Replies to post #293222 on Avid Bioservices Inc (CDMO)

[patientlywaiting]

CJ, THANKS........Hopefully people will take the time to read your post AGAIN because you actually did answer one of my previous questions.

[cheynew]

Here's hoping 4/3 starting at 8 AM is a really big day for us.

[cjgaddy]

Immunovaccine PR’d the AACR’17 IMMUNOVACCINE+PPHM #3657, ”PSTargeting Enhances Anti-Tumor Activity of a Tumor Vaccine(DepoVax), HPV-Induced Tumor Model” today. See below.

Apr1-5 2017: “AACR 2017”, WashDC
http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=105

4-4-17/8am #3657 - Session: BITES BISPECIFICS & CHECKPOINTS
”Phosphatidylserine-Targeting Antibodies Enhance Anti-Tumor Activity of a Tumor Vaccine in a HPV-Induced Tumor Model”
=> Genevieve Weir 1, Tara Quinton 1, Jeff T. Hutchins 2, Bruce D. Freimark 2, Marianne Stanford (VP/Res., Immunovaccine)
1=Immunovaccine, Inc., Halifax, NS, Canada [ https://www.imvaccine.com ]
2=Peregrine Pharmaceuticals
[Note: clearly, this study is combining PPHM’s Anti-PS with ImmunoVaccine’s DepoVax Vaccine Adjuvanting Platform https://www.imvaccine.com/depovax.php ]
ABSTRACT:
Antibodies targeting phosphatidylserine (PS) have been shown to induce anti-tumor responses by induction of tumor-specific T cells. Based on this observation, we evaluated the responses of PS and PD-1 targeting antibody therapy to enhance anti-tumor responses of a HPV16 peptide vaccine formulated in DepoVax (DPX) in mice bearing HPV-transformed C3 mouse tumors. The addition of PS-targeting antibody (mch1N11) [“Mouse version of Bavituximab”] to DPX/metronomic cyclophosphamide (mCPA) immunotherapy prolonged survival in comparison to mice receiving an isotype control in combination with DPX/mCPA. When anti-PD-1 was added to mch1N11 + mCPA, there was no increase in survival. The addition of mch1N11 to DPX/mCPA immunotherapy had no effect on tumor growth or survival in the aggressive B16-F10 model. TIL analysis revealed an increase in CD8+ T cells, antigen specific CD8+ T cells and PD-1+ T cells in the tumor with mch1N11 treatment. The expression of surface markers for macrophages (CD68high, F4/80) and dendritic cells (CD11c) were also increased in the tumors of mice treated with mch1N11. RT-qPCR analysis of the tumor confirmed higher mRNA expression of T cells markers (CD8, Granzyme B, PD-1) and antigen presenting cell markers (F4/80, CD74). In the spleen, expression of cell surface markers for monocytes (CD11b) and PD-1+ T cells (CD8) were elevated in groups treated with mch1N11 in combination with anti-PD-1. Combined, these findings indicate that in this model, PS-targeting antibodies can enhance the activity of phagocytic cells involved in antigen presentation. We have found that PD-1 expression increases as anti-tumor activity increases, therefore these results also provide an indication that antibodies targeting PS enhance the anti-tumor immune response induced by DPX/mCPA therapy. The observations suggest that PS-targeting antibodies may enhance therapeutic vaccines for the treatment of cancer.
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4-5-17 Immunovaccine PR: “...Immunovaccine Presents Preclinical Research at AACR’17... Part of Ongoing Effort to Identify Novel Combinations of DepoVax-based Immuno-oncology Candidates to Improve the Responses of Other Novel Immunotherapy Agents… preclin. data presented demonstrated that phosphatidylserine (PS) targeting antibodies can enhance the anti-cancer activity of its DepoVax-based therapeutic vaccine platform. In the study, researchers combined a Peregrine Pharmaceuticals’ PS-targeting antibody compound (mch1N11) with a DepoVax-based HPV16 peptide vaccine & metronomic cyclophosphamide (mCPA). This combined immunotherapy prolonged survival in C3 mouse models as compared to mice receiving an isotope control in combination with DepoVax/mCPA. Addl. analysis also demonstrated an increase in T cells in the tumor following treatment. Taken together, researchers believe that the data suggests that the antibody targeting PS can increase the anti-tumor immune response induced by a DepoVax-based cancer immunotherapy. Marianne Stanford, PhD, VP/Res., ”This study is another step in our exploration of combining DepoVax-based cancer vaccines & other promising immuno-modulatory compounds. Our process of generating supportive preclin. data to guide a potential clinical path forward has been effective in identifying these novel combinations in the past. We now look forward to continued work with our partners to advance combination candidates into and through the clinic, with the goal of expanding treatment options for hard-to-treat cancers.” The study was designed to analyze the potential synergistic effects of combining DPX-based immunotherapies with bavituximab, Peregrine’s investigational chimeric monoclonal antibody that targets PS...” https://www.imvaccine.com/releases.php?releases_id=421
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...Ahhhhh, ImmunoVaccine & Dr. Wolchok – zero doubt IMO how & why PPHM & Immunovaccine have hooked up...
ImmunoVaccine & Jedd Wolchok go back to ASCO’13:
6-3-13: “Our poster (Ph1 data) is one of few selected for detailed discussion at ASCO by Dr. Jedd Wolchok, top cancer immunotherapy thought leader… Immunovaccine Inc. believes that these immune responses are consistent in profile to those necessary from a cancer vaccine to potentially impact disease progression. These study results were further discussed by Dr. Jedd Wolchok of Memorial Sloan-Kettering CC, a top thought leader in the area of cancer immunotherapy, at the poster discussion session that followed.”
https://www.imvaccine.com/communications.php?communications_id=11

[cjgaddy]

PPHM/MSKCC(Jedd Wolchok Lab) Collab: #1/Bavi+PD1+Rad, #2/Bavi+”ACT”
CHRONOLOGICAL HISTORY (May2015 – Apr2017):

