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SITC’17(Nov8-12) Abstracts released (Sunrise, PPHM+MSKCC/preclin)…

Nov8-12 2017: “(SITC) Society for Immunotherapy of Cancer 32nd Annual Meeting”, Natl-Harbor MD
”The premier destination for scientific exchange, education, and networking in the Cancer Immunotherapy Field”
SITC = The Society for Immunotherapy of Cancer http://www.sitcancer.org
SITC 2017 Meeting: http://www.sitcancer.org/2017/home
Abstracts: http://www.sitcancer.org/2017/abstracts All abstracts submitted to the SITC 32nd Annual Meeting will be published in the Journal for ImmunoTherapy of Cancer (JITC), the official journal of SITC. Regular abstracts will be published on Nov7 & LBA's will be pub. on Dec7.
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1. #P87: “Results of Epigenetic-Based Quantitative PCR Assisted Immune Cell Counting Analysis in Bavituximab SUNRISE Trial Subgroup”
https://www.sitcancer.org/2017/abstracts/titles/biomarkers-immune-monitoring
Nikoletta L. Kallinteris 1, Thomas O. Kleen 2, Min Tang 1, Shen Yin 1, Tobi Guennel 3, Jennifer Lai 1, Victor Nowakowski 2, Steven Olek 2, Steve King 1, Joseph S. Shan 1
1 Peregrine Pharmaceuticals
2 Epiontis GmbH, Berlin, Germany
3 Precision Medicine, Frederick MD
SITC’17 #P87 ABSTRACT:
BACKGROUND
SUNRISE (NCT01999673 https://www.clinicaltrials.gov/ct2/show/NCT01999673 ), a global, double-blind, randomized Phase III trial of docetaxel bavituximab (D+B) or docetaxel+placebo (D+P) in previously treated non-squamous NSCLC, demonstrated similar OS in the intent-to-treat population (n=597). In the subgroup of 93 pts who received subsequent Immune Checkpoint Inhibitors (ICI), mOS was not reached (95%CI, 15.2-NA) in the D+B group (n=46) and was 12.6 mos. (95%CI, 10.4-17.8) for patients in the D+P group (n=47) (HR for death, .46; P=.006). Epigenetic-based quantitative real-time PCR assisted cell counting (qPACC) of immune cells in blood was used to potentially identify predictive biomarkers.
METHODS
DNA was isolated from peripheral blood mononuclear cells (PBMC) from randomized ptss and treated with bisulfite leading to conversion of de-methylated cytosine (epigenetically active) residues into uracil, but left methylated ones unaffected. The de-methylation status of DNA regions, previously identified of being specific to respective immune cell phenotypes sorted by FACS: CD3+, CD4+, CD8+, TFH, TH17, PD1, Foxp3, naive CD8, MDSC, CD14+, NK56+, B-cells, GNLY, and CCR6+, was quantitated by qPACC. The number of de-methylated gene copies per biomarker was quantitated and translated into % total of cells in the sample. Each biomarker was classified as high or low based on the median value across all pts and correlated to OS. Hazard ratios (HR) and confidence intervals (CI) were estimated using a Cox proportional-hazards model.
RESULTS
Pre-treatment (pre-tx) samples were evaluable by qPACC for 62 (32 D+B, 30 D+P) out of the 93 pts who received ICI as next line therapy after the SUNRISE assigned treatment. High pre-tx (>=median) levels correlated with statistically significant OS benefit favoring D+B for the following biomarkers: CD3+ (HR=.37, p=.023), CD4+ (HR=.32, p=.012), CD8+ (HR=.42, p=.036), PD-1 (HR=.33, p=.017), GNLY (HR=0.25, p=.011), FoxP3 (HR=.34, p=.032), naïve CD8+ (HR=.32, p=.034), B-cells (HR=.24, p=.007), MDSC (HR=.33, p=.037) NK56+ (HR=.29, p=.026). Low (<) pre-tx levels of THF correlated with OS favoring D+B (HR=.34, p=.033). No OS difference was observed for pre-tx high or low levels for TH17, CCR6, or CD14+.
