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brand new: Harvard docs discuss blocking PS to stimulate anti-tumor immune responses--------------------
New paper out, in the latest Clinical Cancer Research-
Capitalizing on the Immunogenicity of Dying Tumor Cells
http://www.ncbi.nlm.nih.gov/pubmed/18347160?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Catia Fonseca and Glenn Dranoff
Abstract:
Cancer cell death occurs continually during tumor development and progression, whereas the
selective killing of surviving cancer cells remains the primary objective of antineoplastic treatments.
Recent insights into the immunologic consequences of cancer cell death have begun to
elucidate the ways in which host antitumor immunity is shaped during cancer pathogenesis and
then modulated by therapeutic intervention. Dying tumor cells evoke a range of host responses,
dependent in part upon the mode of cell death, which may either impede or foster additional
immune-mediated cancer destruction.Within the tumor microenvironment, the capture of
apoptotic tumor cells by macrophages and dendritic cells may trigger tolerance networks that
contribute to immune suppression, whereas the uptake of necrotic cancer cells may engender
inflammatory pathways that fuel antitumor cytotoxicity. Milk fat globule epidermal growth factor
8, a phosphatidylserine-binding protein, and MHC class I chain ^ related protein A, an NKG2D
ligand, play key roles in these competing outcomes. A deeper understanding of the mechanisms
underlying the immunogenicity of dying cells informs the crafting of strategies that exploit endogenous
or treatment-induced cancer cell death as the basis for stimulating sustained host antitumor
cytotoxic reactions.
excerpts -
Under steady-state conditions, the capture of apoptotic cells
serves as an immunoregulatory event that helps maintain
tolerance, whereas the detection of necrotic cells evokes an
inflammatory cascade that mobilizes effector responses. However,
the development and progression of cancer typically
involves both apoptotic and necrotic forms of cell death. What
are the implications of this mixed pattern of cellular demise for
the induction of antitumor immunity?.
..........
The concurrent acquisition of apoptotic and necrotic cells by
dendritic cells and macrophages in the tumor microenvironment,
however, might result in a set of conflicting signals that
drive tolerance and effector responses in parallel. Under these
conditions, a form of immunologic ‘‘gridlock’’ may ensue, in
which neither the regulatory nor activation pathways achieve
full control.
...........
Perhaps antineoplastic treatments modulate the mixture of apoptotic and necrotic cell death within tumors, thereby altering the balance of effector and regulatory T cells in favor of more
intense and sustained protection. How might this be
achieved?
...........
The principles governing the host reaction to the turnover of
normal cells provide a useful framework for considering the
consequences of cancer cell destruction (4). The programmed
death of normal cells (apoptosis) involves a well-orchestrated
sequence of events that culminates in the formation of surface
blebs and the sequestration of intracellular components with
the potential to effectuate lysis (16). Apoptosis is a critical
feature of tissue homeostasis, and the orderly detection and
clearance of cellular corpses is essential for proper tissue
remodeling and renewal. Defects in the management of early
apoptotic cells may allow the resurrection of some cells that
otherwise were committed to die, thereby increasing the risk
of transformation (17, 18). Various parenchymal cells seem
capable of ingesting their dying neighbors, but the host
immune system is especially well-adapted for scavenging
cellular remnants and debris (19).
The principal immune components charged with this task
are macrophages and dendritic cells, the key mononuclear
phagocytes. These antigen-presenting cells use a multiplicity
of receptor/ligand pairs to recognize and engulf apoptotic
cells (20). Whereas scavenger receptors, complement components,
and collectins all play important roles in clearance,
a primary ‘‘eat me’’ signal seems to be phosphatidylserine.
The centrality of this detection scheme is underscored by
its conservation throughout metazoans, including the paradigmatic
model system, Caenorhabditis elegans (21). Phosphatidylserine
is normally retained within the inner leaflet
of the surface membrane through the tonic activities of a
transporter/flippase, but upon execution of programmed
death, this lipid is translocated to the exterior envelope of
the cell (22).
Mononuclear phagocytes accomplish phosphatidlyserine based
uptake of apoptotic cells through several secreted and
surface proteins (Fig. 1). Milk fat globule epidermal growth
factor 8 (MFG-E8) and the closely related molecule Del-1 are
released into the tissue microenvironment, wherein their
discoidin domains bind phosphatidylserine on cellular corpses.
These are then internalized through the binding of RGD
sequences, encoded in the epidermal growth factor domains
of MFG-E8 and Del-1, to the avh3 and avh5 integrins
expressed on the phagocyte surface (23, 24). A second set of
opsonins that similarly bind phosphatidylserine are growth
arrest–specific gene 6 and protein S, although these secreted
proteins promote phagocyte engulfment through interactions
with the tyro family of receptor tyrosine kinases (Mer, Axl,
and Tyro-3; refs. 25, 26). The membrane proteins TIM-1 and
TIM-4 additionally detect phosphatidlyserine and contribute
to the uptake of apoptotic cells by phagocytes (27). The
essential role of these pathways in tissue homeostasis is
underscored by the development of persistent inflammation
in mice harboring mutations in these gene products (28).
Indeed, the efficient clearance of cellular corpses by mononuclear
phagocytes results in the elaboration of immunosuppressive
mediators, particularly transforming growth factor
h and IL-10, which empower dendritic cells and macrophages
to stimulate FoxP3+ expressing and other regulatory T-cell
subsets that support the maintenance of immune tolerance.
..........
MFG-E8 and perhaps other phosphatidylserine-binding proteins
are produced in the tumor microenvironment, where they
may promote Treg expansion and local immunosuppression
(30). Inhibiting the capture of dying cells through these
pathways might therefore attenuate maintenance of the local
tolerance networks (Fig. 2). In a therapeutic model of
established melanoma in mice, the combination of granulocyte
macrophage colony-stimulating factor–secreting tumor cell
vaccines with a dominant-negative MFG-E8 mutant, which
blocks phosphatidylserine-based phagocytosis (48), effectuated
the complete regressions of established tumors in the absence
of significant toxicities.
...........
Thus, systemic administration of anti–MFGE8
antibodies or other approaches that mask phosphatidylserine
might complement strategies that trigger immunogenic cell
death.
Furthermore, the gene products involved in the clearance
of apoptotic cells play decisive roles in tumor progression
through fostering angiogenesis, matrix metalloproteinase
production, epithelial-to-mesenchymal transformation, and
epithelial cell migration (49, 50). Thus, targeting these pathways might not only stimulate tumor immunity but also
antagonize pathogenic tumor mechanisms.
............
Conclusions:
Accumulating evidence indicates that the clinical activity
of many cancer therapies involves the interplay of tumor
cell autonomous effects and host immunity. An improved
understanding of the host response to dying tumor cells
provides compelling opportunities to render existing oncologic
treatments more efficacious and to develop novel
schemes to intensify endogenous antitumor reactivity.