APRIL 2017 AACR’17: Two Joint PPHM+MSKCC Posters Presented...
1. MSKCC+PPHM: 4-2-17/1pm #574, “PSTargeting+RAD+AntiPD1 Promotes Anti-Tumor Activity, Melanoma” (same as SITC'16/11-14-16 http://tinyurl.com/js3fca4 )
2. MSKCC+PPHM: 4-3-17/8am #1651, “PSTargeting+Adoptive TCell Transfer (ACT) Eliminates Adv. Tumors w/o Off-Target Toxicities, Melanoma”
AACR’17 DETAILS:
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AACR’17 1. 4-2-17 #574 - Session: CHECKPOINTS 1 [Joint PPHM & Memorial Sloan Kettering]
“Phosphatidylserine Targeting Antibody in Combination with Tumor Radiation & Immune Checkpoint Blockade Promotes Anti-Tumor Activity in Mouse B16 Melanoma”
=> Sadna Budhu 1, Olivier De Henau 1, Roberta Zappasodi 1, Rachel Giese 1, Luis F. Campesato 1, Christopher Barker 1, Bruce Freimark 2, Jeff Hutchins 2, Jedd D. Wolchok 1, Taha Merghoub [Memorial Sloan Kettering]
1=Memorial Sloan Kettering CC, NYC [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ]
2=Peregrine Pharmaceuticals
NOTE: SAME TITLE AS WAS PRESENTED BY Mem.Sloan 11-14-16 SITC’16: see http://tinyurl.com/js3fca4
ABSTRACT:
Phosphatidylserine (PS) is a phospholipid that is exposed on surface of apoptotic cells, tumor cells and tumor endothelium. PS has been shown to promote immunosuppressive signals in the tumor microenvironment. Antibodies that target PS have been shown to reactivate anti-tumor immunity by polarizing tumor associated macrophages into a pro-inflammatory M1 phenotype, reducing the number of MDSCs in tumors and promoting the maturation of dendritic cells into functional APCs. In a mouse B16 melanoma model, targeting PS in combination with immune checkpoint blockade promoted greater anti-tumor activity than either agent alone. This combination was shown to enhance CD4+ and CD8+ T cell infiltration and activation in the tumors of treated animals. Radiation therapy (RT) is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that RT induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in treated tumors. The abscopal effect, a phenomenon in which tumor regression occurs outside the site of RT, has been observed in both preclinical and clinical trials when RT is combined with immunotherapy. In this study, we show that irradiation treatment of B16 melanoma causes an increase in PS expression on the surface of viable tumor and immune infiltrates. We subsequently examined the effects of combining RT with an antibody that targets PS (mch1N11) [“Mouse version of Bavituximab”] and immune checkpoint blockade (anti-PD-1) in B16 melanoma. We found that treatment with mch1N11 synergizes with RT to improve anti-tumor activity and overall survival in tumor bearing mice. In addition, the triple combination of mch1N11, RT and anti-PD-1 treatment displayed even greater anti-tumor and survival benefit. Analysis of local immune responses in the tumors of treated animals revealed an increase in tumor-associated macrophages with a shift towards a pro-inflammatory M1 phenotype after treatment with RT & mch1N11. In addition, analysis of the systemic immune responses in the spleen and tumor draining lymph nodes revealed an increase in CD8 T cell activation, effector cytokine production and differentiation into effector memory cells in the triple combination. This finding highlights the potential of combining these 3 agents to improve outcome in patients with advanced-stage melanoma and other cancers and may inform the design of clinical studies combining PS-targeting antibodies with RT and/or checkpoint blockade.
POSTER #574 IMAGE: http://www.peregrineinc.com/images/stories/pdfs/aacr2017budhu.pdf

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AACR’17 2. 4-3-17/8am #1651 - Session: TUMOR MICROENVIRONMENT & CHECKPOINTS [Joint PPHM & Memorial Sloan Kettering]
“Targeting Phosphatidylserine in Combination with Adoptive T Cell Transfer Eliminates Advanced Tumors without Off-Target Toxicities in a Melanoma Preclinical Model” <=NEW(2nd) MSK STUDY
=> Daniel Hirschhorn-Cymerman 1, Sara Sara Schad 1, Sadna Budhu 1, Zhong Hong 1, Xia Yang 1, Hutchins T. Jeff 2, Bruce D. Freimark 2, Michael J. Gray 2, Jedd Wolchok 1, Taha Merghoub [Memorial Sloan Kettering]
1=Memorial Sloan Kettering CC, NYC [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ]
2=Peregrine Pharmaceuticals
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FROM PPHM’s 4-3-17 PR: http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=1019762
…”Latest Findings from Ongoing Collaboration with Memorial Sloan Kettering (MSK) Support Potential Applications for Combining CAR T & Anti-PS in Treatment of Solid Tumors”… For this study, a team of MSK researchers led by cancer immunotherapy thought-leaders, Taha Merghoub, Ph.D. and Jedd D. Wolchok, M.D., Ph.D., evaluated and compared the anti-tumor activity and off-target toxicities of adoptive T cell transfer therapy in combination with either PS-targeting antibodies or anti-OX40 antibodies in mice with advanced melanomas. Whereas PS-targeting and anti-OX40 demonstrated comparable tumor regression when administered in combination with transferred adoptive T cells, only the PS-targeting combination achieved these results without any off-target toxicities. By contrast, the anti-OX40 treatment combination triggered off-target inflammatory destruction of healthy tissues. Additional study results demonstrated that the PS-targeting antibodies decreased tumor-induced immunosuppression as evidenced by a decrease in immunosuppressive regulatory T cells (Tregs) and M2 macrophages. This finding is consistent with Peregrine’s belief that bavituximab may modulate the immunosuppressive tumor microenvironment and enhance the activity of immunotherapy agents.
Taha Merghoub, Ph.D., Co-Dir. of the Ludwig Collaborative Laboratory at MSK:
“While adoptive T cell transfer remains one of the most exciting new approaches to treating cancer, to date the toxicity associated with the treatment has limited its potential. We are encouraged that these study results showed that the combination of anti-PS and adoptive T cell treatment led to enhanced anti-tumor effect without any evidence of additional off-target side effects. “We believe that these findings may support potential applications for this combination in solid tumors in the future.”
Joseph Shan, Peregrine’s VP of Clinical & Regulatory Affairs:
“These study results provide further support for our belief that anti-PS agents such as bavituximab can play an important role as part of combination cancer treatments. This is directly tied to the agents’ ability to modulate the tumor microenvironment to combat the immunosuppression that limits the activity of CAR T and immunotherapies. Importantly, we are now also seeing evidence that this targeted modulation of the tumor microenvironment by anti-PS allows for enhanced activity of these other treatments without triggering any off-target toxicities. This is opposed to other conventional immunotherapies such as anti-OX40 with systemic mechanisms of action. We believe this advantageous tolerability profile will be a key benefit in positioning anti-PS agents for inclusion in optimal combination cancer regimens.”
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ABSTRACT #1651:
A viable strategy to treat advanced cancers includes transferring of tumor-specific T cells. T cells that recognize tumor antigens can be expanded and reinvigorated ex-vivo. Furthermore, autologous T cells can be genetically modified to express anti-tumor T cell receptors [TCRs] or chimeric antigen receptors [CARs]. Although the potency and specificity of tumor-specific T cells can be manipulated ex-vivo, once re-infused into patients, the T cells are subjected to immunosuppressive mechanisms established by the tumor. An important immune checkpoint regulator within tumors is phosphatidylserine (PS). Innate immune cells exposed to PS secrete suppressive cytokines and chemokines that can significantly impair the function and activation of anti-tumor T cells. Therefore, monoclonal antibodies that block PS activity can increase the anti-tumor potency of transferred T cells to treat aggressive cancers. Here we show that a PS targeting monoclonal antibody in combination with CD4+ T cells that recognize the melanoma antigen Trp1 can regress very advanced melanomas in all treated mice. Combination of anti-Trp1 CD4+ T cells with other immunomodulatory modalities such as anti-OX40 antibodies, can achieve equivalent treatment rates but these are typically accompanied by severe immune related adverse events. In contrast, in this setting, PS blockade did not show any off-target toxicities. Flow cytometry analysis revealed lower levels of CD206 expression concomitant with higher activation markers in macrophages and neutrophils in tumors from anti-PS treated mice. These results suggest that diminishing suppressive mechanisms locally in adoptive transfer protocols is a highly desirable strategy that can eliminate tumors while minimizing related adverse events.
POSTER #1651 IMAGE: http://www.peregrineinc.com/images/stories/pdfs/aacr2017hirschhorn.pdf

