AI
Friday, April 14, 2017 5:33:35 PM
AACR 2017 (WashDC) – All 5 PPHM Poster Images
5 PPHM ABSTRACTS: 2/MemSloan, 1/Immunovaccine, 1/PPHM-Only. There’s also a 5th one (PPHM, Vanderbilt, Precision-for-Medicine, Providence CC) in the “Ph2/3 Clinical Trials” session: “CT159/25: IFN-y Analysis in Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” – this is our new (3rd) Sunrise Biomaker analysis - see below.
...Add ImmunoVaccine Inc. (Halifax https://www.imvaccine.com ) to the list of collaborators.
...#1651(Apr3) is the newly revealed 2nd joint PPHM+Mem.Sloan/Wolchok preclin. study: “PS Targeting + Adoptive T Cell Transfer Eliminates Advanced Tumors without Off-Target Toxicities in a Melanoma Model”. IMO, the Wolchok Lab is saying in #1651 that the effectiveness of either type of Adoptive TCell Transfer (ACT), be it TCRs or CAR T (ie, the newer gene-modified T cells approaches), is improved by combining with Bavi and makes for a “highly desirable strategy.” - see more below.
...Memorial Sloan’s Dr. Jedd. Wolchok is co-author of 9 AACR’17 abstracts. 2 of the 9 are w/PPHM re: PS-Targeting. With biotechs, he has one each with Genocea Biosciences(ex-vivo screening), Infinity Pharm(Ph1), Leap Ther.(Ph1), and two with BMS(Ph1+Ph3). The 8th is MSKCC ONLY, and the 9th is jointly w/Cedars-Sinai/LA. http://www.abstractsonline.com/pp8/#!/4292 .
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AACR’17: http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=105
Abstracts: http://www.abstractsonline.com/pp8/#!/4292
SUMMARY of PPHM’s 5 AACR’17 ABSTRACTS: ...Details below.
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” <=NEW(2nd) Joint MemSloan/PPHM study SEE: http://tinyurl.com/lxlltd6
3. PPHM: 4-4-17/8am #3652, “PSTargeting+LAG3+AntiPD1 Significantly Enhances Anti-Tumor Activity, Triple- MBC”
4. IMMUNOVACCINE+PPHM: 4-4-17/8am #3657, ”PSTargeting Enhances Anti-Tumor Activity of a Tumor Vaccine(DepoVax), HPV-Induced Tumor” https://www.imvaccine.com
5. PPHM+VANDERBILT+PRECISIONMEDICINE+PROVIDENCECC: 4-3-17/1pm #CT159/25 (Session: Phase II/III Clinical Trials in Progress), “IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” (Sunrise Biomarker #3) SEE: http://tinyurl.com/ktzr782
ALSO: Peregrine Exhibiting – booth #3312.
AACR’17 DETAILS (5 PPHM ABSTRACTS)...
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1. 4-2-17/1pm #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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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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3. 4-4-17/8am #3652 - Session: BITES BISPECIFICS & CHECKPOINTS
“Combinational Activity of LAG3 & PD-1 Targeted Therapies is Significantly Enhanced by the Addition of Phosphatidylserine Targeting Antibodies and Establishes an Anti-Tumor Memory Response in Murine Triple Negative Breast Cancer”
=> Michael J. Gray, Jian Gong, Jeff Hutchins, Bruce Freimark (Peregrine Pharmaceuticals)
ABSTRACT:
Previous studies utilizing NanoString immune profile analysis demonstrated that intratumoral levels of LAG3 (lymphocyte activation gene 3) mRNA increased in response to phosphatidylserine (PS) and PD-1 targeting antibodies in murine triple negative breast cancers (TNBC). This suggests LAG3 acts to attenuate immune system activation during I/O therapies - and that PD-1 and LAG3 function cooperatively in suppressing immune system activation. Here we show that adding PS targeting antibodies can further enhance the effectiveness of antibodies targeting LAG3 and/or LAG3+PD-1. We first examined expression of LAG3 and PD-1 in the murine TNBC model E0771 and found that tumor associated T-cells (CD4+ and CD8+) have expression of both markers. Mice implanted with TNBC tumors were next treated with antibodies targeting PS, PD-1, and LAG3 alone and in combination with each other. Interestingly, the addition of PS targeting antibodies not only increased the effectiveness anti-PD-1 effectiveness as previously observed, but also enhanced anti-LAG3 treatment, showing that PS targeting antibodies are capable of augmenting additional I/O therapeutic regimens. Comparison of anti-PD-1+LAG3 combination