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. ------- 3-24-17 Immunovaccine PR: “Immunovaccine to Present New Preclin. Combo Therapy Data at AACR’17” …Immunovaccine conducted this research in collaboration with Peregrine Pharm. with the goal of analyzing the potential enhanced anti-cancer activity of combining DepoVax-based cancer immunotherapies with Peregrine's lead clinical product candidate bavituximab… Immunovaccine Dir./Res. Genevieve Weir will present data analyzing the potential for enhanced anti-tumor responses of PS & PD-1 targeting antibody therapies when combined with an HPV16 peptide vaccine formulated in Immunovaccine's proprietary DepoVax technology. "Our work with Peregrine, and the research it has produced, fits squarely into our corporate objective of exploring clinical stage immunotherapies that may have synergistic effects when combined with our lead candidate, DPX-Survivac," said Marianne Stanford (PhD) VP/Res. for Immunovaccine. "We look forward to discussing the results of this study, and its potential implications, with our colleagues in the scientific community at this year's AACR meeting."https://www.imvaccine.com/releases.php?releases_id=418
------------------------ 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.”
Learning more about “ACT”, MSKCC+PPHM 4-3-17 AACR’17 #1651
Apr1-5: AACR 2017, WashDChttp://tinyurl.com/mxz23gz- SUMMARY of PPHM’s 5 AACR’17 ABSTRACTS: 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 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 See 3-24-17: 5. PPHM+VANDERBILT+PRECISIONMEDICINE+PROVIDENCECC: 4-3-17/1pm #CT159/25 (Session: Ph2/3 Clinical Trials in Progress), “IFN-y Analysis In Blood & Tissue as a Potential Prognostic and/or Predictive Biomarker” (abstract embargoed, Sunrise Biomarker #3) - See below. ALSO: Peregrine Exhibiting – booth #3312.
= = = = = = = = = = = = = = = = AACR’17 PPHM#2: 4-3-17/8am #1651 - Session: TUMOR MICROENVIRONMENT & CHECKPOINTS “Targeting Phosphatidylserine in Combination with Adoptive T Cell TransferEliminates 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 ABSTRACT: 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 blockadedid 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. ---------- 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: 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 ------------------------------ 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 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 = = = = = = = = = 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
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 TransferEliminates 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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