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8-2015: Presently there are 3 types of Adoptive Cell Transfer (ACT) using effector T cells that are advancing on a path towards regulatory approval:
1. TILs (tumor infiltrating lymphocytes) have been developed with slow but continuing progress over several decades.
2. CARs (chimeric antibody receptors) – newer gene-modified T cells strategy
3. TCRs (T-cell receptors) – newer gene-modified T cells strategy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507286/

...“Adoptive T cell transfer is like ‘giving patients a living drug’,” states Renier J. Brentjens, MD/PhD, of Memorial Sloan Kettering Cancer Center (MSKCC).
… https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
...“Adoptive T cell therapy (ACT) is one stone in this new pillar, a potentially powerful approach to cancer treatment that relies on the infusion of tumor-specific T cells.”
… https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327320
MSK Tweet 4-3-17 https://twitter.com/sloan_kettering :
...See bottom right: “SWIM” - Swim Across America http://www.swimacrossamerica.org

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Interesting 3-31-17 Sloan Kettering Tweet re: AACR’17
3-31-17 9:20amET “Getting ready for #AACR17? #Immunotherapy will be a hot topic. Learn more about how it works (video). @AACR”
https://twitter.com/sloan_kettering
Points to this 4-2016 Video (1:20):
“Immunotherapy – How It Works” https://www.youtube.com/watch?v=COQ1AeoGyco
Beg@:39:
“Immunotherapy drugs release this brake and empower immune cells to fight the cancer.
Sometimes the immune system needs a tune-up before it can fight cancer.
Immune cells can be removed from the body, armed with new proteins that can target cancer cells, and given back to a patient in large numbers.
Once inside the body, the modified immune cells recognize and attack the cancer.
This approach is called CAR T cell therapy. [an Adoptive Cell Transfer “ACT” strategy]
Despite the promise of immunotherapy, not everybody responds.
MSKCC scientists are exploring ways to improve immunotherapy.”

