Replies to post #184063 on Avid Bioservices Inc (CDMO)

[geocappy1]

I thought SK said no biopsies with Sunrise trial. I will feel better when Gabrilovich mentions pphm by name.

[biopharm]

the bottom line, Dmitry is the MD talking MDSC's and MDSC's "CAN" predict overall survival

its funny how its been KOL Dmitry Gabrilovich, whom continues to directly relate how MDSC's is the hidden link to support that surrogate endpoint of overall survival and Bristol Myers Squibb had prior ties already moving in this direction ...

MDSC-based Blood Test for Predicting Response to Cancer Therapy Commercialized by Serametrix

Nov 19, 2013

The test was developed at New York’s Memorial Sloan-Kettering Cancer Center under the direction of Drs. Jedd Wolchok and Alex Lesokhin.

http://www.serametrix.com/Press-Releases/mdsc-blood-test.html

... and Dr. Jedd Wolchock has been a longtime direct tie to BMS...

http://cancerimmunolres.aacrjournals.org/content/early/2014/06/30/2326-6066.CIR-14-0013.abstract

Memorial Sloan Kettering Researchers Report on Major Advances in the Treatment of Metastatic Eye and Skin Melanoma

June 3, 2013

“We pursued the ipilimumab and nivolumab combination because they each impact the immune system in a distinct but complementary way,” says Dr. Wolchok. “Ipilimumab activates a person’s immune system, prompting their T cells to begin attacking the tumor, while nivolumab further activates those T cells in a different manner, allowing them to continue the attack.”

Previous studies had shown that ipilimumab alone could prolong overall survival in advanced melanoma patients, and nivolumab alone could produce durable tumor responses in melanoma and other cancers. Combining the drugs was “quite logical,” Dr. Wolchok adds, and well supported by preclinical and clinical trial data.

http://www.mskcc.org/blog/msk-researchers-report-major-advances-treatment-metastatic-eye-and-skin-melanoma

I wonder how Vaccinations will work out with Bavituximab and PS Targeting..... which possibly are clearly improving the MDSC's..etc and bloodwork that Dr. Jedd Wolchok must be aware of....

Endogenous and Exogenous Vaccination in the
Context of Immunologic Checkpoint Blockade

Dr. Jedd Wolchok

Disclosure
• Consultant: Bristol-Myers Squibb

http://www.sitcancer.org/meetings/am10/presentations/index.php?filename=Wolchok_AM10_secure.pdf

The purpse of this post is simply to show Dr. Jedd Wolchok clearly already knows of the importance of MDSC's and how it can be used as a surrogate endpoint that links to overall survival..... just as Peregrine KOL Dmitry Gabrilovich is in the middle of clearly showing. Further... Dr Jedd Wolchok seen with his ties to "Serametrix" out of San Diego and bloodwork to check for MDSC's ....

Bloodtests for overall MDSC's or subparts..etc are coming and how long before its going to be announced is the question?

[biopharm]

Dmitry Gabrilovich : Peregrine Pharmaceuticals KOL :

Dmitry is the expert on MDSC's and just posting the main MDSC page from Wiki as it was just updated August 5, 2014 and this will be guaranteed to change over the next month or two

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MDSC (myeloid-derived suppressor cells) are a heterogenous population of immune cells from the myeloid lineage, to which dendritic cells, macrophages and neutrophils also belong. These cells possess strong immunosuppressive activities. The word "myeloid" was originated from Greek language ("Myelos" +"eidos"), meaning "bone marrow" or "spinal cord". "Myeloid lineage" is a cluster of different cell types that all originated from bone marrow stem cells. Although bearing a diverged path of development than T cells, which were originated from thyroid, myeloid lineage cells interacts with T cells in many functional mechanisms, some of which, are still under heated debate and close examination in scientific community.