Analogous to the way in which an intact host response is
required for antimicrobial agents to achieve pathogen
control in infectious diseases, protective antitumor immunity
will likely synergize with multiple forms of cancer
therapy. Paradoxically, the critical role of genomic instability
in driving tumor pathogenesis and the evolution of
drug-resistant variants renders cancer cells highly amenable
to immune recognition. Perhaps this vulnerability may now
be actualized through capitalizing on the host response to
death.
------------
Great to see the Harvard researchers discussing this.
j
from the updated CAVD page- Haynes contribution-
http://www.cavd.org/progressAbstracts.shtml
"We have completed the first protection trial to determine if anti-beta-2-glycoprotein-1 antibodies can prevent infection or early viral destruction of the immune system in acute SIV infection."
Bavituximab is actually an "anti-beta-2-glycoprotein-1" mab,
as is the mab (IS1) they isolated from an antiphospholipid syndrome patient in the CHAVI 005 protocol.
"Harrison, Bing Chen and Larry Liao have made single chain Fv 4E10 antibodies and whole IgG1 2F5 Mabs with mutations that selectively eliminate gp41 or lipid reactivity. They have demonstrated that both 2F5 and 4E10 require the capacity to bind to lipids to neutralize HIV-1."
Not only they "require the capacity to bind to lipids to neutralize HIV-1", but also, I think we'll see that successful neutralizing mabs NEED ONLY bind a lipid, (PS).
j
thanks thing, nice find.
That's very good to see.
j
Glenn Dranoff - immunosuppressive PS in tumors -
Clin Cancer Res. 2008 Mar 15
Capitalizing on the immunogenicity of dying tumor cells.
Fonseca C, Dranoff G.
Authors' Affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Cancer cell death occurs continually during tumor development and progression, whereas the selective killing of surviving cancer cells remains the primary objective of antineoplastic treatments. Recent insights into the immunologic consequences of cancer cell death have begun to elucidate the ways in which host antitumor immunity is shaped during cancer pathogenesis and then modulated by therapeutic intervention. Dying tumor cells evoke a range of host responses, dependent in part upon the mode of cell death, which may either impede or foster additional immune-mediated cancer destruction. Within the tumor microenvironment, the capture of apoptotic tumor cells by macrophages and dendritic cells may trigger tolerance networks that contribute to immune suppression, whereas the uptake of necrotic cancer cells may engender inflammatory pathways that fuel antitumor cytotoxicity. Milk fat globule epidermal growth factor 8, a phosphatidylserine-binding protein, and MHC class I chain-related protein A, an NKG2D ligand, play key roles in these competing outcomes. A deeper understanding of the mechanisms underlying the immunogenicity of dying cells informs the crafting of strategies that exploit endogenous or treatment-induced cancer cell death as the basis for stimulating sustained host antitumor cytotoxic reactions.
http://www.ncbi.nlm.nih.gov/pubmed/18347160?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
-----------
Very nice to see Dranoff say this,
j
class action suit against Vertex -
http://biz.yahoo.com/bw/080313/20080313006088.html?.v=1
Coughlin Stoia Geller Rudman & Robbins LLP Files Class Action Suit against Vertex Pharmaceuticals Incorporated
...The complaint charges Vertex and certain of its officers and directors with violations of the Securities Exchange Act of 1934. Vertex is a pharmaceutical company engaged in the discovery, development and commercialization of small molecule drugs for the treatment of serious diseases.
The complaint alleges that during the Class Period, defendants made false and misleading statements about the development of Vertex’s HCV protease inhibitor, telaprevir or VX-950, for the treatment of hepatitis C. Specifically, defendants made favorable statements regarding VX-950 but failed to disclose unfavorable data from a trial of the drug called PROVE 2. When the truth was disclosed on November 2, 2007, Vertex’s stock price dropped from $31.64 to $24.08 in two trading days.
According to the complaint, defendants’ statements regarding VX-950 and the PROVE 2 trial were materially false and misleading because they failed to disclose unfavorable data regarding VX-950 from the PROVE 2 trial compared to PROVE 1. Specifically, PROVE 1 showed that patients taking VX-950 experienced 16% greater total viral reduction after twelve weeks compared to the control group. The results of PROVE 2, which defendants did not disclose during the Class Period, showed an advantage over the control group of only six percent...
and VEA info -
Abstract Number: 4051
Session Title:
Immunoconjugates, Peptides, and Protein Therapeutics
Presentation Title:
Vasopermeation enhancement agents: Antibody and immune cell localization in the tumor microenvironment
Presentation Start/End Time:
Tuesday, Apr 15, 2008, 8:00 AM -12:00 PM
Location:
Author Block:
Keith A. Luhrs, Kelly A. Felton, Wendy J. Schulte, Desmond BS Pink, Aparna I. Roy, Van Nguyen, Lilly Mechetner, Bruce Freimark, Debra A. Harris, Christian Frosch, Steven W. King, Andries Zijlstra, John D. Lewis, Missag H. Parseghian. Peregrine Pharmaceuticals, Inc., Tustin, CA, Innovascreen Inc.,, Halifax, NS, Canada, BioBroker, Baesweiler, Germany, Vanderbilt University, Nashville, TN, University of Western Ontario, London, ON, Canada
Vasopermeation Enhancement Agents (VEAs) are a new class of biologics that are designed to boost the uptake of cancer therapeutics at the tumor site relative to healthy tissues. This results in a greater efficacy of the therapeutics without increasing dosages given to the patient. VEAs comprise tumor-specific antibodies fused to vasoactive compounds that are co-administered with standard chemotherapeutics. The lead vasoactive compound under investigation is a fragment of Interleukin-2 (IL-2) fused to a novel tumor-targeting antibody. The concept entails causing the specific enhanced uptake of a co-administered chemotherapeutic drug through the establishment of an increased vascular permeability at the tumor site. In recent years, we have demonstrated tumor-specific vasoactivity of VEA constructs using a unique in vivo avian extraembryonic tissue system. Earlier work by our group using intravital fluorescence imaging in the chorioallantoic membrane (CAM) has allowed us to visualize and quantify interstitial penetration of blood plasma into xenograft tumor implants over time for a panel of VEA candidates. Here, we present data tracking the localization of VEA constructs to the tumor microenvironment in vivo and the identification of a newly-recruited heterophil population that is not normally prevalent in tumors, even in ones targeted by our control antibodies. Studies comparing results in avian and murine tumor models have been conducted to further evaluate the avian system as an alternative to mouse models for evaluating VEA activity in vivo. Localization of VEAs to xenograft tumors in a traditional nude mouse model are presented, along with a visual analysis of immune cells that are enriched in the tumor microenvironment in the presence of these vasoactive compounds. Furthermore, a comparison is presented of the efficacy results for some key VEA constructs in our avian system and a murine tumor model. We believe we are the first to report on an avian embryonic system being utilized for the commercial evaluation of a potential drug candidate illustrating its applicability in drug development and its synergy with conventional murine models. Furthermore, we believe this comparison of the CAM and murine tumor systems may be an important step forward in the efficient and cost effective in vivo screening of biologics affecting tumor vasculature.