=============AND, THIS 3-23-17 PARKER FOUNDATION RELEASE ON AACR’17:
3-23-17: “Parker Institute for Cancer Immunotherapy Scientists to Present Research on Checkpoint Inhibitors, Adoptive Cell Therapy, and Other Advances in Immuno-oncology at AACR 2017”
Investigators affiliated with the Parker Institute for Cancer Immunotherapy will present some of the most anticipated immuno-oncology research at the 2017 AACR Annual Meeting. The event takes place at the Walter E. Washington Convention Center in Washington, DC, April 1-5 2017. . .
Other adoptive cell therapy abstracts of interest:
• ”Targeting Phosphatidylserine in Combination with Adoptive T Cell Transfer Eliminates Advanced Tumors without Off-Target Toxicities in a Melanoma Preclinical Model” [see http://tinyurl.com/nx5q5os ]
The principal investigator is Taha Merghoub, PhD, Parker Institute member researcher at Memorial Sloan Kettering Cancer Center. Co-authors include Parker Institute Center Director Jedd Wolchok, MD, PhD, at Memorial Sloan Kettering Cancer Center.
http://www.parkerici.org/media/2017/parker-institute-for-cancer-immunotherapy-scientists-to-present-research-on
----------ACT NOTES:
NOTE1:
From 3-2014 Immunotherapy article: “Cancer immunotherapy, particularly adoptive cell transfer (ACT), has shown great promise in the treatment of patients with late-stage disease, including those who are refractory to std. Therapies” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372895
NOTE2:
The Parker Foundation: “The Immunotherapy Dream Team”
Through the support from SEAN PARKER, Stand Up To Cancer (SU2C) and the Cancer Research Institute (CRI) formed an Immunology Research Dream Team dedicated to cancer immunology: “Immunologic Checkpoint Blockade & Adoptive Cell Transfer in Cancer Therapy.” The Immunotherapy Dream Team is focused on 2 approaches for this translational cancer research project, which will unite laboratory & clinical efforts towards the immunological treatment, control, and prevention of cancer.
The 1st is investigating blockades (by inhibitory molecules called “checkpoints”) of T lymphocytes’ inhibitory receptors, which block immune responses; and the use of antibodies to remove the checkpoints, once again allowing white blood cells called T lymphocytes to kill the cancer cells.
Second, the Immunotherapy Dream Team is pursuing multiple Adoptive Cell Transfer (ACT) approaches, which increase immunity.”
DREAM TEAM LEADERSHIP: 10 scientists, incl. MSKCC’s Jedd D. Wolchok & Michel Sadelain.
http://parker.org/initiatives/immunotherapy
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NOTE: Mem. Sloan’s Dr. Jedd. Wolchok wasco-author of 9 AACR’17 abstracts. 2 of the 9 are w/PPHM re: PS-Targeting. With biotechs, he had one each with Genocea Biosciences(ex-vivo screening), Infinity Pharm(Ph1), Leap Ther.(Ph1), and two with BMS(P1+3). The 8th was MSKCC ONLY, and the 9th was jointly w/Cedars-Sinai/LA. http://www.abstractsonline.com/pp8/#!/4292 .
PEREGRINE (Joint Mem.Sloan Kettering Wolchok Lab & PPHM):
1. 4-2-17 #574 “Phosphatidylserine Targeting Antibody in Combination with Tumor Radiation & Immune Checkpoint Blockade Promotes Anti-Tumor Activity in Mouse B16 Melanoma” <=Same as SITC’16 11-14-16.
2. 4-3-17 #1651 “Targeting Phosphatidylserine in Combination With Adoptive T Cell Transfer Eliminates Advanced Tumors Without Off-Target Toxicities in a Melanoma Preclin. Model” <=NEW/2nd PPHM+MSK.
NON-PEREGRINE:
3. (MSK ONLY): 4-2-17 #874 “Lifting the iron curtain: Imaging cellular barriers to combination chelation-immune checkpoint therapy”
4. (MSK & Genocea Bio. http://www.genocea.com GNCA/$130mm MktCap) 4-2-17 #632 “Genome-scale neoantigen screening using ATLAS prioritizes candidate antigens for immunotherapy in a NSCLC patient”
5. (MSK & Cedars-Sinai/LA) 4-4-17 #4705 “CTLA4 blockade with HER2-directed therapy yields clinical benefit in women undergoing radiation therapy for HER2+ breast cancer brain metastases”
6. (MSK & Infinity Pharm.) 4-4-17 #CT089 “A Ph1, first-in-human study of IPI-549, a PI3K-y inhibitor, as monotherapy & in combo w/nivolumab in adv. solid tumors”
7. (MSK & Leap Ther.) 4-2-17 #CT018 “Intratumor & peripheral Treg modulation as a pharmacodynamic biomarker of the GITR agonist antibody TRX-518 in the 1st in-human trial”
8. (MSK & BMS) 4-3-17 #CT073 “(Ph1) Immunomodulatory effects of NIVO+IPI or NIVO/mono in adv. melanoma: CheckMate038”
9. (MSK & BMS) 4-3-17 #CT075 “OS results from a Ph3 of NIVO+IPI in treatment-naïve pts w/adv. Melanoma: CheckMate067”

FYI: JULY 2014: Mem. Sloan’s Jedd Wolchok Video: “Immunotherapy for Metastatic Melanoma - PD-1 Clinical Trials”… Dr. Wolchok (1:42), “We will not rest until every patient can have a durable response.” http://cyberspaceandtime.com/kvWeW8Zt0sU.video (1:49)

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Nov9-13 2016: “(SITC) Society for Immunotherapy of Cancer 31st Annual Meeting”, Natl-Harbor MD
”The premier destination for scientific exchange, education, and networking in the Cancer Immunotherapy Field”
SITC = The Society for Immunotherapy of Cancer http://www.sitcancer.org
SITC 2016 Meeting: http://www.sitcancer.org/2016
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Abstracts #199 (11-11-16) is the joint MSKCC/PPHM one; its Senior author is Dr. Taha Merghoub (Jedd Wolchok Lab, Memorial Sloan Kettering), who said this in the 5-29-15 PPHM/MSK Collab. Announcement PR (see below): "A key focus of the Wolchok Lab's research is studying novel immunotherapy combinations that work together to enable the immune system to recognize & destroy cancer. This collaboration will allow us to focus on the role & contribution of PS blockade therapy in determining which combination of the current and next generation of immune modulators is likely to increase the extent and amplitude of anti-tumor response. This important pre-clinical & translational work will potentially guide the design of the next generation of clinical studies with bavituximab."
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11-14-16 – SITC’16: Joint MSKCC & PPHM Poster, “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma”) (#199) … See: http://tinyurl.com/js3fca4
11-14-16/PR: “New Study Demonstrates Anti-Tumor Advantages for Combination Treatment Featuring Peregrine Pharmaceuticals' PS-Targeting Antibodies in a Preclinical Melanoma Model”
* Promising Results of MSK Study Evaluating Combinations of PS-Targeting Treatment, Anti-PD-1 and Radiation in Mouse B16 Melanoma Model Presented at SITC 2016
* New Data from Second Study Conducted by Peregrine Shows Triple Combination of PS-Targeting Treatment, Anti-PD-1 and Anti-LAG3 Created Long-Term Immunity in Triple Negative Breast Cancer Model; Protected Animals when Re-Challenged with Breast Cancer Cells
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=999202
TUSTIN, Nov. 14, 2016: Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM/PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, today announced the presentation of positive data from multiple new preclinical studies of the company's phosphatidylserine (PS)-targeting antibodies. Study results highlight that PS-targeting antibodies similar to bavituximab synergize with checkpoint inhibitors and radiation to improve anti-tumor activity in various animal tumor models. Importantly, the improved anti-tumor activity seen in these studies was even greater when PS-targeting therapy was a part of triple combination treatment including anti-PD-1 and another therapy. Data were presented by Peregrine scientists, as well as researchers from Memorial Sloan Kettering Cancer Center (MSK), at the Society for Immunotherapy of Cancer (SITC) 2016 Annual Meeting, which was held November 9-13, 2016 in National Harbor, MD. [ http://www.sitcancer.org/2016 ]