MDSC are usually defined in mouse models as myeloid cells expressing high levels of CD11b and GR1, which exhibit potent T cell inhibitory activities. In human, MDSC are generally defined as expressing high levels of CD33, CD11b. However, it remains to be resolved as there are no international consensus on how human subsets of MDSC should be defined. [1]

Generally speaking, regardless of whether they are from mice or human, MDSC cells' suppressor function lies in their ability to inhibit T cell proliferation and activation. In healthy individuals, immature myeloid cells formed in the bone marrow differentiated to dendritic cells, macrophages and neutrophils. However, under chronic inflammatory conditions (viral and bacterial infections) or cancer, myeloid differentiation is skewed towards the expansion of MDSCs. These MDSCs infiltrate inflammation sites and tumors, where they stop immune responses by inhibiting T cells and NK cells, for example. MDSCs also accelerate angiogenesis, tumor progression and metastasis. Therefore, they have become a key therapeutic target.

Clinical and experimental evidence has shown that cancer tissues with high in?ltration of MDSC are associated with poor patient prognosis and resistance to therapies.[2][3][4][5]

It has been shown that the c/EBPß transcription factor plays a key role in the generation of in vitro bone marrow-derived and in vivo tumor-induced MDSC. Moreover, STAT3 promotes MDSC differentiation and expansion and IRF8 has been suggested to counterbalance MDSC-inducing signals. [2]

Cytokines are key signals involved in the generation of MDSC. Tumor cell lines overexpressing colony stimulating factors (e.g. G-CSF and GM-CSF) have long been used in in vivo models of MDSC generation. GM-CSF, G-CSF and IL-6 allow the in vitro generation of MDSC that retain their suppressive function in vivo. In addition to CSF, other cytokines such as IL-6, IL-10, VEGF, PGE2 and IL-1 have been implicated in the development and regulation of MDSC.[2][6]

MDSC activity was originally described as suppressors of T cells, in particular of CD8+ T-cell responses. the spectrum of action of MDSC activity also encompasses NK cells, dendritic cells and macrophages. Suppressor activity of MDSC is determined by their ability to inhibit the effector function of lymphocytes. Inhibition can be caused different mechanisms. It is primarily attributed to the effects of the metabolism of L-arginine. Another important factor influencing the activity of MDSC is oppressive ROS.[2][7]

In addition to host-derived factors, pharmacologic agents also have profound impact on MDSC. Chemotherapeutic agents belonging to different classes have been reported to inhibit MDSC. Although this effect may well be secondary to inhibition of hematopoietic progenitors, there may be grounds for search of selectivity based on long-known differential effects of these agents on immunocompetent cells and macrophages.[2]

The rapidly accumulating new information has shed new light on molecular pathways and diversity of MDSC. As usual, new evidence raises new questions or revisits old questions.[2]
References

Poschke et al, (2012) "On the armament and appearance of human myeloid-derived suppressor cells". Clinical Immunology doi 10.1016/j.clim.2012.06.003
Mantovani, Alberto (1 December 2010). "The growing diversity and spectrum of action of myeloid-derived suppressor cells". European Journal of Immunology 40 (12): 3317–3320. doi:10.1002/eji.201041170.
Allavena, P.; Mantovani, A. (1 February 2012). "Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment". Clinical & Experimental Immunology 167 (2): 195–205. doi:10.1111/j.1365-2249.2011.04515.x.
Galdiero, Maria Rosaria; Bonavita, Eduardo; Barajon, Isabella; Garlanda, Cecilia; Mantovani, Alberto; Jaillon, Sébastien (1 November 2013). "Tumor associated macrophages and neutrophils in cancer". Immunobiology 218 (11): 1402–1410. doi:10.1016/j.imbio.2013.06.003.
Gabrilovich, Dmitry I.; Ostrand-Rosenberg, Suzanne; Bronte, Vincenzo (21 March 2012). "Coordinated regulation of myeloid cells by tumours". Nature Reviews Immunology 12 (4): 253–268. doi:10.1038/nri3175.
Gros, A.; Turcotte, S.; Wunderlich, J. R.; Ahmadzadeh, M.; Dudley, M. E.; Rosenberg, S. A. (26 July 2012). "Myeloid Cells Obtained from the Blood but Not from the Tumor Can Suppress T-cell Proliferation in Patients with Melanoma". Clinical Cancer Research 18 (19): 5212–5223. doi:10.1158/1078-0432.CCR-12-1108.
Kusmartsev, S; Nefedova, Y; Yoder, D; Gabrilovich, DI (Jan 15, 2004). "Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.". Journal of immunology (Baltimore, Md. : 1950) 172 (2): 989–99. PMID 14707072.