--------
j
and BAVI CYTOKINE info ---------------
Abstract 4079
Session Title: Immunoconjugates, Peptides, and Protein Therapeutics
Presentation Title:
Antibody targeting of phosphatidylserine produces a cytokine microenvironment that enhances innate anti-tumor immune responses
Presentation Start/End Time:
Tuesday, Apr 15, 2008, 8:00 AM -12:00 PM
Author Block:
Monica L. Friedrich, Claudia Guevara, Daniel Falcon, Kristifer Garcia, Cristy Bautista, Connie Chang, Bruce Freimark. Peregrine Pharmaceuticals, Inc., Tustin, CA
Anionic phospholipids, principally phosphatidylserine (PS), become exposed on the external surface of vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. PS exposure on cells (e.g. during apoptosis) causes macrophages to produce anti-inflammatory cytokines, leading to the engulfment of the dying cells without induction of inflammation. In the present study, we evaluate the ability of a panel of chimeric and human antibodies to exert anti-tumor effects through various mechanisms, including ADCC on cellular targets expressing PS and modulation of pro-inflammatory cytokines and chemokine production. In the presence of antibodies that target PS, human peripheral blood mononuclear cells mediate specific killing of human tumor cells treated with paclitaxel or etoposide and enhance the production of TNFa by human monocytes in vitro. In addition, preliminary data indicate that bavituximab modulates the production of tumor-derived chemokines in vitro. Current studies are in progress to evaluate the anti-tumor response of chimeric and human anti-PS antibodies in NOD/SCID mice. Single-dose pharmacokinetic analysis of bavituximab in NOD/SCID mice was similar to previous studies conducted in immune competent rats and non-human primates. These data suggest that multiple cellular and cytokine/chemokine responses in the tumor microenvironment may contribute to the anti-tumor activities of bavituximab.
----------
SO nice to read :)
j
AACR Abstract Number: 2341
Session Title: New Targets 1: Mechanisms
Presentation Title: Targeting mutant p53 protein and tumor vasculature: An effective combination therapy for advanced breast tumors
Presentation Start/End Time: Monday, Apr 14, 2008, 8:00 AM -12:00 PM
Author Block:
Yayun Liang, Cynthia L. Besch Williford, Indira Benakanakere, Sandra L. Brandt, Philip E. Thorpe, Salman M. Hyder. Univ. of Missouri, Columbia, MO, Simmons Cancer Center, University of Texas Southwestern, Dallas, TX
Mutations in tumor suppressor p53 facilitate tumor cell survival and resistance to chemotherapeutic drugs. Consequently, restoring p53 function within tumors is a promising strategy for targeted cancer therapy. Furthermore, vascular targeting agents, for treatment of cancer are designed to cause selective shutdown of tumor blood vessels, offer yet another opportunity to reduce tumor load. Anionic phospholipids (AP), exposed on the surface of tumor endothelial cells, serve as an excellent marker for vascular disruption. Thus, treatment strategies which incorporate both of these pathways may result in improved and more potent responses. The aim of this study was to determine whether combination therapy targeting mtp53 and tumor blood vessels could be an effective therapeutic strategy for suppression of advanced breast cancer. We therefore tested therapeutic effects of PRIMA-1 which re-activates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by binding to AP on tumor endothelial cells, causing selective shutdown of tumor blood vessels. Two advanced breast tumor models that express mtp53, and are also Her-2/neu positive (BT-474) or negative (HCC-1428), were used to evaluate this combination therapy. Fluorescence staining and tumor blood vessel perfusion assays were performed to determine therapeutic mechanisms of action. Our results showed that (1) Combination treatment with PRIMA-1 and 2aG4 suppressed BT-474 tumor growth additively leading to complete arrest of tumor progression during treatment; (2) Some BT-474 tumors were completely eradicated when PRIMA-1 or 2aG4 was used alone; combination treatment led to synergistic loss of tumors in nude mice; (3) An increased anti-tumor effect was observed with PRIMA-1 plus 2aG4 treatment in HCC-1428 tumor model; HCC-1428 tumors did not progress with 2aG4 or PRIMA-1 treatment and regressed slightly when combination treatment was tested; however, combination therapy did not lead to complete remission of HCC-1428 tumors; (4) The incidence of lymph node metastasis in nude mice bearing BT-474 breast tumors was reduced by combined treatment using PRIMA-1 plus 2aG4.(5) No toxic effects were observed in any treatment groups.While seeking mechanistic explanations for anti-tumor effects we found that (a) PRIMA-1 induced exposure of AP in vitro in endothelial (HUVEC) cells, in BT-474, and extensively in HCC-1428 tumor cells; (b) PRIMA-1 plus 2aG4 treatment severely disrupted the ability of tumor blood vessels to perfuse in BT-474 and HCC-1428 tumors. These results indicate that PRIMA-1 plus 2aG4 combination therapy has a complementary and potent anti-tumor activity and could define a new strategy for suppression of advanced breast cancers. Supported by Dept. of Defense Breast Cancer Pgm W81XWH-06-1-0646, NIH CA-86916, and in part by Susan G Komen for Cure BCTR0600704 and PDF0600723.
----------
j
AACR Abstract Number: 2841
Session Title: Tumor Vaccines
Presentation Title: An immunocytokine that binds to phosphatidylserine generates an effective cell-based tumor vaccine in mice
Presentation Start/End Time: Monday, Apr 14, 2008, 1:00 PM - 5:00 PM
Author Block: Xianming Huang, Dan Ye, Philip E. Thorpe. UT Southwestern Medical Ctr., Dallas, TX
Cell-based tumor cell vaccines have so far had limited success at inducing immunity in naive mice. In the present study we sought to create an effective tumor vaccine by taking advantage of two recent discoveries: (i) that phosphatidylserine (PS) exposed on apoptotic tumor cells is immunosuppressive; (ii) that fusion proteins composed of antibodies and cytokines (immunocytokines) can enhance the immunogenicity of the cells to which they bind. We reasoned that interleukin-2 (IL-2) fused to an antibody directed against PS would block the immunosuppressive effect of the PS on the tumor cells, while simultaneously enhancing T-cell activation. The immunocytokine was generated by genetically fusing murine IL-2 to the C-terminal of the heavy chain of the antibody, 2aG4, which binds to PS in a b2-glycoprotein I dependent fashion. The tumor was the nonimmunogenic 4T1 murine breast carcinoma, which is spontaneously metastatic, highly aggressive and will produce lethal tumors from an innoculum of ten cells or fewer in syngeneic mice. BALB/c mice were immunized four times with irradiated 4T1 cells coated with 2aG4-IL-2. One week after the last immunization, mice were implanted with 2x104 live 4T1 cells into the mammary fat pad. Eight out of ten mice did not develop tumors and remained tumor free 270 days later. In the control groups, which received tumor cells treated with 2aG4 alone or with IL-2 fused to a control antibody of irrelevant specificity, only 2 out of 10 mice remained tumor free. All mice immunized with irradiated 4T1 cells alone developed tumors. Our results show that anti-PS-IL-2 fusion proteins can enhance the immunogenicity of nonimmunogenic tumors to provide protection against a lethal tumor challenge.
