OncoSec Medical Inc (ONCSQ)

[guti]

The rationale for combining CSF-1 and Keytruda include:

1. Multiple mechanisms of action: CSF-1 inhibition blocks invasion and metastases of cancer cells, while Keytruda prevents the abrogation of the immune attack on cancer cells;
2. Complementary actions in heterotypic cellular interactions in the cancer micro-environment: CSF-1 inhibits the function of MDSCs, a subset of heterogeneous bone marrow-derived hematopoietic cells that are found in the peripheral blood of cancer patients and positively correlate to malignancy. Solid tumors contain MDSCs that maintain an immune-suppressive network in the tumor microenvironment. So, Keytruda and CSF-1 may act in a complementary fashion in restoring cancer immunity.

For example, certain breast cancers produce CSF-1, which promote macrophage infiltration and M2 differentiation. High Th2 CD4+ T cells with low CD8+ T cells results in a protumoral environment with increased metastatic risk. Interactions between M2 macrophages and MDSCs lead to high levels of IL-10 and low levels of IL-12, further reinforcing the M2 phenotype and increasing levels of Th2-type CD4+ T cells. These CD4+ T cells produce IL-4, which also polarizes macrophages toward M2, creating a feedback loop. Meanwhile, CD8+ T cells are suppressed, resulting in an overall immune-permissive environment for tumor growth and spread. So basically an increase in level of IL-12 will be needed for the CSF-1 Inhibitor PLX3397 combination with Keytruda to work for multiple cancers.

Coincidently on May 2015, Merck entered into collaboration with Plexxikon to combine PLX3397 with its PD-1 antibody, Keytruda, after Oncosec and UCSF had decided to evaluate the safety, tolerability and efficacy of the combination of Keytruda with ImmunoPulse IL-12 in metastatic melanoma.