http://en.wikipedia.org/wiki/Myeloid-derived_Suppressor_Cell

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Remember... Dmitry is just now speaking out much more vocally, regarding MDSC's, as in his last presentation.

1st Annual Summit on Practical Applications of Immune and Oncolytic Therapies in Oncology

The role of myeloid-derived suppressor cells as a therapeutic target

.... now the entire presentation you need to watch. Dmitry even gets the crowd laughing a bit at the end : ) though, I like the part leading up to the 8 min mark:

:MDSC as predictors of clinical outcome in cancer:

Melanoma:

* Clinical responders to ipilimumab therapy showed significantly less MDSC as compared to non-responders. MDSC may be used as predictive marker of response

* Frequency of MDSC correlated with disease progression and decreased overall survival.

* ....
....

[biopharm]

the bottom line, Dmitry is the MD talking MDSC's and MDSC's "CAN" predict overall survival and he starts off the video with some general talking points re: leucocytes/neutrophils .. immune system..etc before showing in various cancer indications-- its MDSC's that speak the truth about overall survival.

Do I really think the the DMC will allow SunRise to go further than it needs to, once PS Targeting is proven to fall directly inline with positioning MDSC's on that path of a positive overall survival? Nope
...
...
I believe Dmitry is playing a major role in solidifying the changes that take place regarding our immune systems and most likely this will all play a part in some blood test to test for cancer in general due to many changes... some involving white blood cells aka = leucocytes (which there are 5 types)

1) Neutrophils
2) Eosinophils
3) Basophils
4) Monocytes
5) Lymphocytes - just will expand on this for now..

if one gets confused about the various white blood cells = leucocytes, here is a short video that explains some of the functions / side effects below:

Dr. Susan Leclair explains why we should take a minute to understand eos (eosinphils), basos (basophils) and monos (monocytes) and what they indicate in your lab results. Why do basos fluctuate? Why do we see an increase in eos in some myeloproliferative diseases? Dr. Leclair gives a concise illustrative overview of these white cells and what they mean for your health and well-being.

Eosinophils, Basophils and Monocytes: What Do These Lab Results Mean?

http://www.patientpower.info/video/eosinophils-basophils-and-monocytes-what-do-these-lab-results-mean

....the above comes from "Patient Power.." and David Carbone and Scott Antonia (both Peregrine KOL's) have a couple videos each on the site:

http://www.patientpower.info/lung-cancer/understanding

[biopharm]

Must See Presentation..Dmitry Gabrilovich : Peregrine Pharmaceuticals KOL :
..
..

I believe Dmitry is playing a major role in solidifying the changes that take place regarding our immune systems and most likely this will all play a part in some blood test to test for cancer in general due to many changes... some involving white blood cells aka = leucocytes (which there are 5 types)

1) Neutrophils
2) Eosinophils
3) Basophils
4) Monocytes
5) Lymphocytes - just will expand on this for now..

Two main types of lymphocytes are B-cells and T-cells. B-cells are characterized by the presence of immunoglobulins on their surface, and upon stimulation with antigen, they are transformed into plasma cells. Plasma cells are then able to secrete antibodies specific to the antigen. T-cells take part in cell mediated immune response, which does not depend on the presence of circulating antibodies.