vs. single anti-PD-1 or anti-LAG3 treatments showed moderately more anti-tumor activity than single treatments, however the addition of PS targeting antibodies to either checkpoint inhibitor was as equally effective in inhibiting tumor growth as observed in the anti-LAG3+PD-1 treatment. Further comparison of antibody treatments targeting PD-1+LAG3 vs. PS+PD-1+LAG3 demonstrated that the addition of PS targeting antibodies resulted in a significant decrease in tumor growth with complete tumor regression in 80% of the animals (along with the ability to completely reject secondary TNBC challenge) compared to 0% in the anti-PD-1+LAG3 treatment group. Immunoprofiling showed that the addition of PS targeting antibodies to these checkpoint therapies, including the combination of anti-PD-1+LAG3, resulted in a phenotype associated with enhanced immune system activation and immune-surveillance including increased tumor infiltrating lymphocytes (TILs) with upregulation of T-cell associated activation pathways, increased Th1 to Th2 profile, and enhanced antigen presentation processing /presentation mechanisms along with cytokines associated with immune system activation. Overall our data demonstrate that adding PS targeting antibodies to clinically relevant therapies, including PD-1 and LAG3, may significantly enhance their ability to activate and redirect the host immune system into recognition and elimination of tumor cells compared to single and combinational treatments that lack PS targeting antibodies.
POSTER #3652 IMAGE: http://www.peregrineinc.com/images/stories/pdfs/aacr2017gray.pdf
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4. 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.
POSTER #3657 IMAGE: (from ImmunoVaccine.com)
https://www.imvaccine.com/userfiles/IMMUNOVACCINE%20AACR%20Poster%202017MAR14%20GW(2).pdf
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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
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#5. 4-3-17/1pm #CT159/25 - Session: Phase III Clinical Trials & Phase II/III Clinical Trials in Progress
http://www.abstractsonline.com/pp8/#!/4292/presentation/12566
”IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker”
=> Nikoletta Kallinteris 1, Leora Horn 2, Min Tang 1, Tobias Guennel 3, Shen Yin 1, Jennifer Lai 1, Joseph Shan 1, Rachel E. Sanborn [Providence CC, Dir./Thoracic-Oncology http://cancergrace.org/faculty/rachel-sanborn-md - Dr. Sanborn's Conflicts of interest: DNA, AZN]
1=Peregrine Pharmaceuticals
2=Vanderbilt-Ingram Cancer Center, Nashville, TN
3=Precision for Medicine, Frederick, MD
4=Providence Cancer Center, Portland, OR
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FROM PPHM’s 4-4-17 PR: http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=1020046
…”SUNRISE Data Analysis Demonstrates Stat. Significant Overall Survival (OS) Improvement in Patients Receiving Bavituximab+Docetaxel and Subsequent Immunotherapy Compared to Placebo+Docetaxel and Subsequent Immunotherapy”… AACR’17 presentation (#CT159/25) of results of a new analysis of the Phase III SUNRISE trial… Data demonstrated that for patients in the study's BAVI+DOCE treatment arm who received subsequent immunotherapy, the mOS was not reached, while mOS was 13.0mos. for patients in the study's DOCE+PLACEBO arm who received subsequent immunotherapy [HR=0.43; p=.005]. These are the first clinical results reported supporting the hypothesis that bavituximab may modulate the tumor microenvironment to enhance the anti-tumor activity of immunotherapy agents... The presentation highlighted an analysis in which the company evaluated the impact of subsequent immunotherapy treatment, as well as patients' pre-treatment interferon gamma (IFN-y) levels on overall survival. Overall, low peripheral IFN-y correlated with more favorable OS in the patients receiving BAVI+DOCE and is a biomarker of interest. Data were also analyzed by low vs. high IFN-y levels. For patients with low pre-treatment IFN-y levels who received subsequent immunotherapy, those in the BAVI+DOCE arm did not reach mOS compared to mOS of 12.1mos. for the DOCE+PLACEBO arm [HR=0.24; p<.001].
