Monthly Archives: August 2014

Lion Biotechnologies and TIL therapy for melanoma

There is so much here to raise suspicion.

Lion Biotechnologies was born ugly, from a merger with Genesis Biopharma, essentially forming a public company within the shell of what some people suspect was originally a pump and dump operation (link). This up-listing maneuver came at the cost of most of Lion’s equity, as Genesis shareholders held 83.6% of the combined company and Lion shareholders initially received 8.2%, with the promise of doubling that stake to 16.4% of the combined company based on achievement of certain milestones. The merger was completed in July of 2013 and the stock continued trading under the ticker symbol GNBP until September 2013, when Genesis announced a 1 for 100 reverse stock split that essentially took place immediately, locking shareholders in place. The merged company changed its name to Lion Biotechnologies and hatched the new listing symbol LBIO. Muddying the picture just a bit more, the company is run by Manish Singh, Ph.D., the former ImmunoCellular Therapeutics chief executive who resigned from that company in August 2012. One rumor circulating then was that he was sacked after suspicions were raised about ImmunoCellular’s Phase 1 data reporting and promotion. That company has stabilized since he departed, moving its’ oncology vaccine program into Phase 2.

LBIO has moved aggressively into the cellular immunotherapy space, licensing technology developed by Dr. Steve Rosenberg and colleagues at NCI (using the same CRADA model that Kite Pharma uses) and building collaborative relationships with MD Anderson and the Moffitt Cancer Research Institute. They pulled in an MD Anderson investigator, Laszlo Radvanyi Ph.D. as CSO and earlier this week appointed industry veteran Elma Hawkins Ph.D. as President and COO. These are likely all good moves toward establishing and building credibility, although the company remains dogged by bad PR, most recently being pulled (by subpoena) into an SEC investigation of Galena Biopharma, a seemingly unrelated company. Speculation about this “wide net” investigation by the SEC has focused on Dr. Singh and possible past involvement with an investor relations firm (link 2). This seems unlikely to have anything to do with LBIO itself.

The final piece of the puzzle is more transparent, which is that the shell merger/reverse split reboot was financed in large part via a private placement with Roth Capital. There is nothing wrong here, except that people tracking stocks in this space tire a bit of the relentless pumping that Roth does on behalf of LBIO, although it is of course their right and possibly their obligation to do so. One puff piece stated “we see 196% upside!” – and I’d have to comment, stealing a line here from Billy Bob Thornton, “that’s a pretty specific number”. I guess we could also wonder what if anything the original shareholders of Genesis and Lion have left of their equity.

Moving on.

LBIO’s CSO, Dr. Laszlo Radvanyi, spoke a few weeks ago at the Immunomodulatory Antibodies for Cancer Conference in Boston, part of the ImVacs package. It was an impressive talk, very upbeat, and contained some data and technology that was new to me. So I took a closer look.

The basis for the technology is a riff on something we discussed earlier, as presented by the NCI’s Rosenberg at ASCO (link 3). Tumor infiltrating lymphocytes (TILs) are found in large numbers in some solid tumor types, and can be isolated when the tumor is removed. The presence of TILs is correlated with improved survival at least in some indications. It has been known for quite some time that expanded TILs can be injected back into the patient where they, sometimes, effectively attack and eradicate the tumor. The problem with the technology is that, like all personalized cellular therapies (CAR, TCR, some types of tumor vaccines), it is cumbersome to perform. When logistics are such a challenge, you really want to see robust benefit from the treatment. This is what LBIO is suggesting it can deliver. Dr. Radvanyi walked us through a brief history of TIL technology, hitting the highpoints. His statement that standard TIL therapy has shown overwhelming and superior efficacy versus competing therapeutics for in melanoma was one I had not heard before, and I reserve judgment on this – after all if it was really that good everyone would be adopting this technology, and I really don’t see that happening.