------------------------
j
AACR Abstract Number: 2551
Session Title: New Approaches to Biological Therapy
Presentation Title: Combination of a monoclonal anti-phosphatidylserine antibody with docetaxel strongly inhibits the growth and metastasis of hormone-refractory prostate cancers in mice
Presentation Start/End Time: Monday, Apr 14, 2008, 2:10 PM - 2:25 PM
Author Block: Yi Yin, Philip E. Thorpe. UT Southwestern Medical Center, Dallas, TX
The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new regimes to improve the prognosis. Phosphatidylserine (PS) is an anionic phospholipid located normally on the inner leaflet of the plasma membrane in mammalian cells. In the tumor microenvironment, PS becomes externalized on vascular endothelium. The vascular-targeting monoclonal antibody, 2aG4, binds PS and promotes an inflammatory response against tumor blood vessels, resulting in vessel destruction by ADCC and retardation of tumor growth. Prior studies have shown that docetaxel increases PS exposure on tumor vasculature. We hypothesized that combinating 2aG4 with docetaxel should increase the therapeutic index of docetaxel for the treatment of HRPC. Male SCID mice orthotopically bearing PC3/Luc prostate tumor were treated with control antibody C44 (4 mg/kg), docetaxel (10 mg/kg), 2aG4 (4 mg/kg) alone or in combination twice weekly. The tumor burden and metastasis were monitored by bioluminescence imaging (BLI). Therapy beginning 3 weeks after orthotopic implantation of 1´106 PC3/luc cells resulted in a reduced primary tumor burden by 37% in mice treated with 2aG4, by 62% in mice treated with docetaxel, and by 95% in those given both drugs. The percentage of detectable metastatic lesions was 0% (0/6) in mice treated with the combination as compared with 100% (6/6), 67% (4/6), 50% (3/6) with C44, 2aG4 and docetaxel alone, respectively. Therapy beginning 3 weeks after orthotopic implantation of 5´106 PC3/luc cells resulted in a prolongation in survival of 11 days with 2aG4, 31 days with docetaxel, and 58 days with the combination of both drugs. The combination was also superior to the individual drugs at preventing regrowth of hormone-refractory LNCaP xenografts in SCID mice after castration. Tumors in mice treated with the combination regressed to 50% of their initial volume. In mice treated with 2aG4, docetaxel or C44 alone, tumors grew by 1.56, 1.52 and 5.43 fold, respectively. Treatment of tumor-bearing animals with the combination therapy reduced tumor microvessel density by 90%, as compared with 49% for 2aG4 and 42% for docetaxel. Moreover, the combination therapy was no more toxic to the mice than was docetaxel alone as judged by physical signs and body weight changes. Our results indicate that 2aG4 enhances the anti-tumor growth, anti-metastatic activity and the survival benefits of docetaxel without contributing toxicity. The explanation for the superior activity of the combination appears to be that docetaxel increases PS exposure on tumor vessels, but not on vessels in normal tissues, thus amplifying the target for attack by 2aG4. The present results provide the foundation for using bavituximab, a chimeric version of 2aG4, plus docetaxel to treat HRPC patients.
---------
j
AACR: Thorpe is co-chair of 3 hour mini-symposium -
Session Title:
New Approaches to Biological Therapy
Session Title:
New Approaches to Biological Therapy
Session Type:
Minisymposium
Session Start:
4/14/2008 1:00:00 PM
Session End:
4/14/2008 4:30:00 PM
Location:
Room 25A-C, San Diego Convention Center
Session Leaders:
Louis M. Weiner, Lombardi Comprehensive Cancer Center, Washington, DC,Philip E. Thorpe, UT Southwestern Medical Ctr., Dallas, TX
Presentations:
Chairperson
Chairperson
Monday, 1:00 p.m. - 1:10 p.m.--Introduction
Monday, 1:10 p.m. - 1:25 p.m.--Direct inhibition of the Notch transactivation complex with stapled peptides in T-ALL
Monday, 1:25 p.m. - 1:40 p.m.--A stapled p53 helix targets both HDM2 and HDMX to restore p53 activity in human cancer
Monday, 1:40 p.m. - 1:55 p.m.--Essential role of KLF6-SV1 in regulating tumor cell apoptosis and greatly increasing median and overall ovarian cancer survival: identification and pre-clinical targeting of a novel prosurvival/anti-apoptotic protein
Monday, 1:55 p.m. - 2:10 p.m.--Sensitizer/inducer strategy of XIAP inhibitors combined with TRAIL: A new paradigm for apoptosis-based therapy of pancreatic cancer
Monday, 2:10 p.m. - 2:25 p.m.--Combination of a monoclonal anti-phosphatidylserine antibody with docetaxel strongly inhibits the growth and metastasis of hormone-refractory prostate cancers in mice
Monday, 2:25 p.m. - 2:40 p.m.--Immunotoxin and paclitaxel synergy results from a decrease in shed target antigen levels in the extracellular space of tumors
Monday, 2:40 p.m. - 2:55 p.m.--b2-Microglobulin antibody inhibition of androgen receptor expression and survival in prostate cancer
Monday, 2:55 p.m. - 3:10 p.m.--A novel approach for generation of fully human monoclonal antibodies using single cell PCR and in vitro translation
Monday, 3:10 p.m. - 3:25 p.m.--The anti-B7-H3-4Ig antibody TES7 recognizes cancer stem cell lines, modulates angiogenic factor secretion, and exhibits potent anti-tumor activity in vivo
Monday, 3:25 p.m. - 3:40 p.m.--Novel enzyme IDO2 is the preferred biochemical target of D-1MT which relieves tumor immune suppression and stimulates tumor regression
Monday, 3:40 p.m. - 3:55 p.m.--Zinc finger nucleases targeting the glucocorticoid receptor allow IL-13 zetakine transgenic CTLs to kill glioblastoma cells in vivo in the presence of immunosuppressing glucocorticoids
Monday, 3:55 p.m. - 4:10 p.m.--Co-treatment with vorinostat and Aurora kinase inhibitor MK-0457 exerts synergistic antileukemia activity against AML and CML cells, including those expressing mutant Bcr-AblT315I
Monday, 4:10 p.m. - 4:30 p.m.--Discussion
----------
j
Yeah, so much to look into. Most of the work I posted last night, which I find so fascinating, involving immunosenescence as it relates to CMV infection, was from 2007 & 2008..
j
KT,
CMV is a herpes virus. Yes it is an enveloped virus, with exposed PS, which Bavi has been proven to bind.
The majority of us are infected with CMV.
It was actually the most impressive preclinical experiment run by Thorpe & Ran. They ran an "80/20" experiment, (which means they injected enough to kill roughly 80% of the test animals in each of two groups).