Joseph Shan, Peregrine’s VP of Clinical & Regulatory Affairs:
"We are extremely encouraged by the results of these exploratory analyses which provide further clinical rationale for combining bavituximab and checkpoint inhibitors. This will be the key focus for upcoming early phase clinical trials, which includes a study of bavituximab and pembrolizumab in head and neck cancer through our ongoing collaboration with the NCCN.”
...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. PS-targeting antibodies have demonstrated an ability to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. Bavituximab is believed to override PS immunosuppressive signaling by blocking the engagement of PS with its receptors and sending an alternate immune activating signal.
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ABSTRACT #159/25:
BACKGROUND: SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-y levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome.
METHODS: Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-y levels using the Simoa TM assay (Myriad RBM, Austin, TX). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-y by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-y levels with OS. Patients were classified paradoxically as IFN-y "low" with a favorable disease prognosis vs. "high" associated with more aggressive disease based on the median.
RESULTS: Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-y high or low (< cut-off) using cut-off 0.093 pg/ml, which is the median IFN-y value in the D+B group. Median overall survival (mOS) in all patients with IFN-y low is 11.3mos. (95% CI, 10.1-13.5) vs. 10.4mos. (95% CI, 8.4-11.3) in all IFN-y high; p=0.047. mOS of D+B arm is 11.6mos. (95% CI, 10.2-13.9) and 11.1mos. (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-y low. mOS of D+B arm is 9.0mos. (95% CI, 6.7-11.2) and 10.6mos. (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-y high. With the limited intratumoral IFN-y gene expression data (n=33), no statistically significant correlation with OS was observed.
CONCLUSIONS: Correlative approaches identified low peripheral low IFN-y at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors.
POSTER #159/25 IMAGE:
http://www.peregrineinc.com/images/stories/pdfs/aacr2017kallinteris.pdf
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**NOTE: Per JDM find, we know that 96 Sunrise Pts received “Subsequent Immunotherapy” - see 10-13-16 ASM SKing Slide#14: http://tinyurl.com/n2bajew
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This AACR’17 #CT159/25 IFN-y is certainly the 3rd Sunrise Biomarker.
Known Ph.3 Sunrise Biomarkers/UTSW’s Dr. David Gerber et al:
#1=B2GPI: 10-10-16 http://tinyurl.com/hp73njt
#2=Complement & IL-10 Pathways(12-7-16/IASLC delayed, “not done”, after prelim. abstract said, “Pts=193, within the 1st subgroup of N=104, a 2nd subgroup isolated: MOS 5.9=>12.5mos”
#3=IFN-y (this 4-3-17 AACR’17 one, #CT159/25)
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***Maybe Dr. Ranee Mehra (Johns Hopkins, PPHM’s NCCN Bavi+Keytruda Head&Neck Ph2 P.I.) will stop by...
...Dr. Mehra’s work with Biomarker IFN-y seems to dovetail into PPHM’s newly revealed Sunrise Biomarker #3 to be presented 4-3-17 at AACR’17: #CT159/25, “IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” ( http://tinyurl.com/zaz525l ).
Note: DR. RANEE MEHRA was co-author of ASCO’16, “Biomarkers & Response to Pembro(Keytruda) in Recurrent/Metastatic Head & Neck Cancer” - Conclusion: “The IFN-y signature score was significantly associated with ORR, PFS, and OS (all, P< .001)… PD-L2 & IFN-y signature may be associated with clinical response to Pembro[Keytruda] and may offer addl. strategies to improve prediction of response.” http://meetinglibrary.asco.org/content/165708-176
MORE: http://tinyurl.com/h8gzkww
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INTERESTING: Mem. Sloan’s Dr. Jedd. Wolchok is co-author of 9 AACR’17 abstracts. 2 of the 9 are w/PPHM re: PS-Targeting. With biotechs, he has one each with Genocea Biosciences(ex-vivo screening), Infinity Pharm(Ph1), Leap Ther.(Ph1), and two with BMS(Ph1+Ph3). The 8th is MSKCC ONLY, and the 9th is 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.
