The Big Tent: Tumor Microenvironment Targets Heat Up – part 2 of an occasional series

I recently asked folks for their favorite hot targets in the tumor microenvironment space. Among a flurry of responses I got these two related answers:

mcbio CSF-1R

 Screen Shot 2014-11-23 at 6.36.37 PM

These responses from @mcbio316 and @Festivus159 were very timely, given what happened 4 days later (and a big shout-out to mcbio, whose post had preceded this):

Bristol-Myers Squibb and Five Prime Therapeutics Announce Exclusive Clinical Collaboration to Evaluate the Combination of Investigational Immunotherapies Opdivo (nivolumab) and FPA008 in Six Tumor Types

Five Prime Therapeutics, Inc. November 24, 2014 8:59 AM GlobeNewswire

  • NEW YORK and SOUTH SAN FRANCISCO, Calif., Nov. 24, 2014 (GLOBE NEWSWIRE) — Bristol-Myers Squibb Company (BMY) and Five Prime Therapeutics, Inc. (FPRX) today announced that they have entered into an exclusive clinical collaboration agreement to evaluate the safety, tolerability and preliminary efficacy of combining Opdivo (nivolumab), Bristol-Myers Squibb’s investigational PD-1 (programmed death-1) immune checkpoint inhibitor, with FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R). The Phase 1a/1b study will evaluate the combination of Opdivo and FPA008 as a potential treatment option for patients with non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, pancreatic cancer, colorectal cancer and malignant glioma. Bristol-Myers Squibb has proposed the name Opdivo, which, if approved by health authorities, will serve as the trademark for nivolumab.

So BMS will immediately move FPA008, but all measures an early stage and largely unproven therapeutic, into combination therapy trials with nivolumab for the treatment of solid tumors. Not to be outdone, Roche has already positioned it’s CSF1R targeted therapeutic, as noted by @jq1234t:

 JQ screen shot

There are a number of interesting questions to answer here: What does CSF1R do, why is it so interesting, how does it impact the tumor microenvironment, how are these trials being done and (a favorite of mine), who else has assets in development?

CSF1R is the receptor for macrophage-colony-stimulating factor (aka M-CSF or CSF-1). The receptor is a control node for macrophage differentiation. CSF1R also serves as a receptor for the monocyte survival factor IL-34. Although the ultimate outcome depends on many factors, signaling through CSF1R is necessary for myeloid lineage precursor cell differentiation into macrophages, and it is this feature that interests us in the tumor microenvironment setting. We cannot gloss over the fact that this is a pleiotropic and complex biological system but it is safe to say that by the time we are confronted by an immunosuppressed tumor (as in the case of combo therapy with anti-PD-1/PD-L1 therapeutics), our pathway focus is on tumor associated macrophages (TAM), their impact on the tumor microenvironment and their susceptibility to CSF1R-targeted therapy.

Roche poached this figure that I’m now borrowing (with fair reference to Chen and Mellman, 2013).

Roche version Cancer Immunity Cycle

In the original figure (see Immunity 39: – an open access article), Chen and Mellman placed the PD-1 pathway inhibitors with a variety of microenvironmental modulators (IDO1, Arginase, TGFb) that together prevent, in distinct ways, cancer cell death. The Roche version of the figure, reproduced above, has been modified to include CSF1R among other targets in the “killing cancer cells” category.

Broad strokes, what does this mean? TAM, the tumor associated macrophages mentioned above, are dependent on CSF1R signaling. TAM are myeloid lineage-derived cells that are co-opted by the resident tumor as part of it’s microenvironmental support system. TAM are potently angiogenic, remodel the stroma (extracellular matrix and related components) and are immunosuppressive. Among the plethora of critical factors produced by TAM we find the hypoxia response proteins and growth factors that drive angiogenesis, tissue remodeling and immunosuppression, i.e. HIF2a, MMP-9, EGF, VEGF and TGFbeta, cytokines that can maintain this response in a chronic state (IL-10, IL-4) and chemokines that attract myeloid cells and regulatory T cells (CCL22, CCXL8). The TAM population can be directly regulated by tumor cell secretion of CSF-1, thus the importance of the CSF1R target. Multiple labs have produced preclinical data showing that anti-CSF1R antibody therapy can rapidly and effectively deplete tumors of the TAM population, and that this depletion has an impact on tumor growth and survival.