One group got 3G4 (Bavituximab).
One group didn't.
In the group that didn't, as expected, roughly 80% died from the CMV infection.
In the "Bavi" group, 100% of the animals survived.
See also the Peregrine Bavi viral "fact sheet" or the PR's discussing the CMV work, or the Thorpe/Ran/King patents discussing same.
- from the PPHM Bavi viral page:
* 100% of animals lethally infected with mouse derived (murine) cytomegalovirus (CMV) and treated with bavituximab survived as compared with 20% survival in control treated animals
* Animals lethally infected with Pichinde virus (a model for Lassa fever, a fatal viral hemorrhagic fever that is on the U.S. government’s biodefense Category A watch list) and then treated with bavituximab showed a 50% survival rate as compared to zero survivors in the control treated group
* Surviving animals infected with Pichinde virus did not show any signs of viral infection several months after treatment with bavituximab and were considered to have been disease free
* Surviving animals had long-term immunity to further infection with the Pichinde virus
* Bavituximab protected lethally infected animals whether treated at the time of viral challenge or after symptoms had developed indicating an active viral infection
---------
j
short interest down again,
--------
j
Exp Gerontol. 2008 Feb
The immune system in extreme longevity.
Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M.
Dipartimento di Medicina Interna e Scienze Biomediche, Università di Parma, Via Gramsci 14, 43100 Parma, Italy.
Recent observations indicate that immunosenescence is not accompanied by an unavoidable and progressive deterioration of the immune function, but is rather the result of a remodeling where some functions are reduced, others remain unchanged or even increased. In addition, it appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison to the more recent and sophisticated adaptive compartment that exhibit more profound modifications. The T-cell branch displays an age-dependent decline of the absolute number of total T-cells (CD3+), involving both CD4+ and CD8+ subsets, accompanied by an increase of NK cells with well-preserved cytotoxic function and by a reduction of B-cells. One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T-cells (CD95-), which is particularly profound at the level of the CD8+ subpopulation of the oldest old subjects. The progressive exhaustion of this important T-cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral, neoplastic, bacterial ones), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells that are replaced by large clonal expansions of CD28- T-cells. The origin of CD28- cells has not been completely clarified yet, but it is assumed that they represent cells in the phase of replicative senescence characterized by shortening telomers and reduced proliferative capacity. A major characteristic of the immune system during aging is the up-regulation of the inflammatory responses which appears to be detrimental for longevity. In this regard, we have recently observed a progressive age-dependent increase of type 1(IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4, IL-6, IL-10) positive CD8+ T-cells; in particular, type 1 cytokine-positive cells significantly increased, with age, in all CD8+ subsets particularly among effector/cytotoxic and memory cells. A major force able to drive a chronic pro-inflammatory state during aging may be represented by persistent viral infections by EBV and CMV. Therefore, we have determined the frequency and the absolute number of viral antigen-specific CD8+ T-cells in subjects older than 85 years, who were serologically positive for CMV or EBV. In the majority of these subjects we detected the presence of T lymphocytes positive for epitopes of CMV or EBV. In all subjects the absolute number of CMV-positive CD8+ cells outnumbered that of EBV-positive ones. In addition, the majority of CMV+ T cells were included within the CD28- subpopulation, while EBV+ T cells belonged mainly to the CD28+ subset. These data indicate that the chronic antigenic stimulation induced by persistent viral infections during aging bring about important modifications among CD8+ subsets, which are particularly evident in the presence of CMV persistence. The age-dependent expansions of CD8+CD28- T-cells, mostly positive for pro-inflammatory cytokines and including the majority of CMV-epitope-specific cells, underlines the importance of chronic antigenic stimulation in the pathogenesis of the main immunological alterations of aging and may favour the appearance of several pathologies (arteriosclerosis, dementia, osteoporosis, cancer) all of which share an inflammatory pathogenesis.
http://www.ncbi.nlm.nih.gov/pubmed/17870272?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA
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Med Microbiol Immunol. 2008 Feb
Dynamics of T cell memory in human cytomegalovirus infection.
Waller EC, Day E, Sissons JG, Wills MR.
Department of Medicine, Level 5, Addenbrookes Hospital, University of Cambridge, Hills Rd, Cambridge, CB2 2QQ, UK.
Primary human cytomegalovirus (HCMV) infection of an immunocompetent individual leads to the generation of a robust CD4+ and CD8+ T cell response which subsequently controls viral replication. HCMV is never cleared from the host and enters into latency with periodic reactivation and viral replication, which is controlled by reactivation of the memory T cells. In this article, we discuss the magnitude, phenotype and clonality of the T cell response following primary HCMV infection, the selection of responding T cells into the long-term memory pool and maintenance of this memory T cell population in the face of a latent/persistent infection. The article also considers the effect that this long-term surveillance of HCMV has on the T cell memory phenotype, their differentiation, function and the associated concepts of T cell memory inflation and immunosenescence.
http://www.ncbi.nlm.nih.gov/pubmed/18301918?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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J Immunol. 2007 Sep 15
Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects.
Vescovini R, Biasini C, Fagnoni FF, Telera AR, Zanlari L, Pedrazzoni M, Bucci L, Monti D, Medici MC, Chezzi C, Franceschi C, Sansoni P.
Department of Internal Medicine and Biomedical Sciences, University of Parma, Parma, Italy.
A progressive, systemic, and low-grade proinflammatory status is one of the major characteristics of immunosenescence. Emerging data suggest a possible contribution of CMV, known to chronically infect a large proportion of humans, lifelong from newborns to centenarians. To test this hypothesis, we evaluated functional T cell responses to two CMV immunogenic proteins, pp65 and IE-1, in 65 chronically infected subjects aged 25-100 years. PBMC were stimulated with mixtures of peptides spanning the entire sequence of both proteins, and Ag specificity and magnitude of intracellular IFN-gamma- and TNF-alpha-positive cells were then analyzed within both CD4+ and CD8+ T cells. Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN-gamma induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN-gamma in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases.
http://www.ncbi.nlm.nih.gov/pubmed/17785869?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Exp Gerontol. 2007 Aug
No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study.
Strindhall J, Nilsson BO, Löfgren S, Ernerudh J, Pawelec G, Johansson B, Wikby A.
Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Box 1026, 551 11 Jönköping, Sweden.
