Thursday, October 27, 2016

Killing melanoma (in mice) is enhanced in cells treated with reovirus and radiation OR with a combo of tumor-antigen-targeting-antibody, IL-2, anti-PD1 and a T cell vaccine!!!!

While mice are not people (except for my dear Ed!!!) and ratties are - mice usually take on our troubles first!!!  Though not everything that helps the mice, helps the is a start....

Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signaling.  Gráinne, Kyula, Mansfield, et al.  Oncotarget, July, 2016.

"Oncolytic viruses selectively target and replicate in cancer cells, providing us with a unique tool with which to target and kill tumour cells. These viruses come from a diverse range of viral families including reovirus type 3 Dearing (RT3D), a non-pathogenic human double-stranded RNA oncolytic virus, which has been shown to be an effective therapeutic agent, both as a mono-therapy and in combination with traditional chemotherapeutic drugs. This study investigated the interaction between RT3D and radiotherapy in melanoma cell lines with a BRAF mutant, Ras mutant or BRAF/Ras wild type genotype. The data indicates that RT3D combined with radiotherapy significantly increased cytotoxicity relative to either single agent, independent of genotype, both in vitro and in vivo. The mechanism of enhanced cytotoxicity was dependent on an increase in viral replication, mediated by CUG2 up-regulation and subsequent down-regulation of pPKR and p-eIF2α, leading to the activation of mitochondrial apoptotic signaling resulting in increased cell death."

As noted in an article in Oncology Network regarding this study: Radiotherapy supercharges cancer targeting viruses to treat melanoma the editor notes, 
"The findings show that combining oncolytic viruses with radiotherapy could be an exciting new way to treat melanoma. Reoviruses are common viruses that are generally harmless to normal cells, but they can be deadly to cancer. Previous research has shown that the oncolytic virus RT3D is resistant to high doses of radiation, and so could be used with radiotherapy to treat skin cancers like melanoma. Researchers at the ICR and The Royal Marsden treated melanoma cells using combinations of radiotherapy and RT3D, to investigate their effects on cellular mechanisms in melanoma. The RT3D virus showed higher replication rates in melanoma when used with radiotherapy, helping it to kill more cancer cells than either treatment separately."

Thanks, to Linda Dylla for sharing this report.  For what it's worth.

Then there's this:

Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses.  Moynihan, Opel, Szeto, et al. Nat Med. 2016 Oct 24. 

Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.
Whew!!!  Melanoma Big Dogs have been saying (and I've been reporting here) that combo's are the wave of future melanoma treatment.  This study is certainly throwing it all at 'em!!!  Side effects here we come!  But....if it works....
 - c

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