Initial results from Peregrine's ongoing collaboration with MSK researchers were featured in a poster presented by Sadna Budhu, PhD, at SITC 2016. A team of MSK researchers led by cancer immunotherapy thought-leaders, Taha Merghoub, PhD and Jedd D. Wolchok, MD, PhD [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ], evaluated the effects of combining PS-targeting, anti-PD-1 and radiation therapies in the mouse B16 melanoma model. Study data showed that PS-targeting antibodies synergize with both anti-PD-1 and radiation therapy to improve anti-cancer activity. PS-targeting treatment in combination with radiation, as well as triple combination of PS-targeting treatment, anti-PD-1 and radiation, led to a reduction in tumor burden. Median survival for the triple combination treatment still had not been reached at the end of the 80-day observation period with other arms in the study showing median survival that ranged from 24-70 days.

Researchers also evaluated the impact of the PS-targeting and radiation combination treatment on the level and type of immune activity. These results demonstrated that the combination led to a change in the tumor microenvironment, shifting it from immunosuppressive in which tumors are protected to immune active in which tumors are more susceptible to treatment. Analysis of local immune responses in the tumors of the treated animals showed that the combination treatment increased the number of tumor associated macrophages and shifted the macrophage polarization from the immunosuppressive M2 type to the immune active M1 type. When systemic immune responses were analyzed following triple combination of PS-targeting treatment, anti-PD-1 and radiation, researchers also saw evidence of increased immune activity. This was illustrated by key indicators of immune activity, including increases in CD8+ T-cell activation, effector cytokine production and differentiation into effector memory cells.

"Based on these study results, we believe that the targeting of PS is having meaningful activity within the tumor microenvironment in the B16 melanoma model," stated Dr. Jedd Wolchok. "It appears that this activity creates a more immune active environment in which other treatments, including radiation, are able to have a greater anti-tumor impact."

"We have noted that the combination of PS-targeting treatment and radiation, as well as triple combination of PS-targeting treatment, radiation and anti-PD-1, resulted in clear advantages in anti-tumor activity in the mouse B16 melanoma model," said Dr. Taha Merghoub, PhD, co-director of the Ludwig Collaborative Laboratory at MSK. "We believe that these findings suggest the potential benefit of combining these agents to improve the outcomes of patients with cancer. With this in mind, we think this research may play an important role in designing future clinical trials of PS-targeting agents in melanoma and other cancers."
[Note: FULL SITC’16 ABSTRACT #199: http://bit.ly/2dHTEVn
...Full Poster Image: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]

A second study, conducted by Peregrine, evaluated the effects of combining PS-targeting, anti-PD-1 and anti-LAG3 therapies in the E0771 triple negative breast cancer (TNBC) model. Initial findings from this study were previously reported and demonstrated that eight of the ten (80%) animals receiving the PS-targeting, anti-PD-1 and anti-LAG3 treatment combination experienced complete tumor regressions, whereas there were no animals (0/10) in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression. New data presented for the first time at SITC demonstrated that the triple combination established a specific and prolonged anti-tumor immune response which protected those eight animals that achieved a complete tumor regression against a re-challenge with the same E0771 TNBC model tumor cells. This sustained anti-tumor response demonstrates the ability of the triple combination treatment to trigger immune system memory and support adaptive immune responses against reemerging disease in the E0771 TNBC model.
[Note: FULL SITC’16 ABSTRACT #213: http://bit.ly/2dpUy4C ]
...Full Poster Image: http://peregrineinc.com/images/stories/pdfs/sitc_2016_gray.pdf ]

Further highlighting the immune impact of the PS-targeting/anti-PD-1/anti-LAG3 treatment combination were initial results of a new analysis from this study using the nCounter ® PanCancer Immune Profiling Panel from NanoString Technologies ®. Data from the analysis demonstrated that the triple combination induced a greater shift in the tumor microenvironment from immunosuppressive to immune active as compared to all other treatment groups. This was evidenced by greater increases in the activity of several critical immune activating pathways, including presentation and processing of antigens and signaling and activation of T-cells, for the triple combination as compared to all other treatments.

"It is very encouraging to see the consistent increase in anti-tumor activity triggered by triple combination treatments that combine PS-targeting agents and anti-PD-1 with other cancer treatments. By demonstrating this activity across multiple studies in multiple tumor models, we are continuing to build scientific support for the therapeutic potential of adding PS-targeting therapies in combination with other cancer treatments, including checkpoint inhibitors such as anti-PD-1," said Jeff T. Hutchins, PhD, Peregrine's VP, Preclinical Research. "As cancer research continues to explore the potential of combination treatments that marry complementary mechanisms, we are pleased to see that our efforts continue to generate data supporting the role that PS-targeting agents such as bavituximab may play in this area."

Bavituximab is an investigational monoclonal antibody that targets PS. Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. Previous studies demonstrated PS-targeting antibodies shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor responses. Peregrine continues to support and guide clinical development through the evaluation of the preclinical equivalent of bavituximab, ch1N11, in animal model studies.