In the present NONA immune longitudinal study, we investigate the previously identified Immune Risk Profile (IRP), defined by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and increased numbers of CD8+CD28- cells, relative 6-year survival and age in NONA individuals. These subjects have now reached age 92, 96, and for the first time in this study, 100 years at follow-up. A 55 year old middle-aged group was used for comparison. Immunological monitoring included the analysis of numbers of lymphocytes and neutrophils, the T-cell subsets CD3+CD4+, CD3+CD8+, CD8+CD28+, CD8+CD28-, and the CD4/CD8 ratio. Longitudinal data were analysed by multivariate analyses of variance (MANOVA) from four measurement occasions at 2-year inter-intervals. One-way ANOVA was used for cross-sectional comparisons at baseline and the 6-year follow-up. The results confirmed the importance of the IRP as a major predictor of mortality in this population of very old. Moreover, the results suggested that survival to the age of 100 years is associated with selection of individuals with an "inverted" IRP that was stable across time, i.e., maintenance of a high CD4/CD8 ratio and low numbers of CD8+CD28- cells. The results underlines the importance of a longitudinal study design in dissecting immune parameters predictive of survival and show for the first time that centenarian status is associated with avoidance of the IRP over at least the previous 6 years and probably throughout life.
http://www.ncbi.nlm.nih.gov/pubmed/17606347?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire.
J Virol. 2007 Jul
The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire.
Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA.
C.R. U.K. Institute for Cancer Studies, Vincent Drive, Edgbaston, University of Birmingham, Birmingham B15 2TA, United Kingdom.
Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8(+) T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4(+) T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4(+) T-cell immune response increases from a mean of 2.2% of the CD4(+) T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4(+) T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4(+) T-cell repertoire in healthy aged donors, including an increase in CD57(+) expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4(+) T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.
http://www.ncbi.nlm.nih.gov/pubmed/17409149?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Analyses of immunosenescent markers in patients with autoimmune disease.
Clin Immunol. 2007 May
Analyses of immunosenescent markers in patients with autoimmune disease.
Thewissen M, Somers V, Venken K, Linsen L, van Paassen P, Geusens P, Damoiseaux J, Stinissen P.
Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Agoralaan, Diepenbeek, Belgium, and Department of Clinical and Experimental Immunology, University Hospital Maastricht, The Netherlands.
The objective of this study was to evaluate the degree of immunosenescence in patients with autoimmune disease. T cell receptor excision circles (TREC) and the percentage of CD4+CD28null T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4+CD28null T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4+CD28null T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus. Further analysis of CD4+CD28null T cells provided indications for a restricted T cell receptor (TCR) BV gene expression and cytoplasmic stores of various cytotoxic molecules. This study indicates that the immune system of patients with autoimmune diseases shows signs of an accelerated aging. Both genetic factors, such as HLA DR4, and environmental factors, like CMV infection, might speed up this immunosenescence and contribute in this way to disease pathogenesis.
http://www.ncbi.nlm.nih.gov/pubmed/17317320?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Role of persistent CMV infection in configuring T cell immunity in the elderly.
Immun Ageing. 2007 Mar
Role of persistent CMV infection in configuring T cell immunity in the elderly.
Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G.
Gruppo di Studio sull'Immunosenescenza, Dipartimento di Biopatologia e Metedologie Biomediche, University of Palermo, Italy.
Ageing is associated with declines in many physiological parameters, including multiple immune system functions. The rate of acceleration of the frequency of death due to cardiovascular disease or cancer seems to increase with age from middle age up to around 80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are often associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. Thus, the manner in which CMV and the host immune system interact is critical in determining the "age" of specific immunity. We may therefore consider immunosenescence in some respects as an infectious state. This implies that interventions aimed at the pathogen may improve the organ system affected. Hence, CMV-directed anti-virals or vaccination may have beneficial effects on immunity in later life.
http://www.ncbi.nlm.nih.gov/pubmed/17376222?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Hum Immunol. 2007 Feb
Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly.
Weinberger B, Lazuardi L, Weiskirchner I, Keller M, Neuner C, Fischer KH, Neuman B, Würzner R, Grubeck-Loebenstein B.
Immunology Division, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Despite general acceptance that immunologic changes are associated with aging and latent infection with Cytomegalovirus (CMV), no clear-cut distinction has so far been made between strictly age-related and CMV-induced changes. We therefore compared CD4+ and CD8+ naïve (CD45RA+CD28+), memory (CD45RA-CD28+), and effector (CD28-) T cells in CMV-positive (n = 164) and CMV-negative (n = 87) elderly persons and correlated CD8+ and CD4+ effector T cells with other T-cell subpopulations. Percentages of CD8+ as well as CD4+ effector T cells were higher, but percentages of naïve and memory cells were lower in CMV-positive compared to CMV-negative elderly persons. Negative correlations within CD8+ T-cell subsets were found to be present in both CMV-positive and CMV-negative elderly individuals. In contrast, correlations within CD4+ T-cell subpopulations and a positive correlation between CD8+ and CD4+ effector T cells were found in CMV-positive individuals only. Our results demonstrate that (a) in the elderly different T-cell subsets compete for space within the CD8+, but not the CD4+ T-cell population; (b) CMV induces changes in the CD4+ compartment that differ from the solely age-related changes seen in CMV-negative elderly population; and (c) the CMV-status of a population has to be taken into account before a conclusion on the effect of aging on the composition of the T-cell pool can be reached.
http://www.ncbi.nlm.nih.gov/pubmed/17321897?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Immunity and ageing in man.
Exp Gerontol. 2006 Dec
Immunity and ageing in man.
Pawelec G.
University of Tübingen Center for Medical Research, Waldhörnlestr. 22, D-72072 Tübingen, Germany.
Immunosenescence resulting in decreased ability to control infectious disease contributes to morbidity and mortality not only in the very elderly, but in all likelihood already from middle age. Studying immunity in humans is therefore essential for developing treatments to restore dysregulated immune responses and assure healthy longevity. The past year has seen many significant advances in our knowledge of age-associated alterations to immunity in elderly people, only some of which can be briefly reviewed here.
http://www.ncbi.nlm.nih.gov/pubmed/17118601?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
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Human immunosenescence: does it have an infectious component?
Ann N Y Acad Sci. 2006 May
Human immunosenescence: does it have an infectious component?
Pawelec G, Koch S, Franceschi C, Wikby A.
University of Tübingen Medical School, Center for Medical Research, ZMF, Germany.
The rate of acceleration of the frequency of death due to cardiovascular disease or cancer increases with age from middle age up to around 75-80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly are particularly susceptible to novel infectious agents such as SARS, as well as to previously encountered pathogens. Why is this? The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. We suggest that, in fact, CMV, not age per se, is the prime driving force behind many or most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells in the elderly. Thus, the manner in which CMV and the host immune system interact (over which period? on which genetic background? with which co-infections?) is critical in determining the "age" of adaptive immunity and hence human longevity. In this respect, immunosenescence is infectious.
http://www.ncbi.nlm.nih.gov/pubmed/16803971?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA
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Human immunosenescence: is it infectious?
Immunol Rev. 2005 Jun
Human immunosenescence: is it infectious?
Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A.
University of Tübingen Medical School, Center for Medical Research, ZMF, Germany.