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”
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2-28-17: Collabs with Mem.Sloan(Wolchok), Duke, MDA, Rutgers, ImmunoVaccine, UTSW… http://tinyurl.com/heg9t3v
BAVI MOA 11-14-16: SITC’16: Joint Memorial Sloan Kettering (Wolchok Lab) & PPHM poster on Triple Combo Rad+Bavi+aPD1 vs. Melanoma http://tinyurl.com/js3fca4
“PS Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma” (same as AACR’17 4-2-17 #574)
DR. JEDD WOLCHOK: "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. 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."
DR. TAHA MERGHOUB (Co-Dir., Ludwig Collaborative Lab at MSK): "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. 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."
5-29-15: Peregrine & Sloan Kettering Enter Collab. to “Investigate Novel PS-Targeting Immunotherapy Combos” http://tinyurl.com/o3k9ux8
...Dr. Wolchock states, ”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.”
...Dr. Taha Merghoub states, "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.”
POSSIBLE GENESIS OF IMMUNOVACCINE COLLAB???
11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
SITC’16 PPHM/Mem.Sloan Poster – same as AACR’17 4-2-17 #574…
4-11-17/J.Hutchins speaking at Immune Profiling World-Congress'17, WashDC http://tinyurl.com/zlr5cyj
Feb2017: Chgd. To HEAT BIO!!!!!!!!!!!
xxxApr10-12 2017: “Terrapinn’s Immune Profiling World Congress 2017”, WashDC
Part of “World Vaccine Congress Washington 2017” (1 of 8 Co-Conf’s)
“The Immune Profiling World Congress USA brings together experts to discuss profiling of the immune system, how using high throughput technologies can aid therapeutic design & treatment strategies in infectious & non-infectious diseases, including cancer.”
http://www.terrapinn.com/conference/world-vaccine-congress-washington/index.stm
http://www.terrapinn.com/conference/immune-profiling-usa/
4-11-17/Day1 12:10pm: Jeff Hutchins (VP/PreClinRes., PPHM)
“Increasing the Benefits of Immune Checkpoint Therapies Through Increased Tumor Infiltrating Activated T-Cells”
*Expanding the responding population
*Sharing pre-clinical & translation data
CHGD to: 12:10 “How Immuno-Oncology Combinations Utilizing A Multi-Antigen Vaccine Could Enhance Immune Checkpoint Therapy Benefits”
*Novel therapeutic vaccines drive antigen specific tumor-infiltrating lymphocytes to unlock clinical benefits in patients with poor checkpoint therapy prognosis
*Immune profiling methods on patient derived samples validate the mechanism of action for the combination approach
*Two platforms, 3 products focused on synergistic combination therapies in oncology
Dr Jeff Hutchins, CSO, VP/PreclinDEV, Heat Biologics, Inc.
- - - - - -
Chair: Dr Alison Deckhut Augustine, Branch Chief Basic Immunology, NIAID/NIH
DAY1 SPEAKERS 4-11-17(10):
...Bali Pulendran – Emory
...Dr Masahide Yano - FDA
...Dr Jeff Hutchins – Peregrine
...Dr Ali M. Harandi – Univ. of Gothenburg
...Dr Mahesh Yadav - Genentech
...Giuseppe Del Giudice - GSK Vaccines
...Mark M Davis - Stanford Univ.
...Alessandro Sette - La Jolla Infectious Disease Inst.
...Peter W. Che - Repertoire Genesis, Inc
...Dr Wayne C Koff - Human Vaccines Project, Intl. Aids Vaccine Initative
DAY2 SPEAKERS 4-12-17(4):
...Dr Roy Baynes (PD-1 Antibodies) – Merck
...Mr Bruno Gomes - iTeos Therapeutics
...Mr Lei Zheng - Johns Hopkins
...Dr Rakesh Dixit - MedImmune
5 PPHM ABSTRACTS: 2/MemSloan, 1/Immunovaccine, 1/PPHM-Only. There’s also a 5th one (PPHM, Vanderbilt, Precision-for-Medicine, Providence CC) in the “Ph2/3 Clinical Trials” session: “CT159/25: IFN-y Analysis in Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” – this is our new (3rd) Sunrise Biomaker analysis - see below.
...Add ImmunoVaccine Inc. (Halifax https://www.imvaccine.com ) to the list of collaborators.
