ISF35 - the viral vector for a CD40 agonist - used as an intratumoral/intralesional melanoma treatment!!!

On the subject of intratumoral treatment of melanoma - drugs that are injected directly into the tumor, as the prior post on IMO-2125, a TLR agonist discussed, along with ALL these other intralesional/intratumoral therapies covered here:  ASCO 2017: All things intralesional/intratumoral
 - we've learned a couple of things:

1.  These drugs can have significant "by-stander" effect.  Meaning - they can kill not only the tumor they are injected it...but others...distant from the site of the injected tumor.

2.  As many melanoma experts said years ago, they will most likely turn out to be most effective when paired with systemic immunotherapy (as most of the research that is on-going is doing currently.

But...there's another one on the horizon.  It's been a long time in coming.  I posted this back in 2014:

CD40 Antibody therapy for melanoma....another way to activate the immune system?

And now, there's this:

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Singh, Vianden, Cantwell, et al. Nat Commun. 2017 Nov 13.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8⁺ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8⁺ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8⁺ T cells, and an increased ratio of intratumoral CD8⁺ T cells to CD4⁺ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.

A triple-decker approach!!!  I like it!!  Now where is the slick MD Anderson poster boards for this one?????

Fingers crossed, ratties!  Fingers crossed. - c