Morbidity and mortality due to infectious disease is greater in the elderly than in the young, at least partly because of age-associated decreased immune competence, which renders individuals more susceptible to pathogens. This susceptibility is particularly evident for novel infectious agents such as in severe acute respiratory syndrome but is also all too apparent for common pathogens such as influenza. Many years ago, it was noted that the elderly possessed oligoclonal expansions of T cells, especially of CD8(+) cells. At the same time, it was established that cytomegalovirus (CMV) seropositivity was associated with many of the same phenotypic and functional alterations to T-cell immunity that were being reported as biomarkers associated with aging. It was discovered that CMV was the prime driving force behind most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells. Independently, longitudinal studies of a free-living population of the very old in Sweden over the past decade have led to the emerging concept of an 'immune risk phenotype' (IRP), predicting mortality, which was itself found to be associated with CMV seropositivity. These findings support our hypothesis that the manner in which CMV and the host immune system interact is critical in determining the IRP and hence is predictive of mortality. In this sense, then, we suggest that immunosenescence is contagious.
http://www.ncbi.nlm.nih.gov/pubmed/15882359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA
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from conf call:
SK quote: re: phase II bavi docetax breast cancer trial:
'the trial has progressed very nicely and we are well into the first set of 15 patients in the trial.'
"Data from this should be available before the middle of the year"
nice to hear.
Also- another Cotara update around the time of ASCO.
(late May - early June)
I wonder how much Cotara data the Rodman analyst will need to feel comfortable upping his recommendation.
Also - according to a Q&A on the conf call, it seems PPHM has approximately an additional 2 months AFTER any hypothetical delisting 'deadline' for an appeal process, bringing the timeline out to some time around September, at which point, we should be getting ANOTHER update from Cotara & Bavituximab phase II trials.
Actually, with three phase II Bavituximab (open-label, non dose-escalation) cancer trials up and running, I think we'll be getting quite a few updates in the Spring/Summer months.
But what I found most interesting and surprising was hearing that the HIV, and influenza, and biodefense programs have expanded and are 'extremely active', and that we'll be seeing journal articles soon that include data from our anti-PS against HIV, AND influenza & biodefense from outside grants.
j
SK quotes: re: anti-PS HIV, influenza, & biodefense work at Duke & elsewhere:
"We have also continued supporting HIV, influenza, & biodefense research programs [plural] at Duke University, UTSW & other supporting institutions.
These research collaborations [plural] have expanded, and are extremely active.
We look forward to presenting data through peer-reviewed journal articles [plural] in the near future, that highlight the potenital of our anti-PS technology, in these [plural] difficult to treat diseases [plural].
A real positive for these preclinical programs [plural], is that they [plural] have significant support from outside grants [plural]."
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looking forward to learning more about that...
j
RETROVIROLOGY: Feb 2008 -------------------
Alteration of viral lipid composition by expression of the phospholipid floppase ABCB4 reduces HIV vector infectivity
This is primarily about increasing the amount of PC on the outside of HIV virions, but there is nice mention now, as established fact, of the roles played by PS in HIV infection, both on the virus, and on cells :)
j
Alteration of viral lipid composition by expression of the phospholipid floppase ABCB4 reduces HIV vector infectivity
FULL TEXT of this Feb 2008 paper from the Journal of Retrovirology:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18241333
ABSTRACT
Because HIV budding takes place at specialized membrane microdomains which are enriched in cholesterol and sphingolipids (rafts), the lipid content of HIV reflects the composition of these membrane domains [1-4]. However, accumulating evidence suggest that retroviral membrane composition is not just a reflection of the producer cells' membrane but that components of the viral membrane play an important part in the viral life cycle.
HIV membrane cholesterol has been shown to be important for viral integrity and function, depletion of cholesterol from HIV by incubation with cyclodextrin results in altered morphology and reduced infectivity of the viral particles [2]. The presence of phosphatidylserine (PS) in the viral membrane is essential for infection of monocytes, but not T cells, by HIV[5]. Whether other membrane components of HIV are also important is less well established.
The importance of the lipid composition of target cells is somewhat better understood. Treatment of target cells with sphingomyelinase and cholesterol oxidase reduces the susceptibility of these cells to HIV by changing the conformation of HIV chemokine co-receptors [6]. Target cells with artificially increased levels of ceramide are less well infected by HIV because they endocytose viral particles more efficiently[7].
Phosphatidylserine is also important for infectivity, incubation of target cells with liposomes composed of PS increased their susceptibility to transduction with a variety of retroviral vectors[8]. In HIV, PS present in the viral membrane has been shown to be important for the infection of monocytes[5].
Together, these studies indicate the importance of HIV and target cell membrane composition for viral function and suggest that a better understanding of the role of different lipids in the HIV life cycle might lead to the development of novel therapeutics to combat HIV infection....
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Peregrine Cotara data at ASCO
That's nice to hear. I'm hoping we see Bavituximab at ASCO also.
The more folks who learn about Bavi's MOA(s), and the function of phosphatidylserine, the better.
Alison Stopeck, (the doc who presented the Bavi phase 1 data at the recent angio conf.) has brought other phase I data to ASCO several times.
j
all kinds of indications(most not yet studied)
I'd say, off the top of my head,
(besides all cancers and viral infections...),
Anti-PS should be investigated as therapy, based on it's MOA, against:
sepsis,
atherosclerosis,
diabetes,
malaria,
sickle cell anemia,
trypanosoma,
tuberculosis and other mycobacteria,
rheumatoid arthritis,
toxoplasma,
lupus,
and there are more...
When you understand that PS signals a fundamental shift in immune response (towards homeostasis and away from a big bad fight), and that the foreign invaders that get the better of us "wear" PS, (essentially 'tricking' our immune system into the wrong response), and that diseases that get the better of us are associated with defective clearance of apoptotic (PS-exposing) cells, or an overwhelming amount of apoptotic or activated cells (and their debris), you start seeing how important a safe therapeutic anti-PS could be.
in a nut shell,
it's looking like,
evolution has favored pathogenesis that resembles apoptosis.
Having a proprietary drug platform with the ability to interrupt that pathway is, well, it's pretty big.
j
Feb 2008: PS-blocking as vaccine aid: Joel Shilyansky:
at the 3rd Annual Academic Surgical Congress:
"blocking phosphatidylserine enhances the efficacy of neuroblastoma vaccine."
http://www.academicsurgicalcongress.org/abstracts/SUSASC2008ControlData2_Detail.cfm?ID=255
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I'm looking forward to reading about what Dr. Shilyansky has been up to, in the upcoming AACR abstscts...
(Thorpe too of course :)
j
excerpt: If this technology successfully passes clinical trials, the team believe that the same antibody-binding technique could be used to deliver arsenic-77 to tumours instead. This heavier isotope emits beta radiation which would destroy the tumour, perhaps providing a highly selective treatment for a wide range of cancers.