...#1651(Apr3) is the newly revealed 2nd joint PPHM+Mem.Sloan/Wolchok preclin. study: “PS Targeting + Adoptive T Cell Transfer Eliminates Advanced Tumors without Off-Target Toxicities in a Melanoma Model”. IMO, the Wolchok Lab is saying in #1651 that the effectiveness of either type of Adoptive TCell Transfer (ACT), be it TCRs or CAR T (ie, the newer gene-modified T cells approaches), is improved by combining with Bavi and makes for a “highly desirable strategy.” - see more below.
...Memorial Sloan’s Dr. Jedd. Wolchok is co-author of 9 AACR’17 abstracts. 2 of the 9 are w/PPHM re: PS-Targeting. With biotechs, he has one each with Genocea Biosciences(ex-vivo screening), Infinity Pharm(Ph1), Leap Ther.(Ph1), and two with BMS(Ph1+Ph3). The 8th is MSKCC ONLY, and the 9th is jointly w/Cedars-Sinai/LA. http://www.abstractsonline.com/pp8/#!/4292 .
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AACR’17: http://www.aacr.org/Meetings/Pages/MeetingDetail.aspx?EventItemID=105
Abstracts: http://www.abstractsonline.com/pp8/#!/4292
SUMMARY of PPHM’s 5 AACR’17 ABSTRACTS: ...Details below.
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” <=NEW(2nd) Joint MemSloan/PPHM study SEE: http://tinyurl.com/lxlltd6
3. PPHM: 4-4-17/8am #3652, “PSTargeting+LAG3+AntiPD1 Significantly Enhances Anti-Tumor Activity, Triple- MBC”
4. IMMUNOVACCINE+PPHM: 4-4-17/8am #3657, ”PSTargeting Enhances Anti-Tumor Activity of a Tumor Vaccine(DepoVax), HPV-Induced Tumor” https://www.imvaccine.com
5. PPHM+VANDERBILT+PRECISIONMEDICINE+PROVIDENCECC: 4-3-17/1pm #CT159/25 (Session: Phase II/III Clinical Trials in Progress), “IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” (Sunrise Biomarker #3) SEE: http://tinyurl.com/ktzr782
ALSO: Peregrine Exhibiting – booth #3312.
AACR’17 DETAILS (5 PPHM ABSTRACTS)...
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1. 4-2-17/1pm #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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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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3. 4-4-17/8am #3652 - Session: BITES BISPECIFICS & CHECKPOINTS
“Combinational Activity of LAG3 & PD-1 Targeted Therapies is Significantly Enhanced by the Addition of Phosphatidylserine Targeting Antibodies and Establishes an Anti-Tumor Memory Response in Murine Triple Negative Breast Cancer”
=> Michael J. Gray, Jian Gong, Jeff Hutchins, Bruce Freimark (Peregrine Pharmaceuticals)
ABSTRACT:
Previous studies utilizing NanoString immune profile analysis demonstrated that intratumoral levels of LAG3 (lymphocyte activation gene 3) mRNA increased in response to phosphatidylserine (PS) and PD-1 targeting antibodies in murine triple negative breast cancers (TNBC). This suggests LAG3 acts to attenuate immune system activation during I/O therapies - and that PD-1 and LAG3 function cooperatively in suppressing immune system activation. Here we show that adding PS targeting antibodies can further enhance the effectiveness of antibodies targeting LAG3 and/or LAG3+PD-1. We first examined expression of LAG3 and PD-1 in the murine TNBC model E0771 and found that tumor associated T-cells (CD4+ and CD8+) have expression of both markers. Mice implanted with TNBC tumors were next treated with antibodies targeting PS, PD-1, and LAG3 alone and in combination with each other. Interestingly, the addition of PS targeting antibodies not only increased the effectiveness anti-PD-1 effectiveness as previously observed, but also enhanced anti-LAG3 treatment, showing that PS targeting antibodies are capable of augmenting additional I/O therapeutic regimens. Comparison of anti-PD-1+LAG3 combination vs. single anti-PD-1 or anti-LAG3 treatments showed moderately more anti-tumor activity than single treatments, however the addition of PS targeting antibodies to either checkpoint inhibitor was as equally effective in inhibiting tumor growth as observed in the anti-LAG3+PD-1 treatment. Further comparison of antibody treatments targeting PD-1+LAG3 vs. PS+PD-1+LAG3 demonstrated that the addition of PS targeting antibodies resulted in a significant decrease in tumor growth with complete tumor regression in 80% of the animals (along with the ability to completely reject secondary TNBC challenge) compared to 0% in the anti-PD-1+LAG3 treatment group. Immunoprofiling showed that the addition of PS targeting antibodies to these checkpoint therapies, including the combination of anti-PD-1+LAG3, resulted in a phenotype associated with enhanced immune system activation and immune-surveillance including increased tumor infiltrating lymphocytes (TILs) with upregulation of T-cell associated activation pathways, increased Th1 to Th2 profile, and enhanced antigen presentation processing /presentation mechanisms along with cytokines associated with immune system activation. Overall our data demonstrate that adding PS targeting antibodies to clinically relevant therapies, including PD-1 and LAG3, may significantly enhance their ability to activate and redirect the host immune system into recognition and elimination of tumor cells compared to single and combinational treatments that lack PS targeting antibodies.