Dmitry Gabrilovich has been on board ship Peregrine for quite some time and it looks like other groups are finally beginning to start spreading their own publications...and how much data does Peregrine have surrounding MDSC's ???

-------------

Neutrophil-to-Lymphocyte Ratio Predicts PSA Response and Prognosis in Prostate Cancer: A Systematic Review and Meta-Analysis


Jian Cao ,
Xuan Zhu ,
Xiaokun Zhao,
Xue-Feng Li,
Ran Xu

PLOS

Published: July 1, 2016
dx.doi.org/10.1371/journal.pone.0158770

Abstract

An unprecedented advance has been seen in castration-resistant prostate cancer (CRPC) treatments in the past few years. With a number of novel agents were approved, there is a pressing need to develop improved prognostic biomarkers to facilitate the personalised selection and sequencing of these novel agents. Emerging evidence indicates that the neutrophil-to-lymphocyte ratio (NLR) is associated with poorer survival in patients with prostate cancer (PCa). However, the importance of the NLR for the prediction of the PSA response (PSARS) and biochemical recurrence (BCR) has been largely neglected. Here, we conducted a systematic review and meta-analysis to evaluate the prognostic value of the NLR for the PSARS, BCR, and survival in PCa. A systematic database search was performed using Embase, PubMed, the Cochrane Library, and the China National Knowledge Infrastructure (CNKI). A meta-analysis was performed by pooling hazard ratios (HRs), odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). A total of 22 studies were included in the meta-analysis. Our results suggest that an elevated NLR predicts a lower PSARS rate (OR = 1.69, 95% CI: 1.40–1.98) and a higher possibility of BCR (HR = 1.12, 95% CI: 1.02–1.21). Additionally, we confirmed that an elevated NLR was a prognostic predictor of shorter overall survival (OS) in both metastatic castration-resistant PCa (mCRPC) (HR = 1.45, 95% CI: 1.32–1.59) and localized PCa (LPC) (HR = 1.12, 95% CI: 1.01–1.23) and that it predicted worse progression-free survival (PFS) in CRPC (HR = 1.42, 95% CI: 1.23–1.61) and poorer recurrence-free survival (RFS) (HR = 1.38, 95%CI: 1.01–1.75) in LPC. Our results suggest that an elevated NLR might be employed as a prognostic marker of biochemical changes and prognosis to facilitate risk stratification and decision making for individual treatment of PCa patients. The potential mechanisms underlying these associations and future research directions are also discussed.

http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0158770

[biopharm]

Must See Presentation..Dmitry Gabrilovich : Peregrine Pharmaceuticals KOL :

... the bottom line, Dmitry is the MD talking MDSC's and MDSC's "CAN" predict overall survival and he starts off the video with some general talking points re: leucocytes/neutrophils .. immune system..etc before showing in various cancer indications-- its MDSC's that speak the truth about overall survival.

if one has not seen the prior video with Dmitry Gabrilovich then you should ...because it looks like we are on the verge of breaking out with news that MDSC's is a valid FDA biomarker, especially when we see that many others are seeing the same, statistically significant results.

-----------------------------------------------------

Myeloid-derived suppressor cells may serve as biomarkers for idiopathic pulmonary fibrosis

Sept 2, 2016

Researchers at Helmholtz Zentrum München, a partner in the German Center for Lung Research (DZL), have discovered that the number of myeloid-derived suppressor cells (MDSC) is increased in the blood of patients with idiopathic pulmonary fibrosis (IPF). The higher the number of MDSC, the more limited the lung function. The findings on this new biomarker have now been published in the 'European Respiratory Journal'.

Patients with fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), show progressive worsening of lung function with increased shortness of breath and dry cough. To-date, this process is irreversible, which is why scientists are searching for novel biomarkers or indicators, which enable earlier diagnosis of this disease, with the aim to better interfere with disease progression.