Michael Welch, an expert in radiopharmaceuticals at Washington University in St. Louis, is impressed by the results. "The team have shown some of the highest selectivity for tumours achieved with antibodies," he told Chemistry World. "This could be very important if they can translate it to the clinic."
http://www.rsc.org/chemistryworld/News/2008/March/05030801.asp
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j
one of many good news articles about the Bavi/As74 paper-
http://www.rsc.org/chemistryworld/News/2008/March/05030801.asp
j
Thorpe's bavi/arsenic 74 paper is now online, abstract is here -
http://www.ncbi.nlm.nih.gov/pubmed/18316558?dopt=AbstractPlus
j
If you want to learn more about today's news -
I posted some of it, with a link to it here-
(see pages 89-115 of Jennewein's paper).
http://investorshub.advfn.com/boards/read_msg.asp?message_id=10876985
also here-
http://investorshub.advfn.com/boards/read_msg.asp?message_id=19518686
and more info here-
http://investorshub.advfn.com/boards/read_msg.asp?message_id=19517929
What hasn't been mentioned lately, is the radioTHERAPEUTIC possibilities using a couple OTHER arsenic isotopes joined to Bavi, like As76 & As77....................
Meaning, Bavi can bring along a radio-killer much like Cotara can..... AND - it can be used as IMAGING agent, DOSIMETRY agent, and THERAPEUTIC agent, all in one :)
and THAT'S what the more recent Department of Defense breast cancer grant is about.
good stuff.
j
and AACR abstracts should be up in a couple weeks..
that's where the bavi/glioma vaccine work was presented last year, which was, to me, the best validation of bavi's immune-modulating MOA I've seen.
That work had implications for successful autologous therapeutic vaccines for any cancer.
j
another great find thing108,
looking forward to reading the paper.
j
senrex,
re: the work being unique, you nailed it when you said-
..."probably looking at the "mab" part of "Bavituximab"...
It depends on how closely you look at the work.
In general terms of targeted therapy with mabs against cancer, there are obviously others.
More specifically, in terms of companies pursuing mabs to phospholipids as treatments to cancers, or viral infections, the "work is unique"
Targeting aminophospholipids (like PS), deliberately, (which would have sounded nuts to most any immunologist just 10 yrs ago), is all Peregrine.
The closest other related work I'm aware of, is the CHAVI 005 protocol, (Bart Haynes), which may be studying mabs that target a phospholipid, originally isolated from people with autoimmune diseases.
There's also some work at The Walter Reed Institute, (Carl Alving), which is looking into neutralizing HIV via mabs targeting phosphatidylinositol phosphate, (PIP).
(both of those I've posted about quite a bit here on Ihub).
Peregrine's work using mabs to PS, and especially being all alone in human trials targeting PS, (let alone now in phase 2 cancer trials), is unique.
Even speaking more generally, the idea of targeted therapy for cancer or viruses through targeting something that is NOT a cancer or viral antigen, is a concept that is still early in the curve of catching on.
j
marcad,
Presently, I think it's better to refer to what they're researching at Duke (and Harvard) as "bavi as well as other than Bavi". That's all we know so far. It's clear from King's statements that Duke is looking into Bavi and other PPHM anti-PS mabs.
According to CFO Lytle at the conf. in NYC a couple weeks ago, we should expect a paper out of Duke soon. He seemed to attach a lot of importance to an upcoming viral paper out of Duke. He used the word "groundbreaking" if I remember correctly.
it's very exciting,
j
marcad,
Peregrine's PS-targeting platform is just that - a platform. There are numerous (potential) drugs we've heard about. The most advanced is Bavituximab. But there are also:
* more humanized Bavi mab
* anti-PS mabs joined to various cytokines,
* "betabodies", (which you can look up...)
* "receptorbodies"..
* 'double' Beta-2-glycoprotein-I
* don't forget anti-PE (we haven't heard much about targeting PE, but the pre-clinical stuff was good)...
* other anti-PS mabs (as mentioned by King below)
* duramycin based drugs
* etc, etc, etc......... read the patents.
From the statments below, it sounds like Peregrine/Duke/Gates Foundation are interested in more than just Bavituximab.
Below are some statements from CEO King from various conf calls-
notice how the more recent statements mention "other" PPHM anti-PS mabs.
Also - in the DTRA loss press release, which was Dec 2007, King says this:
"Based on recent data from our collaborators, we are more enthusiastic than ever about the potential of our anti-PS technology platform for the treatment of viral infections, and we see many potential applications in this area."
http://pphm.client.shareholder.com/releasedetail.cfm?ReleaseID=281980
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3-12-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/2dtmca
SK: “Expanding the patient population we are treating to potentially include HCV/HIV co-infected individuals is a 3rd focus area… Our interest in this patient population has been further stimulated by solid evidence, thru our collab’s at Duke, that Bavi binds to HIV virus, binds to HIV-infected cells, and may have potent neutralizing effects on the virus.
3-12-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/2dtmca
SK: “ the funding that's coming out of there [Duke] is actually funding a lot of studies that are being done with bavituximab as a model..."
"The collaboration is going extremely well, the data we're generating is really helping us in the way we think about our development of bavituximab for HCV & HIV,"
7-11-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/2c9kwr
SK: “We have also been collaborating with researchers at Duke and other institutions to better understand the potential of Bavituximab in an HIV setting. Significant findings of these studies include data supporting Bavituximab binding to mult. strains of HIV and binding to HIV-infected cells
9-10-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/38lky9
SK: “Our collab. with HIV researchers at Duke remains strong and is making good progress. The collab. is providing exciting, new insights into the potential of Bavituximab.."
"we are happy with the collaboration and are getting a lot of data from the studies they are doing,"
"Our role in the studies is primarily to provide materials that are then being tested"..
"We are working with a group at Duke. In particular, we participated in a pgm that has been funded through the Gates Foundation [CAVD]. The CHAVI pgm is actually a separate pgm. They are both studying phospholipids as potential targets for the dev. of vaccines. So, in order to pursue that, they’ve been testing Bavituximab.."
There are add’l studies being planned. It’s a very large pgm that’s being run, again, simultaneously through these 2 different pgms – the CHAVI and then the Gates pgm [CAVD]. We are as anxious as anyone else to be able to get some of this info. out there. I know the guys at Duke will want to get it out there at the appropriate time. We are getting a lot of insight into, not just Bavituximab, but other antibodies that we have generated through our various collaborations. Over the long run, that’s going to be some extremely valuable info. that is only going to strengthen our overall antiviral pgm.”
2-10-07 QTLY. CONF. CALL (KING/LYTLE): http://tinyurl.com/393mau
SK: DUKE – “In addition to the clinical study, we are continuing a significant amount of preclinical work in the antiviral area. Our leading collaboration is with researchers at Duke University and a number of other institutions, including Harvard. This collaboration is progressing very nicely and we are highly encouraged by the results we have seen. As a reminder, we are exploring the potential of Bavituximab and several other anti-PS antibodies for their potential in the treatment and prevention of HIV infections. This collaboration is particularly important because without the collaboration we would not be able to conduct this informative research into the potential of our anti-PS platform for the treatment of HIV. Both we and our collaborators believe we are getting close to being able to share results of these studies either through publications or presentations in the upcoming months.”
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