POSTER #3652 IMAGE: http://www.peregrineinc.com/images/stories/pdfs/aacr2017gray.pdf
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4. 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.
POSTER #3657 IMAGE: (from ImmunoVaccine.com)
https://www.imvaccine.com/userfiles/IMMUNOVACCINE%20AACR%20Poster%202017MAR14%20GW(2).pdf
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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
= = = = = =THIS A NEW (3RD) KNOWN SUNRISE BIOMAKER ANALYSIS:
#5. 4-3-17/1pm #CT159/25 - Session: Phase III Clinical Trials & Phase II/III Clinical Trials in Progress
http://www.abstractsonline.com/pp8/#!/4292/presentation/12566
”IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker”
=> Nikoletta Kallinteris 1, Leora Horn 2, Min Tang 1, Tobias Guennel 3, Shen Yin 1, Jennifer Lai 1, Joseph Shan 1, Rachel E. Sanborn [Providence CC, Dir./Thoracic-Oncology http://cancergrace.org/faculty/rachel-sanborn-md - Dr. Sanborn's Conflicts of interest: DNA, AZN]
1=Peregrine Pharmaceuticals
2=Vanderbilt-Ingram Cancer Center, Nashville, TN
3=Precision for Medicine, Frederick, MD
4=Providence Cancer Center, Portland, OR
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FROM PPHM’s 4-4-17 PR: http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=1020046
…”SUNRISE Data Analysis Demonstrates Stat. Significant Overall Survival (OS) Improvement in Patients Receiving Bavituximab+Docetaxel and Subsequent Immunotherapy Compared to Placebo+Docetaxel and Subsequent Immunotherapy”… AACR’17 presentation (#CT159/25) of results of a new analysis of the Phase III SUNRISE trial… Data demonstrated that for patients in the study's BAVI+DOCE treatment arm who received subsequent immunotherapy, the mOS was not reached, while mOS was 13.0mos. for patients in the study's DOCE+PLACEBO arm who received subsequent immunotherapy [HR=0.43; p=.005]. These are the first clinical results reported supporting the hypothesis that bavituximab may modulate the tumor microenvironment to enhance the anti-tumor activity of immunotherapy agents... The presentation highlighted an analysis in which the company evaluated the impact of subsequent immunotherapy treatment, as well as patients' pre-treatment interferon gamma (IFN-y) levels on overall survival. Overall, low peripheral IFN-y correlated with more favorable OS in the patients receiving BAVI+DOCE and is a biomarker of interest. Data were also analyzed by low vs. high IFN-y levels. For patients with low pre-treatment IFN-y levels who received subsequent immunotherapy, those in the BAVI+DOCE arm did not reach mOS compared to mOS of 12.1mos. for the DOCE+PLACEBO arm [HR=0.24; p<.001].
Joseph Shan, Peregrine’s VP of Clinical & Regulatory Affairs:
"We are extremely encouraged by the results of these exploratory analyses which provide further clinical rationale for combining bavituximab and checkpoint inhibitors. This will be the key focus for upcoming early phase clinical trials, which includes a study of bavituximab and pembrolizumab in head and neck cancer through our ongoing collaboration with the NCCN.”
...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. PS-targeting antibodies have demonstrated an ability to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. Bavituximab is believed to override PS immunosuppressive signaling by blocking the engagement of PS with its receptors and sending an alternate immune activating signal.
