Tumor Associated Macrophages are already on. One proposed mechanism of bavi is not to active macrophages, but utilize their plasticity to turn from a M2 suppressor type to a M1 inflammatory state.
What I can say after reviewing all of PPHM's MOA data presented in 2011 and 2012 is that there definitely appears to be a shifting to inflammatory cytokines (IL-12, IL-1, TNF-alpha) and a depression of suppressive cytokines (IL-10, TNF-beta). These stimulatory cytokines have been shown by multiple other (non-pphm affiliated) researchers to shift the M2/M1 balance.
What is interesting is that up to 50% of tumors are comprised of these Tumor Associated Macrophages (TAM), mostly in a M2 immunosuppresive state. The problem isn't stimulating the innate (macrophages, dendritic cells) in cancer, it is trying to have the pro-inflammatory types be more prevalent.
From the data that has been presented on Bavi, I can say that I am 'slightly convinced' that there is shifting of this microenvironment. It should be noted that all of these pathways are interlinked, and if you shift from M2 to M1, then you get additional CD4+ TH1 cells, and more IL-12, less IL-10, which stimulates more M1, etc.. etc. Also, dendritic cells are allowed to mature in the presence of less IL-10, and can act as APCs (antigen presenting cells).
PPHM has been keen to talk about PS exposure on endothelia cells lately, and the science holds as growth factors (e.g. VEGF - target of Avastin) are downregulated in a pro-inflammatory environment. Also note that cytotoxic T cells and Natural Killer (NK) cells are activated, which are key players in the body's anti-tumor defense system.
If Bavi works by slowly shifting this mass of macrophages within the microenvironment to an inflammatory state over time, I can appreciate OS as the best marker of activity. Note that no Bavi human trial has had a clear negative OS result to my knowledge. Also, one last point, there has been research done (outside of pphm) showing long-term (5 yrs or longer) NSCLC survivors had higher M1 to M2 macrophage ratio than short-term survivors (1 yr or less). This study was looking at a mix of stages and ECOG performance, so not directly applicable to pphm's NSCLC indication (stage IV - 1st or 2nd line), but still encouraging nevertheless.