CONCLUSIONS
High pre-tx levels (>=median) of circulating immune cells including T cells, B-Cells, MDSCs, NK cells correlated with significant improvement of OS in patients who received D+B then ICI compared to D+P then ICI in the SUNRISE trial. These results support further investigation of these markers in future bavituximab clinical trials
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ALSO SEE: Sunrise Biomarkers (#1/B2GPI #2/COMPL,IL10 #3/IFN-y #4/PD-L1), upd. ASCO’17
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2. #P262: “Phosphatidylserine Targeting Antibody In Combination With Tumor Radiation & Immune Checkpoint Blockade Promotes Anti-Tumor Activity in Mouse B16 Melanoma”
https://www.sitcancer.org/2017/abstracts/titles/combination-therapy
Sadna Budhu 1, Rachel Giese 1, Olivier De Henau 1, Roberta Zappasodi 1, Luis Felipe Campesato 1, Aditi Gupta 1, Christopher Barker 1, Bruce Freimark 2, Jedd D. Wolchok 1, Taha Merghoub 1
1 Memorial Sloan Kettering Cancer Center, NYC
2 Peregrine Pharmaceuticals, Inc.
SITC’17 #P262 ABSTRACT:
BACKGROUND
Phosphatidylserine (PS) is a phospholipid that is exposed on surface of apoptotic cells, viable tumor cells, tumor endothelium and activated immune cells. It has been shown to promote immunosuppressive signals in the tumor microenvironment. 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. 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.
METHODS
Mice were injected intradermally on the hind limb with 10^5 B16F10 melanoma cells. 7-10 days after implantation, tumors were treated locally with 15 Gy RT. 1 day after RT, mice were given antibodies to PS (mch1N11) [mouse chimeric/bavituximab] and PD-1 (RMP 1-10) intraperitoneally every 3 days. Tumor surface area and overall survival of mice were used to determine efficacy of the combinations. For FACS analysis, tissues were collected between 1-10 days after RT.
RESULTS
In this study, we show that irradiation 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 and anti-PD-1. 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 the immune response in the tumors of treated animals revealed an increase in M1-like macrophages in the tumors after treatment with RT and mch1N11. In addition, analysis of the systemic immune responses revealed an increase in antigen-specific CD8 T cell infiltration in the tumors as well as increased activation, effector function and differentiation in the triple combination therapy.
CONCLUSIONS
This finding highlights the potential of combining these agents to improve outcome in patients with advanced-stage melanoma and may inform the design of future clinical trials with PS targeting in multiple cancers.
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NOTE:
This same titled joint PPHM+MSKCC poster was presented twice before (to what extent has the content chgd. w/author chgs?):
A. 11-11-16/SITC’16 http://tinyurl.com/js3fca4 MSK: Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Christopher A. Barker, Jedd Wolchok, Taha Merghoub; PPHM: Kyle Schlunegger, Bruce Freimark, Jeff Hutchins
B. 4-2-17 at AACR’17 http://tinyurl.com/lxlltd6 MSK adds: Rachel Giese, Luis F. Campesato; PPHM drops: K.Schlunegger
C. Nov’17/SITC’17: MSK: adds Aditi Gupta; PPHM: drops J.Hutchins
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Peregrine began working w/Mem-Sloan-Kettering(Jedd Wolchok Lab) in Jul'15 (2 known studies a/o 4-2017: #1/Bavi+PD1+Rad, #2/Bavi+”ACT”) to investigate “Novel PS-Targeting Immunotherapy Combos”. See: http://tinyurl.com/lxlltd6
ALSO SEE: PPHM/MSKCC(Jedd Wolchok Lab) Collab: #1/Bavi+PD1+Rad, #2/Bavi+”ACT”, upd. AACR’17
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