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ABSTRACT #159/25:
BACKGROUND: SUNRISE, a global, double-bind, Phase III trial of docetaxel (D) plus bavituximab (B) or D plus placebo (P) in previously treated non-squamous non-small cell lung cancer (NSCLC), demonstrated similar overall survival (OS) in both treatment arms. Immune correlate analyses including pre-treatment IFN-y levels in blood and tumor tissue were used to potentially identify prognostic and/or predictive correlation with clinical outcome.
METHODS: Serum was isolated from all randomized NSCLC patients at screening, periodically during treatment and at disease progression for evaluation of IFN-y levels using the Simoa TM assay (Myriad RBM, Austin, TX). Available archival tissue was also tested for 91- immune gene activation markers, including IFN-y by the Fluidigm-based gene-expression platform (Sirona Dx, Lake Oswego, OR). Kaplan-Meier statistical methods and Cox proportion hazards models were utilized to evaluate and contrast the correlation of peripheral and intratumoral IFN-y levels with OS. Patients were classified paradoxically as IFN-y "low" with a favorable disease prognosis vs. "high" associated with more aggressive disease based on the median.
RESULTS: Pretreatment serum results were available for 582 out of the 597 randomized patients. Each patient was classified to be pre-treatment IFN-y high or low (< cut-off) using cut-off 0.093 pg/ml, which is the median IFN-y value in the D+B group. Median overall survival (mOS) in all patients with IFN-y low is 11.3mos. (95% CI, 10.1-13.5) vs. 10.4mos. (95% CI, 8.4-11.3) in all IFN-y high; p=0.047. mOS of D+B arm is 11.6mos. (95% CI, 10.2-13.9) and 11.1mos. (95% CI, 9.1-14.7) in the D group; p=0.982 for IFN-y low. mOS of D+B arm is 9.0mos. (95% CI, 6.7-11.2) and 10.6mos. (95% CI, 8.9-13.0) in the D group; p=0.252 for IFN-y high. With the limited intratumoral IFN-y gene expression data (n=33), no statistically significant correlation with OS was observed.
CONCLUSIONS: Correlative approaches identified low peripheral low IFN-y at pretreatment as a biomarker of interest correlating with more favorable clinical outcomes and is consistent with the hypothesis that bavituximab may demonstrate more immunomodulatory effects in patients with “immune cold” tumors.
POSTER #159/25 IMAGE:
http://www.peregrineinc.com/images/stories/pdfs/aacr2017kallinteris.pdf
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**NOTE: Per JDM find, we know that 96 Sunrise Pts received “Subsequent Immunotherapy” - see 10-13-16 ASM SKing Slide#14: http://tinyurl.com/n2bajew
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This AACR’17 #CT159/25 IFN-y is certainly the 3rd Sunrise Biomarker.
Known Ph.3 Sunrise Biomarkers/UTSW’s Dr. David Gerber et al:
#1=B2GPI: 10-10-16 http://tinyurl.com/hp73njt
#2=Complement & IL-10 Pathways(12-7-16/IASLC delayed, “not done”, after prelim. abstract said, “Pts=193, within the 1st subgroup of N=104, a 2nd subgroup isolated: MOS 5.9=>12.5mos”
#3=IFN-y (this 4-3-17 AACR’17 one, #CT159/25)
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***Maybe Dr. Ranee Mehra (Johns Hopkins, PPHM’s NCCN Bavi+Keytruda Head&Neck Ph2 P.I.) will stop by...
...Dr. Mehra’s work with Biomarker IFN-y seems to dovetail into PPHM’s newly revealed Sunrise Biomarker #3 to be presented 4-3-17 at AACR’17: #CT159/25, “IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” ( http://tinyurl.com/zaz525l ).
Note: DR. RANEE MEHRA was co-author of ASCO’16, “Biomarkers & Response to Pembro(Keytruda) in Recurrent/Metastatic Head & Neck Cancer” - Conclusion: “The IFN-y signature score was significantly associated with ORR, PFS, and OS (all, P< .001)… PD-L2 & IFN-y signature may be associated with clinical response to Pembro[Keytruda] and may offer addl. strategies to improve prediction of response.” http://meetinglibrary.asco.org/content/165708-176
MORE: http://tinyurl.com/h8gzkww
= = = = = = = = =
INTERESTING: Mem. Sloan’s Dr. Jedd. Wolchok is co-author of 9 AACR’17 abstracts. 2 of the 9 are w/PPHM re: PS-Targeting. With biotechs, he has one each with Genocea Biosciences(ex-vivo screening), Infinity Pharm(Ph1), Leap Ther.(Ph1), and two with BMS(Ph1+Ph3). The 8th is MSKCC ONLY, and the 9th is 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.