Peregrine's clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations [See: http://tinyurl.com/gutgwb5 ]. These trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination. Additionally, Peregrine continues to advance its pre-clinical collaboration with Memorial Sloan Kettering Cancer Center with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab's combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.
ABOUT PEREGRINE *SNIP*
CONCLUSION SECTION FROM THE JOINT MSKCC/PPHM SITC’16 POSTER:



ABSTRACT: #199/SITC’16/11-11-16(MSK+PPHM): “Phosphatidylserine Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma”
AUTHORS:
Sadna Budhu(MSKCC PRESENTING AUTHOR) 1, Olivier De Henau 2, Roberta Zappasodi 1, Kyle Schlunegger 3, Bruce Freimark 4, Jeff Hutchins 5, Christopher A. Barker 6, Jedd D. Wolchok 7, Taha Merghoub(Memorial Sloan Kettering SENIOR AUTHOR)
BACKGROUND:
Phosphatidylserine (PS) is a phospholipid that is exposed on the surface of apoptotic cells, some tumor cells and tumor endothelium. PS has been shown to promote anti-inflammatory and immunosuppressive signals in the tumor microenvironment. Antibodies that target PS have been shown to reactivate anti-tumor immunity by repolarizing tumor associated macrophages to a M1-like phenotype, reducing the number of MDSCs in tumors and promote the maturation of dendritic cells into functional APCs. In a B16 melanoma model, targeting PS in combination with immune checkpoint blockade has been shown to have a significantly greater anti-cancer effect than either agent alone. This combination was shown to enhance CD4+ and CD8+ T cell infiltration and activation in the tumors of treated animals. Radiation therapy is an effective focal treatment of primary solid tumors, but is less effective in treating metastatic solid tumors as a monotherapy. There is evidence that radiation induces immunogenic tumor cell death and enhances tumor-specific T cell infiltration in irradiated tumors. In addition, the abscopal effect, a phenomenon in which tumor regression occurs outside the site of radiation therapy, has been observed in both preclinical and clinical trials with the combination of radiation therapy and immunotherapy.
METHODS:
We examined the effects of combining tumor radiation therapy with an antibody that targets PS (1 N11) [Note: PGN635 (B2GPI-dep.) is Fully-Human Bavituximab=1N11=AT004; Genentech studying 89Zr-PGN635 as a Tumor Imaging Agent, “indep. of cancer type”] and an immune checkpoint blockade (anti-PD-1) using the mouse B16 melanoma model. Tumor surface area and overall survival of mice were used to determine efficacy of the combinations.
RESULTS:
We examined the expression of PS on immune cells infiltrating B16 melanomas. CD11b + myeloid cells expressed the highest levels of PS on their surface whereas T cells and B16 tumor cells express little to no PS. These data suggest that targeting PS in B16 melanoma would induce a pro-inflammatory myeloid tumor microenvironment. We hypothesize that therapies that induce apoptotic cell death on tumor cells would enhance the activity of PS-targeting antibodies. We therefore examined the effects of combining a PS-targeting antibody with local tumor radiation. We found that the PS-targeting antibody synergizes with both anti-PD-1 and radiation therapy to improve anti-cancer activity and overall survival. In addition, the triple combination of the PS-targeting antibody, tumor radiation and anti-PD-1 treatment displayed even greater anti-cancer and survival benefit.
CONCLUSIONS:
This finding highlights the potential of combining these 3 agents to improve outcome in patients with advanced-stage melanoma and may inform the design of future clinical trials with PS targeting in melanoma and other cancers *end*
...FULL POSTER IMAGE: http://peregrineinc.com/images/stories/pdfs/sitc_2016_budhu.pdf ]

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9-8-16/CC - JEFF HUTCHINS (VP/PreClinical Res.) http://tinyurl.com/jmy77g3
“...I would now like to provide an update on Peregrine's preclinical I-O focused internal efforts and our collaboration with Memorial Sloan Kettering Cancer Center. The goal of this work is to evaluate combinations of PS targeting with other checkpoint inhibitors and immune stimulatory agents for the purpose of developing new and increasingly effective anticancer treatments. These programs are advancing well and to-date, we have seen impressive signs of activity with new combinations of PS targeting and other treatment modalities such as checkpoint blockers, T-cell agonists and radiation. These new combinations are improving overall survival accompanied with increases in cyto-reactive T cells into the tumor tissue. This exciting new internal work will be presented at the AACR/CRI Immunotherapy Meeting in New York later this month [Sept25-28] and at ESMO in early October [Oct7-11: http://tinyurl.com/jxdppyo ]. We expect the first results from our collaboration with MSK’s Jedd Wolchok Lab investigators [See MSK Collab: http://tinyurl.com/zkvebh6 ] to be presented at SITC in November [Nov9-13: http://www.sitcancer.org/2016 Natl.Harbor MD] and we will provide more detailed information as that presentation becomes available.”

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5-29-15: Peregrine & Sloan Kettering Enter Collab. to “Investigate Novel PS-Targeting Immunotherapy Combos” http://tinyurl.com/o3k9ux8
...The studies at MSK will be performed under the direction of Taha Merghoub, PhD, [ http://www.mskcc.org/research-areas/labs/members/taha-merghoub-01 ] Associate Attending Biologist, Melanoma and Immunotherapeutics Service, Ludwig Collaborative and the Swim Across America Laboratory, a part of the laboratory of Jedd D. Wolchok, MD, PhD [ http://www.mskcc.org/research-areas/labs/jedd-wolchok ], a leader in the field of cancer immunotherapy. Dr. Wolchok serves as the Chief, Melanoma and Immunotherapeutics Service, Lloyd J. Old Chair for Clinical Investigation as well as an Associate Director of the Ludwig Center for Cancer Immunotherapy at MSK.
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”The phosphatidylserine (PS) signaling pathway is a very interesting target for modulating the immune system's response to cancer. We look forward to exploring the potential of PS-targeting agents alone and with other immune modulators that may lead to novel advances in cancer therapy," said Dr. Jedd Wolchok.
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As part of the collaboration, researchers at MSK will conduct research to further explore the combination of PS-targeting agents, including bavituximab, that block a primary immunosuppressive pathway thereby allowing anti-tumor immune responses with other immuno-stimulatory agents that enhance immune responses. Specifically, MSK researchers will examine the combination of bavituximab alongside models of checkpoint blockade that are unresponsive to inhibition or co-stimulation given the ability of bavituximab to reprogram myeloid derived suppressor cells (MDSC) and increase tumoricidal T-cells in tumors, a mechanism of action that is complementary to checkpoint blockade and T-cell activation.
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"A key focus of the Wolchok Lab's research is studying novel immunotherapy combinations that work together to enable the immune system to recognize & destroy cancer. This collaboration will allow us to focus on the role & contribution of PS blockade therapy in determining which combination of the current & next gen. of immune modulators is likely to increase the extent & amplitude of anti-tumor response. This important pre-clinical and translational work will potentially guide the design of the next gen. of clinical studies with bavituximab," said Dr. Taha Merghoub.
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"We are delighted to be working with a world-renowned pioneer and leader in the immuno-oncology space, recognizing that there remains significant research in order for more cancer patients to realize the benefits of combination immune therapy," said Jeff T. Hutchins, PhD, VP of Preclinical Research at Peregrine. ”Our internal and collaborative research presented over the last year has established a robust foundation of PS-targeting activity on which to initiate this next chapter in PS research and development."
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"This collaboration is an important extension of our established research efforts to further explore and understand the potential of our PS-targeting platform including bavituximab our lead clinical candidate. This research will focus on better understanding how treatment with PS-targeting agents can assist other anti-tumor immunotherapies in order to work better," said Steven King, CEO of Peregrine. ”Our goal is to change the way cancer patients are treated by allowing their immune system to recognize and fight their disease. This collaboration will undoubtedly assist us in identifying potential new opportunities to better treat patients with cancer."