Clinical development to date is scattered. The FPRX program began with a Phase 1 trial in healthy volunteers and rheumatoid arthritis patients (NCT01962337) reflecting the role of diverse macrophage populations in inflammation and autoimmunity. Indeed the FPRX website states “we are currently conducting nonclinical research in areas such as idiopathic pulmonary fibrosis, lupus nephritis and other inflammatory disorders to identify a second target indication by the end of 2014” although this may be trumped by the BMS deal. That trial reported safety and pharmacodynamic endpoints at AACR earlier this year. FPA008 was well-tolerated at all dose levels tested and the drug impacted inflammatory macrophage numbers and, interestingly, bone turnover (this latter effect due to the control of osteoclast differentiation by CSF1R, an important feature in bone metastasis settings perhaps).

In contrast Roche has been testing it’s antibody in a rare disease (a form of giant cell tumor) that is caused by a  t(1;2) translocation resulting in fusion of COL6A3 and M-CSF genes encoding for CSF1. The tumor is characterized by CSF1R+ cells. Roche reported that RG7155 had the following activities (Reis et al. 2014. Cell 25: 846–859):

– Anti-CSF-1R antibody depletes tumor-associated macrophages in cancer patients

– CSF-1R inhibitor shows clinical activity in diffuse-type giant cell tumor patients

– CSF-1R signaling inhibition increases lymphocyte infiltration in cancer patients

That last highlight referring to an effect on immunosuppression and refers to a relative increase of CD8+ T cells versus CD4+ FoxP3+ T regulatory cells, thus feeding the enthusiasm for combination therapy with anti-PD-1/PD-L1 therapeutics. More data is available in their ASCO abstract (

Other clinical stage antibodies include IMC-CS4 from Eli Lilly, in Phase 1 for advanced solid tumors (NCT01346358), ARRY-282 from Array BioPharma and Celgene, which had completed a Phase 1 trial in advanced solid tumors (NCT01316822) before the program was terminated, AMG 820 from Amgen with a completed Phase 1 study in advanced malignancies (NCT01444404), and others. Preclinical programs are visible at many small companies, both private and public, and include small molecule inhibitors of the receptor, e.g the Ambit and Plexxikon programs.

While the enthusiasm seems warranted by the preclinical modeling data and the (to date) apparent tolerability of the antibody therapies, I did receive this one note of caution from @Boston_Biotech:

Bos Biotech screenshot

Nuances, indeed. It is important to consider a few possible issues. First, blockade of CSF1R in mice led to the pronounced and sustained upregulation of CSF-1, and drug doses had to be kept high in order to “drug-through” this level of ligand to block the receptor. Rebound activity at trough or upon drug cessation could be a big problem, as has been described for other systems, including CCL2 blockade in breast cancer models (leading to abundant metastasis). Sticking with breast cancer, it has been reported that blocking CSF1R leads to upregulation of GM-CSF signaling, changing the composition perhaps (but not the stability) of the tumor microenvironment. Finally, as always, we cannot yet see what efficacy drugs will have as monotherapies (its too early) while we race ahead to combo therapies. While its all hands on deck to get these assets into patients, they won’t all work and certainly can’t be sure they will do no harm. However, that said, I think targeting components of the tumor microenvironment, including TAM, is our next best step forward, and I certainly will enjoy watching the data unfold.

next time … what wraps pancreatic cancer up so tight that you can’t treat it until it explodes in a deadly metastasis fireball?

cool stuff.