the cancer even in MSS patients. That would be incredible, but Im reserving my excitement until we get some actual results. I'd like nothing more than to see this happen, but they need to get a move on-- they've been dabbling with Bavituximab for 5 years now. To be fair though, they may have not had the PD-L1 drugs to test it with until recently.


I had invested some money into Peregrine a year or two ago, and I still keep tabs on them. I sold the stock at a moderate loss, had I held on for a few more months I would have made a very nice gain.
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


Return to “Colon Talk - Colon cancer (colorectal cancer) support forum”



Who is online

Users browsing this forum: Nohogirl and 28 guests