The road that has led to the deaths of Millions of people, caused by a defunct immune system, being suppressed via negative charges of flipped PS.... is all coming to an end. I'm not sure why the road itself to get there has many bumps along the way, but its obvious, below... is another likely collaborator to Peregrine Pharmaceuticals. Pay attention to ARG1 and have we heard Peregrine mention ARG1 before ?? YES! It has been a while ... but hey, ok, I get it.... it looks like Peregrine wants to get all their eggs lined up and keep as much under cover as possible, BUT... a reverse split is NOT NEEDED with the info that is out there and negotiations that have taken place.
So back to ARG1... its clear as day below, that there are many collaborations, all trying to be sealed up and I remember CEO Steve King saying before he looks forward to increasing shareholder value and at that time we were trading over $1 ... so this means the value of the PS Targeting platform IS CLEARLY BEING WITHELD TO CURRENT SHAREHOLDERS AND MARKETS.
Data to Be Presented at the SITC Annual Meeting Support Synergy of PS-Targeting and Anti-CTLA-4 Immunotherapies to Enhance Anti-Tumor Treatments in Melanoma
Nov 7, 2014
Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) (NASDAQ: PPHMP), today announced the first of four presentations of clinical and preclinical data related to the company's immuno-oncology development program and its lead investigational immunotherapy drug candidate bavituximab. Data from today's presentation show that the combination of a phosphatidylserine (PS)-targeting antibody equivalent to bavituximab and an antibody targeting the immune checkpoint CTLA-4 yielded statistically significant anti-tumor effects as compared to the anti-CTLA-4 antibody alone. In addition,this combination decreased levels of Arg1, a molecule predominantly expressed by myeloid derived suppressor cells (MDSC) and M2 macrophages; two key cell types that contribute to immunosupressive activity in animal models of melanoma.
Tumors enforce strict connections with the surrounding tissue cells creating a “microenvironment” that supports tumor progression. Moreover, neoplastic cells can also condition distant sites by releasing soluble factors, thus creating de facto a complex interplay that can be viewed as a tumor-driven “macroenvironment”. Within the past few years, my group contributed to define and characterize immunosuppressive elements shaping the tolerogenic tumor macroenvironment. Together with other groups, we pioneered the characterization of myeloid-derived suppressor cells (MDSCs), one of the cell types exerting a powerful inhibitory activity on antitumor T cell responses. Our studies aim at identifying the cellular and molecular bases for the immune dysfunctions induced by growing tumors, with the ultimate goal to relieve the brakes imposed by cancer to either adoptive or passive immunotherapy.
Based on our previous findings, we are currently trying to address different issues related to microenvironment control of adaptive and innate immunity in cancer: Metabolic regulation of innate and adaptive immunity in tumor microenvironment
The inefficacy of T cells to recognize and destroy tumor cells is largely due to the suppressive activity induced by the two enzymes involved in L-arginine metabolism, arginase1 (ARG1) and nitric oxide sinthase 2 (NOS2), supporting the well-established role of L-arginine metabolism in inducing alteration and suppression of anti-tumor T cell responses. Individually and together ARG1 and NOS2 cause modifications directly on T cell signaling pathway, as well as indirectly in the tumor microenvironment, altering many molecules involved in T cell recruitment and function. On the other hand, the presence of NO-producing cells can be also directly associated with cancer cell destruction and tumor regression. We are currently addressing the ambivalent role of the NO in cancerogenesis to dissect the factors favoring either a pro- or an anti- tumorigenic behavior. In particular, in a context of tumor-sepcific ACT we found that NO production and tumor rejection were dependent on NOS2 induction and upregulation. Cellular communications and bystander killing effects in cancer
Bystander effects and cell death following different types of chemotherapies are clear determinant of both therapy efficacy and either activation or silencing of anti-tumour immune responses. It is still difficult to understand which is the net effect as well as how to modulate these complex responses to maximize tumour eradication. This is due to the absence of a strong knowledge in the mechanism of cell–cell communication accountable for the bystander effects and various mediators and pathways have been suggested. Part of these uncertainties comes from lack of studies addressing how bystander signals are generated and diffused in a three-dimensional tumour mass. The short-lived uncharged free radical and messenger molecule NO, produced within the tumor microenvironment, seems to play a key role in the sensitization of bystander cells. However, the role of NO in cancer is multifaceted; indeed, depending on the location, amount, and duration of release, NO can either kill or sustain proliferation of tumour cells. The major goals of this project are: (i) investigate bystander effects in the intact tumour microenvironment by the use of intravital imaging; (ii) explore the immune response in the context of bystander signalling network. These studies are conducted in collaboration with Dott. Barbara Molon and the group coordinated by Prof. Fabio Mammano.
The functional role of myeloid cells in the metastatic spread
Figure 2. Mechanisms of MDSC-dependent inhibition of T cell activation and proliferation. Myeloid-derived suppressor cells (MDSCs) can inhibit efficient anti-tumour T cell responses through a number of mechanisms sketchy depicted in the figure.
Metastatic spread is the main responsible of cancer-associated mortality (Chaffer, C.L., et al., Science, 2011) and it remains the most poorly understood component of cancer pathogenesis. Although solid evidence has accumulated for the contribution of immunoediting in primary tumor development, very little is known about the involvement of adaptive immunity in the regulation, either positively or negatively, of the metastatic process. Different leukocytes contributing to the maintenance of the innate immunity, including monocytes, granulocytes, MDSCs, tumor-associated macrophages (TAMs) and mast cells have been found to assist metastasis formation (Chioda, M., et al., Cancer Metastasis Rev., 2011). In this project, we plan to dissect the molecular pathways underlying the role of myeloid cells in regulating metastasis spread and anti-metastatic adaptive immunity using mice, generated in our laboratory, which either lack the relevant genes in the hematopoietic compartment or constitutively express the genes in the monocyte/macrophage lineage. Nano-Immuno-CHEmotherapy: nanocarriers for the treatment of cancer
We are part of an European multidisciplinary consortium that is attempting to combine nanotechnology and biomedicine for the development of anticancer treatments. Tumor microenvironment determines deep alteration in a the population of myeloid cells (i.e. MDSCs), located preferentially in the spleen, leading to the activation of an immunosuppressive program, which supports tumor growth and expansion. Manipulation of this immunosuppressive network offers thus the opportunity to restore the immune competence in tumor-bearing hosts. On the other hand, the stimulation of a specific immunogenic cell death in tumor cells located both in tumor mass and in tumor-draining lymph nodes, represents a ground-breaking approach to treat aggressive cancers. Taking advantage of the ability of selected nanomedicines to localize and accumulate in these different sites, we plan to deliver directly selected anticancer agents and si/microRNA to various targets, i.e. the MDSCs and the neoplastic cells, switching on a tumor-specific immune response. We aim at reaching an advanced preclinical evaluation stage of these novel nanocarriers systems.
Vincenzo Bronte synoptic CV
2011–present Full Professor of Immunology Medicine Faculty, Verona University, Verona, Italy 2007–present VIMM Principal Investigator 1992–to date Staff scientist – clinical associate at the Istituto Oncologico Veneto, Padua 1992 Ph.D., University of Padua 1988 M.D., University of Padua Group members
"Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that is the cornerstone of a broad clinical pipeline." -- Big Pharmas nightmare... unless they are fortunate enough to have The Bavi Edge!
