Dmitry Gabrilovich : Peregrine Pharmaceuticals KOL :
Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy
Indu R. Ramachandran , Thomas Condamine , Cindy Lin , Sarah E. Herlihy , Alfred Garfall , Dan T. Vogl , Dmitry I. Gabrilovich , Yulia Nefedovacorrespondenceemail
DOI: dx.doi.org/10.1016/j.canlet.2015.10.040 Share on mendeleyShare on facebookShare on twitterShare on emailMore Sharing Services showArticle Info
Publication History
Published Online: November 27, 2015 Accepted: October 7, 2015 Received in revised form: October 5, 2015 Received: September 1, 2015
Highlights
• Myeloid cells play a critical role in regulation of myeloma growth
• PMN-MDSCs and neutrophils equally protect myeloma cells from chemotherapy
• PMNMDSCs and neutrophils mediate chemoprotective effect through soluble factors Abstract
Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM-bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN-MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell-cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM.
Now some may ask what does MDSC's have to do with Peregrine Pharmaceuticals or Bavituximab or PS Targeting ?
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February 9, 2015
Newly Presented Data Shows That Peregrine Pharmaceuticals' PS-Targeting Antibodies Significantly Enhance Anti-Tumor Activity of Immune Checkpoint Inhibitors PD-1 and CTLA-4 in Models of Breast Cancer and Melanoma
PS-Targeting Antibodies Block Tumor Suppression of Immune System Allowing Development of Robust Immune Responses Resulting in Statistically Significant Improvement in Anti-Tumor Activity; Specific Effects Seen in Decreased Levels of MDSCs and Other Immunosuppressive Lymphocytes and Increases in Tumor Fighting Immune Cells
TUSTIN, CA -- (Marketwired) -- 02/09/15 -- Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM) (NASDAQ: PPHMP) today announced preclinical data presentations showing that the PS-targeting antibody equivalent to bavituximab combined with an anti-PD-1 antibody displayed statistically significant improvement in tumor fighting immune cells, activation signals and cytokines in a model of melanoma compared to anti-PD-1 alone. Moreover, cells that suppress the immune system from recognizing tumors, such as myeloid-derived suppressor cells (MDSCs), were reduced by more than 40% in the combination with the PS-targeting antibody versus anti-PD-1 alone.These data, further validating the immune-stimulatory mechanism of bavituximab, are outlined in an oral and poster presentation by Bruce Freimark, Ph.D., director, preclinical oncology research at Peregrine, to be made at the Keystone Tumor Immunology: Multidisciplinary Science Driving Combination Therapy meeting being held February 8-13, 2015 in Banff, Alberta, Canada. Peregrine's lead PS-targeting antibody, bavituximab, is currently being evaluated in second-line non-small cell lung cancer (NSCLC) as part of the SUNRISE pivotal Phase III clinical trial.
"These data build on our growing body of encouraging combination data and strengthen our clinical development plans as we evaluate the direction of combination therapy trials utilizing bavituximab and other checkpoint inhibitors" said Jeff T. Hutchins, Ph.D., vice president of preclinical research at Peregrine. "Our goals are to modify a tumor environment that allows more patients to respond to conventional and immune therapy. As the tumor environment switches from immuno-suppressive to immuno-stimulatory with bavituximab treatment, we believe the addition of other checkpoint inhibitors, like anti-PD-1, may increase the number of patients responding to therapy."
In the presentations titled: "Antibody-Mediated Blockade of Phosphatidylserine Enhances the Anti-Tumor Activity of Immune Checkpoint Inhibitors by Affecting Myeloid-Derived Suppressor Cells (MDSC) and Lymphocyte Populations in the Tumor Microenvironment", Dr. Freimark and his research group, along with colleagues from the University of Texas Southwestern Medical Center led by Xianming Huang, Ph.D., demonstrate that in immunocompetent preclinical models of breast cancer and melanoma, the combination of PS-targeting antibodies and anti-CTLA-4 and anti-PD1 antibodies demonstrate statistically significant anti-tumor responses than either anti-CTLA-4 or anti-PD-1 antibody alone. New data presented show statistically significant changes in levels of tumor infiltrating lymphocytes (TILs), a type of white blood cell implicated in killing tumor cells, in the PS-targeting and anti-PD-1 combination group over single treatment alone in a melanoma model. Specifically, data show increases in a number of markers used to determine immune activation, including CD3 and CD8 cells expressing PD-1, Lag-3 and CD137 (4-1BB). Furthermore, data show that CD8 T cells in the tumor had increased production of IFN-gamma and TNF-a, both known to assist in promoting immune activation and Granzyme-B which is involved in direct tumor killing.
"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!
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