Monday, June 12, 2017

ASCO 2017: Radiation plus ipi plus CD47 blockade for melanoma in mice = promising

CD47  is ~ "(Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobbin superfamily and partners with membrane intergrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRP alpha). This is because the protein IAP produced by CD-47 acts as a don't eat me signal to the immune system and drives organ fibrosis.
CD47 is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration (all the functions a growing cancer cell needs!!!)Furthermore, it plays a key role in immune and angiogenic responses. CD47 is ubiquitously expressed in human cells and has been found to be overexpressed in many different tumor cells.  Expression in equine cutaneous tumors has been reported as well."       Thanks, wikipedia!!
CD47 blockade in melanoma first came to my attention in some obscure journal reports and then, thrid trial down, here: Dec 2016Trials for Joshie (and Paulster and others....if needed)....:

Now there's this:  

CTLA4 and CD47 combinational therapy to extend survival in melanoma.
ASCO 2017. J Clin Oncol 35, 2017. Scheartz, Nath, Lessey-Morillon, et al.

Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) {ipi} have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response

So...poor little mice were given melanoma in their "hind limb", treated with radiation AND ipi or anti-CD47, or both.  The mice treated with both ipi and anti-CD47 PLUS radiation had increased survival (by 25%) compared to those treated with radiation and ipi alone.  Non-irradiated tumors showed little necrosis, but irradiated ones also treated with the combo showed "widespread necrosis"! On the down side: "All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4."  Melanoma tumors already have a predisposition to bleed, so this could be problematic, but hopefully can be dealt with effectively in real live ratties.

Mice so far.  Ratties in process.  Holding out hope. - c  

No comments:

Post a Comment