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Biotech / Medical : Exelixis, Inc. (EXEL) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (894)	11/22/2013 1:05:20 PM
From: tuck	Read Replies (1) \| Respond to of 930

I haven't followed EXEL for a while. But they partnered XL518 concurrently with the IND in 12/06, and EXEL was responsible for development through the end of phase 1. It was my understanding that Genentech would opt in or not at that point. Maybe I misunderstood the opt in timing, but if not, there must have been some sort of amendment to the agreement that was not trumpeted here. In any case, it's been almost seven years since the IND, and 518 is still mired in phase 1? Wowza. I remember something about EXEL slowing development activities to focus on Cabo. I guess they weren't kidding. And now, in spite of having a well heeled partner apparently running this program, aren't they pretty far behind in this space? My rambling pertains to the the idea that really slow development can be a red flag for investors. Maybe it does not apply in this case, but aren't they pretty far behind in this space? TIA & Cheers, Tuck

To: scaram(o)uche who wrote (894)	11/22/2013 8:26:53 PM
From: scaram(o)uche	1 Recommendation Recommended By xr1 Respond to of 930

immunotherapyofcancer.org MAP kinase inhibitors stimulate T cell and anti-tumor activity in combination with blockade of the PD-L1/PD-1 interaction Bryan A Irving*, Jeanne Cheung, Yagai Yang, Marina Moskalenka, Marcin Kowanetz, Heather Maecker and Ira Mellman Journal for ImmunoTherapy of Cancer 2013, 1(Suppl 1):P79 doi:10.1186/2051-1426-1-S1-P79 Pharmacological inhibition of the MAPK pathway with MEK or BRAF antagonists has proved successful in inducing regression of melanoma tumors bearing the targeted activating mutations. Moreover, antibodies targeting T-cell immune checkpoint inhibitors CTLA-4 or PD-L1/PD-1 have demonstrated the capacity to generate durable responses in patients with multiple cancer types. Thus, combining MAPK pathway-targeted agents with antibodies that enhance anti-tumor immunity represents an increasingly attractive treatment paradigm for cancer. However, little is known about the impact of tumor-targeted agents on immune function as similar signaling pathways drive both T-cell activation and cancer cell proliferation. Accordingly, agents targeting MAPK-dependent tumor growth would be predicted to also inhibit T-cell immunity. Here we show that, unexpectedly, potent suppression of T-cell receptor (TCR) function by MEK inhibition can be largely overcome in the presence of co-stimulation by anti-CD28 in vitro or blockade of the inhibitory PD-L1/PD-1 pathway in T cells in vivo. The ability of anti-CD28 to override suppression of T-cell activation by MEK inhibitors was dependent on the PI3K/mTOR pathway. Enhanced anti-tumor activity was also observed combining MEK inhibition with PD-L1 blockade, which was likely potentiated by upregulation of tumor MHC Class I expression through inhibition of MEK. Interestingly, inhibitors targeting BRAF V600E mutations actually augmented TCR-driven proliferation in vitro and T-cell function in vivo when combined with a vaccine or blockade of PD-L1 exclusively in the context of a wildtype BRAF background. These data demonstrate that targeting the MAPK pathway can be compatible with or even enhance T-cell function and provide rationale for combining these inhibitors with immunotherapy in clinical trials.