[biopharm]

4. (MSK & Genocea Bio. http://www.genocea.com GNCA/$130mm MktCap) 4-2-17 #632 “Genome-scale neoantigen screening using ATLAS prioritizes candidate antigens for immunotherapy in a NSCLC patient”

Neoantigens have flipped PS and makes PS Targeting patents astronomical in value.

Microsoft all over this with MSK SU2C etc...and now it is very clear that Roger must step down from the CEO position because how can he just now on this leap into Biomarkers with Microsoft data analytics able to sift thru the PS Targeting data / Biomarkers....

How foolish will Roger be when he knows his reputation is on the line as evidence continues to emerge that shows all are after PS Targeting Biomarkers

Shared cancer neoantigens: Making private matters public

Christopher A. Klebanoff,
Jedd D. Wolchok

DOI: 10.1084/jem.20172188 |
Published December 21, 2017
...
...

Time and again, cancer immunotherapists have unfortunately fallen prey to chasing peptide “ghosts”: highly avid T cells which recognize peptide-pulsed targets that nevertheless fail to recognize HLA-matched, antigen expressing tumor cells. Chheda et al. (2018) avoided this potential pitfall by providing multiple lines of evidence that their candidate epitope is processed, presented, and displayed on the surface of DMG cancer cells. First, the authors used a highly sensitive mass spectrometry-based assay (Bassani-Sternberg et al., 2016) to characterize the peptides bound to MHC molecules isolated directly from DMG cell lines. Using this technique, they identified a variant of the 10-mer mutant peptide only in cells harboring the H3.3K27M mutation but not cells with WT H3.3. Second, using a series of DMG cell lines that all possess the H3.3K27M mutation but are variable in HLA-A2 expression, the authors showed that T cells transduced with the H3.3K27M-specific TCR only recognize HLA-A2+ tumor cells. In an elegant series of reversion experiments, the authors subsequently demonstrated that transduction of HLA-A2 into an HLA-A2- H3.3K27M+ DMG cell line enabled T cell recognition while an anti–HLA-A2 antibody blocked recognition. Critically, additional experiments demonstrated that HLA-A2+ tumor cell lines that were WT for H3.3 were not recognized. This suggests that engineered T cells might be able to distinguish between healthy tissues and tumor cells. Finally, the authors tested whether systemically administered T cells engineered with the mutation-specific TCR treat H3.3K27M+ tumor cells injected within the intracranial cavity of immune-deficient mice. Whereas tumor growth was unabated in mice receiving mock-transduced T cells relative to a saline control, animals receiving TCR engineered cells had a protracted arrest of tumor growth.

Collectively, these data describe an exciting and eminently translatable discovery of a novel “public” neoantigen (see figure). The H3.3K27M26-35 epitope now joins the ranks of other recently uncovered “public” neoantigens resulting from hotspot mutations in driver oncogenes. For example, a series of immunogenic KRAS hotspot mutation–specific epitopes have also been reported which are restricted by HLA-C*08:02 and HLA-A*11:01 (Tran et al., 2016; Wang et al., 2016). Clinically, knowledge of “public” neoantigens could be used to boost what appears in a limited number of tested patients to be a preexisting T cell response using various vaccination approaches. Indeed, this approach using an H3.3K27M26-35 peptide vaccine in combination with the immune-adjuvant Poly-ICLC is now already under way (NCT02960230). It remains to be seen, however, whether any T cell vaccine is potent enough to induce cancer regression in patients with metastatic cancer even if this exceptional class of antigens is targeted (Klebanoff et al., 2011). As suggested by proof-of-concept experiments in the current manuscript, an alternative approach could be to genetically redirect a patient’s T cells to recognize a “public” neoantigen through introduction of a TCR followed by adoptive T cell transfer. The first clinical trial to test this concept in HLA-A*11:01+ patients with cancers harboring the KRAS G12V hotspot mutation has recently been initiated (NCT03190941), and it is possible that the TCR described by Chheda et al. (2018) may rapidly follow suit. Time will tell what the ultimate utility of “public” neoantigens will be. There are ample reasons to believe, however, that they will help democratize the potential benefits of targeting cancer neoantigens to a far greater number of patients more efficiently and rapidly than would otherwise be the case.
...
...
http://jem.rupress.org/content/early/2017/12/20/jem.20172188

Just released ....