What was really interesting though was the more experimental system that he introduced, and if you look at the LBIO website you’ll see it under “next-generation TIL” (link 4). In this system tumor fragments are made from biopsy samples and cultured with IL-2. This apparently works optimally because dendritic cells and monocytes persist in the culture for a week or so. They first activate and then sort the TILs using an agonist anti-4-1BB antibody to enrich for antigen specific activated T cells. This allows you to reduce the number of cells injected (a good thing). He did show dramatic enrichment of TILs that recognized known melanoma antigens, so at the very least this model system works. I think this also suggests the importance of the 4-1BB pathway, at least in this system. Notably, anti-OX-40 antibody failed to expand antigen-specific T cells (note we are talking specifically about CD8+ T cells here, in part because that’s all you’ll have left after a few weeks culture in IL-2).

It seems a nice simple system and worth watching. There were other bells and whistles (transduction techniques) that we’ll skip for now. Other technology  LBIO is funding includes the use of the anti-CTLA4 antibody ipilimumab  in conjunction with TIL therapy (to turn off active immune suppression in the tumor microenvironment). That is being done at Moffitt in a Phase 1 expansion cohort. Be interesting to see what else the company has in mind.

Can LBIO – using this new TIL technology – achieve clinical and commercial success?

stay tuned…

SugarCone Biotech is Seeking an Intern

We are pleased to announce the availability of an Internship, reporting to the Principal. Our intern will research diverse aspects of drug development in support of our ongoing projects. The successful candidate will have several of the following characteristics:

- be currently engaged in or have recently finished a graduate-level program (Ph.D, Pharm D, JD, MS) with extensive training in biological sciences, with specific expertise in immunology, inflammation, and/or oncology.

- be deeply aware of and enthusiastic about current drug development trends in the biotechnology and pharmaceutical industries.

- understand trends in the development of biologics and cellular therapies in oncology and inflammation.

- be well-versed in the the scientific literature and competent in the uses of available search tools to mine the literature.

- be articulate, thoughtful and write with exceptional clarity.

The successful candidate will complement our expertise in the above areas, and have responsibility for novel projects in autoimmune disease, fibrosis, autoimmunity, CNS disorders, hematological malignancies, solid tumor biology, the drug development process and/or the regulatory process (US, UK and EU).

Please send your CV with a cover letter detailing your relevant experience to Paul Rennert at rennertp@sugarconebiotech.com.

TIM-1 and HIV

The story of TIM family proteins and the regulation of viral infection just gets more and more interesting. We’ve previously explored the role of TIM-1 in mediating Ebola and Marburg virus infection. We’ve now published our newest work on modulation of HIV cellular infection by TIM-1:  http://www.pnas.org/content/early/2014/08/14/1404851111.abstract

In Consideration of TIM-3

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There is nothing like hearing science told by passionate and talented investigators, and we got a one-two punch on the subject of TIM-3-mediated immunotherapy from Drs Vijay Kuchroo and Ana Carrizosa Anderson at the ImVacS Immunomodulatory Antibodies for Cancer meeting in Boston on Monday, August 11. The image above is modified from this review, written by the speakers.

Having sent a few years tackling this challenging protein family it was refreshing to see the utility of anti-TIM-3 therapy being supported by robust experimentation. This is a complex story and one that’s hard to get right, but I think these investigators from Harvard Medical School are getting very close.

Let’s have a look.

Vijay Kuchroo introduced several unifying hypotheses – first, that TIM-3 is always co-expressed on T cells along with PD-1, thereby marking such T cells as anergized or exhausted (in any case, non-responsive to TCR-stimulation), and second, that TIM-3 functions as a cell death signal for T cells. The first hypothesis is supported by the literature, and likely portrays the consensus view. The second hypothesis was supported by experiments in which isolated T cells were exposed to soluble Galectin-9 (Gal-9) whereupon these T cells “blew apart” as shown in a short video. This latter hypothesis is apt to be more controversial, as the experimental conditions used are probably not physiological, and the described effect is not anticipated in the Gal-9 literature. Regardless, it was impressive data. It is possible that there is some interplay between TIM-3 binding to Gal-9 and TIM-3 binding to phosphatidylserine (PS) that regulates T cell responses. That’s not been worked out yet. Gordon Freeman later offered the additional hypothesis that Gal-9 serves to attenuate or modulate TIM-3 signaling, perhaps in cis (on the same cell) or trans (across cells).