A team of scientists at the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum München headed by Professor Oliver Eickelberg, Chairman of the CPC and Director of the Institute of Lung Biology as well as the DZL at the Munich partner site, have now discovered that myeloid-derived suppressor cells (MDSC) may serve as such biomarkers. "The role of MDSC has been most extensively studied in cancer, where they suppress the immune system and contribute to a poor prognosis," explained first author Isis Fernandez, MD. The current study suggests that similar mechanisms are also at work in IPF.

In collaboration with the Department of Internal Medicine V (Director: Professor Jürgen Behr) of the Munich University Hospital, the team examined blood samples of 170 study participants, including 69 IPF patients, in terms of the composition of circulating immune cell types. In each patient, these were correlated with lung function. Strikingly, the MDSC count in IPF patients was significantly higher than in the healthy control group. At the same time, the researchers observed that there was an inverse correlation between lung function and circulating MDSC counts: the poorer the lung function, the higher the MDSC count. In control groups of patients with chronic obstructive pulmonary disease (COPD) or other interstitial lung diseases, this inverse correlation was not found. "We conclude that the number of MDSC reflects the course of the disease, especially in IPF," said Fernandez.

To obtain an indication of whether the cells themselves could be the cause of the deterioration in lung function, the researchers measured the activity of genes that are typically expressed by immune cells. They found that these genes were expressed less frequently in samples that exhibited high MDSC counts. This indicates that MDSC - similar to their role in cancer - also compromise the immune system in IPF, according to the scientists.

A look into the lung tissue of IPF patients supports this assumption. "We were able to show that MDSC are primarily found in fibrotic niches of IPF lungs characterized by increased interstitial tissue and scarring, that is, in regions where the disease is very pronounced," said Eickelberg. "As a next step, we seek to investigate whether the presence of MDSC can serve as a biomarker to detect IPF and to determine how pronounced it is." In addition, the researchers want to investigate the mechanisms of accumulation in more detail. "Controlling accumulation or expansion of MDSC or blocking their suppressive functions may represent a promising treatment options for patients with IPF," said Eickelberg.

http://www.news-medical.net/news/20160902/Myeloid-derived-suppressor-cells-may-serve-as-biomarkers-for-idiopathic-pulmonary-fibrosis.aspx

--------------------------------

I think Oliver made the right choice to study medicine vs engineering.

--------------------------------

“Every freaking birthday”, Oliver Eickelberg remembers, his grandfather, uncles, and parents wanted to know when he was going to start studying for his family's chosen vocation—engineering. But the young Eickelberg never felt an emotional pull towards the world of machinery and mathematics, and when the time came to choose, his choice was medicine. It was undoubtedly the right one: at the tender age of 44, Eickelberg is already Chairman of the Comprehensive Pneumology Center, a translational research centre established by the Helmholtz Zentrum Munich, the University Hospital of the Ludwig-Maximilians University Munich, and the Asklepios Hospital in Munich.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61359-2/abstract

-------------------------------

Oliver Eickelberg, MD
Head of the Division of Pulmonary Sciences and Critical Care Medicine

Oliver Eickelberg, MD, is the incoming Division Head for Pulmonary Sciences and Critical Care Medicine at the University of Colorado.
..
..

http://www.ucdenver.edu/academics/colleges/medicalschool/departments/medicine/Pulmonary/About-us/Pages/Division-Head.aspx

-------------------------------

[biopharm]

Must See Presentation..Dmitry Gabrilovich : Peregrine Pharmaceuticals KOL : .

Ok we know Peregrine has already proven PS Targeting reduces MDSCs by at least 40% and here is another late comer talking about MDSCs .....listen to the 6min - 7min mark...

Seems like MDSCs are important to reduce!! Ronin group, you hear this ???


Published Online: Tuesday, Aug 15, 2017
http://www.onclive.com/peer-exchange/strategies-in-kidney-cancer/emerging-immunotherapy-combinations-in-kidney-cancer