Altered self: the not-so-neo-antigens

$265

Jedd D. Wolchok

...
...

https://www.nature.com/articles/nri.2018.7

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NEO-ANTIGEN TCR DEGENERACY CONVERGENCE TEAM

Dream Team Leader
Benjamin Greenbaum, PhD
Assistant Professor
Department of Genetics & Genomic Sciences, Medicine, Oncological Sciences, and Pathology
Icahn School of Medicine at Mount Sinai

Dream Team Co-Leader
Vinod Balachandran, MD
Assistant Attending Surgeon, Hepatopancreatobiliary Service
Member, David M. Rubenstein Center for Pancreatic Cancer Research
Member Researcher, Parker Institute for Cancer Immunotherapy
Memorial Sloan Kettering Cancer Center

Member
Marta Luksza, PhD
Assistant Professor
Department of Oncological Sciences
Icahn School of Medicine at Mount Sinai

Member
Eileen M. O’Reilly, MD
Associate Director for Clinical Research
David M. Rubenstein Center for Pancreatic Cancer Research

Member
Jedd Wolchok, MD, PhD
Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation
Chief, Melanoma & Immunotherapeutics Service
Associate Director, Ludwig Center for Cancer Immunotherapy
Memorial Sloan Kettering Cancer Center

Collaborators

Nina Bhardwaj, MD, PhD
Professor, Department of Medicine
Director of Immunotherapy
Ward Coleman Chair in Cancer Research
Icahn School of Medicine at Mount Sinai

Collaborator
Curtis Callan, PhD
James S. McDonnell Distinguished University Professor of Physics
Princeton University

Collaborator
Timothy Chan, MD, PhD
PaineWebber Chair in Cancer Genetics
Director, Immunogenomics and Precision Oncology Platform
Member, Human Oncology & Pathogenesis Program
Vice Chair, Department of Radiation Oncology
Director, Translational Oncology Division
Memorial Sloan Kettering Cancer Center

Collaborator
Jennifer Chayes, PhD
Distinguished Scientist and Managing Director
Microsoft Research for Boston and New York City
Microsoft Corporation

Collaborator
Simona Cocco, PhD
Directrice de Recherche, Centre National de la Recherche Scientifique
Laboratoire de Physique Statistique
Ecole Normale Supérieure

Collaborator
Jeffrey Drebin, MD, PhD
Chair, Department of Surgery
Memorial Sloan Kettering Cancer Center

Collaborator
Anthony Gill, MD
Staff Specialist, Dept of Anatomical Pathology
Chairman of Australian Pancreatic Genome Initiative and Head of Pancreatic Cancer Research Group at the Garvan Institute of Medical Research
Professor of Surgical Pathology, University of Sydney

Collaborator
Sharon Gillet
Principal Program Manager
Microsoft Research, New England & New York City

Collaborator
Christine Iacobuzio-Donahue, MD, PhD
Attending, Department of Pathology,
Director, MSKCC Medical Donation Program
Director, Cancer Genomics for the David M. Rubenstein Center for Pancreatic Cancer Research
Affiliate Member, Human Oncology and Pathogenesis Program

Collaborator
Dmitry Krotov, PhD
Member, Simons Center for Systems Biology
Institute for Advanced Study

Collaborator
John Langford, PhD
Principal Researcher
Microsoft Research

Collaborator
Lester Mackey, PhD
Researcher
Microsoft Research

Collaborator
Taha Merghoub, PhD
Assistant Attending Lab Member
Co-director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory
Memorial Sloan Kettering Cancer Center

Collaborator
Rémi Monasson, PhD
Professor Chargé de Cours Ecole Polytechnique
Directeur de Recherche, Centre National de la Recherche Scientifique

Collaborator
Thierry Mora, PhD
Researcher
Laboratoire de Physique Statistique
Ecole Normale Supérieure

Collaborator
Vasilis Syrgkanis, PhD
Researcher
Microsoft Research

Collaborator
Aleksandra Walczak, PhD
Permanent Researcher
Laboratoire de Physique Théorique
Ecole Normale Supérieure

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ADDING MULTIMEDIA Stand Up To Cancer Announces $11M Collaborative, Multi-Disciplinary Research Program; Microsoft Will Bring Power of AI to Investigate Immune System Response to Cancers
“Convergence” Teams of Life Scientists, Bioengineers and Microsoft Machine Learning Experts to Investigate New Cancer Therapies

Lustgarten Foundation and Society for Immunotherapy of Cancer (SITC) Provide Key Support

January 30, 2018 10:08 PM Eastern Standard Time
SANTA MONICA, Calif.--(BUSINESS WIRE)--Stand Up To Cancer (SU2C) announces today a “Convergence 2.0” research initiative that awards $11 million to seven multi-disciplinary research teams to investigate immune system response to cancers. The multi-institutional teams being announced today at SU2C’s Scientific Summit draw from the nation’s top academic research centers and will have access to Microsoft Research’s experts in machine learning and artificial intelligence.

“Our first convergence research cohort, announced in 2016, established the effectiveness of a broad multidisciplinary approach for creating models for how cancer grows and reacts to treatment”
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https://www.businesswire.com/news/home/20180130005543/en/Stand-Cancer-Announces-11M-Collaborative-Multi-Disciplinary-Research

Now I officially believe 100% CEO Renegade Roger Lias is mentally unstable IF he does not allow Pergrine Pharmaceuticals ...now CDMO, to continue R&D research with Dr Jedd Wolchok MSK etc which is so damn vital to increase the so called residual value he states, and Roger has no clue it seems.....

**Through the support from SEAN PARKER, Stand Up To Cancer (SU2C) and the Cancer Research Institute (CRI) formed an Immunology Research Dream Team dedicated to cancer immunology: “Immunologic Checkpoint Blockade & Adoptive Cell Transfer in Cancer Therapy.” The Immunotherapy Dream Team is focused on 2 approaches for this translational cancer research project, which will unite laboratory & clinical efforts towards the immunological treatment, control, and prevention of cancer.
The 1st is investigating blockades (by inhibitory molecules called “checkpoints”) of T lymphocytes’ inhibitory receptors, which block immune responses; and the use of antibodies to remove the checkpoints, once again allowing white blood cells called T lymphocytes to kill the cancer cells.
Second, the Immunotherapy Dream Team is pursuing multiple Adoptive Cell Transfer (ACT) approaches, which increase immunity.”
DREAM TEAM LEADERSHIP: 10 scientists, incl. MSKCC’s Jedd D. Wolchok & Michel Sadelain.
http://parker.org/initiatives/immunotherapy

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=129052189