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”
= = = = = = = = = = = = =
2-28-17: Collabs with Mem.Sloan(Wolchok), Duke, MDA, Rutgers, ImmunoVaccine, UTSW… http://tinyurl.com/heg9t3v
BAVI MOA 11-14-16: SITC’16: Joint Memorial Sloan Kettering (Wolchok Lab) & PPHM poster on Triple Combo Rad+Bavi+aPD1 vs. Melanoma http://tinyurl.com/js3fca4
“PS Targeting Antibody in Combination with Checkpoint Blockade & Tumor Radiation Therapy Promotes Anti-Cancer Activity in Mouse Melanoma” (same as AACR’17 4-2-17 #574)
DR. JEDD WOLCHOK: "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. 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."
DR. TAHA MERGHOUB (Co-Dir., Ludwig Collaborative Lab at MSK): "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. 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."
5-29-15: Peregrine & Sloan Kettering Enter Collab. to “Investigate Novel PS-Targeting Immunotherapy Combos” http://tinyurl.com/o3k9ux8
...Dr. Wolchock states, ”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.”
...Dr. Taha Merghoub states, "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.”
POSSIBLE GENESIS OF IMMUNOVACCINE COLLAB???
11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
SITC’16 PPHM/Mem.Sloan Poster – same as AACR’17 4-2-17 #574…
4-11-17/J.Hutchins speaking at Immune Profiling World-Congress'17, WashDC http://tinyurl.com/zlr5cyj
Feb2017: Chgd. To HEAT BIO!!!!!!!!!!!
xxxApr10-12 2017: “Terrapinn’s Immune Profiling World Congress 2017”, WashDC
Part of “World Vaccine Congress Washington 2017” (1 of 8 Co-Conf’s)
“The Immune Profiling World Congress USA brings together experts to discuss profiling of the immune system, how using high throughput technologies can aid therapeutic design & treatment strategies in infectious & non-infectious diseases, including cancer.”
http://www.terrapinn.com/conference/world-vaccine-congress-washington/index.stm
http://www.terrapinn.com/conference/immune-profiling-usa/
4-11-17/Day1 12:10pm: Jeff Hutchins (VP/PreClinRes., PPHM)
“Increasing the Benefits of Immune Checkpoint Therapies Through Increased Tumor Infiltrating Activated T-Cells”
*Expanding the responding population
*Sharing pre-clinical & translation data
CHGD to: 12:10 “How Immuno-Oncology Combinations Utilizing A Multi-Antigen Vaccine Could Enhance Immune Checkpoint Therapy Benefits”
*Novel therapeutic vaccines drive antigen specific tumor-infiltrating lymphocytes to unlock clinical benefits in patients with poor checkpoint therapy prognosis
*Immune profiling methods on patient derived samples validate the mechanism of action for the combination approach
*Two platforms, 3 products focused on synergistic combination therapies in oncology
Dr Jeff Hutchins, CSO, VP/PreclinDEV, Heat Biologics, Inc.
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Chair: Dr Alison Deckhut Augustine, Branch Chief Basic Immunology, NIAID/NIH
DAY1 SPEAKERS 4-11-17(10):
...Bali Pulendran – Emory
...Dr Masahide Yano - FDA
...Dr Jeff Hutchins – Peregrine
...Dr Ali M. Harandi – Univ. of Gothenburg
...Dr Mahesh Yadav - Genentech
...Giuseppe Del Giudice - GSK Vaccines
...Mark M Davis - Stanford Univ.
...Alessandro Sette - La Jolla Infectious Disease Inst.
...Peter W. Che - Repertoire Genesis, Inc
...Dr Wayne C Koff - Human Vaccines Project, Intl. Aids Vaccine Initative
DAY2 SPEAKERS 4-12-17(4):
...Dr Roy Baynes (PD-1 Antibodies) – Merck
...Mr Bruno Gomes - iTeos Therapeutics
...Mr Lei Zheng - Johns Hopkins
...Dr Rakesh Dixit - MedImmune