Dr Kuchroo then presented some very interesting new data that tumor stromal cells produce IL-27 that induces T cell suppression and supports T regulatory cells (Treg). IL-27 therefore emerges as a novel regulator of the tumor Treg environment. The “exhaustion module” was further articulated as follows: the tumor stroma secretes IL-27 that signals through the IL-27 receptor to PRDM1. PRDM1 induces the upregulation of TIM-3, LAG-3, PD-1 and IL-10. Additional new targets were identified using this model, and we can look forward to seeing those described in future – that was very nice work. Conversely, IFNy is upregulated when PD-1 and TIM-3 are blocked, e.g. with antibodies. Since interferons, including IFNy, are known to upregulate PD-L1 (the PD-1 ligand) on tumor cells, a particularly attractive therapy might be a combination of anti-TIM-3 and anti-PD-L1 antibodies. Of note, tumor growth and the development of Tregs is deficient in IL-27R gene-deficient (KO) mice, supporting the exhaustion module model. The inhibition of tumor growth in these KO mice is correlated with increased expression of IL-2, TNF and IFNy in the tumor-draining lymph nodes.

One question was raised which addressed how this model could be reconciled with the finding by Steven Rosenberg and others that PD-1 expression marks activated tumor infiltrating lymphocytes (TILs). The difference may be related to the co-expression, or lack of expression, of TIM-3 and perhaps LAG-3. It would appear that we need a way to characterize the diverse variety of T cells found in tumors, beyond the current TILs and Tregs.

Ana Carrizosa Anderson further discussed TIM-3 expression on TILs and showed that TIM-3+ TILs secrete IL-10 and are therefore Tregs. Such TIM-3+ Tregs are preferentially enriched in tumors, pointing to the active induction as described by Dr Kuchroo. Dr Anderson further showed that anti-PD-L1 plus anti-TIM-3 antibodies deprogram Tregs, shutting down their immune suppressive pathways including their own target’s expression – thus anti-TIM-3/anti-PD-1 treatment shuts down expression of TIM-3, PD-1 and a host of other immunosuppressive factors, shining a light on a mechanism of feedback regulation in human TILs.

Dr Anderson then raised an interesting question regarding colorectal cancer which has so far proved resistant to immunotherapy (ipilimumab, nivolumab). In a preclinical CRC model, the combination anti-TIM3 and anti-PD-1 worked very well, This led to the intriguing question of whether TIM-3 is particularly useful here because of the very high expression of Gal9 is high in gut. I like the focus on the local environment, which may be useful in addressing primary tumors.

Speaking of the local environment, this is a good time to mention a paper on TIM-4, another PS-binding protein in the TIM family. Terry Strom along with Vijay Kuchroo and colleagues recently described a “fragile” TIM-4+ tissue macrophage population with immunosuppressive properties (Thornley et al. 2014). While the paper focuses on immunological models, one can imagine that this target might be further investigated in the immunotherapy setting.

Seemed to me there was a fair amount of unpublished data in these talks that we can look forward to seeing published sometime soon, no doubt. In the meantime I’d bet some invention disclosures and preliminary patent filings are in the works!

stay tuned…

Immunomodulatory Antibodies for Cancer Conference, August 11, 2014

SugarCone Biotech will provide a novel targets overview at the Immunomodulatory Antibodies for Cancer conference taking place tomorrow and Tuesday, August 11-12,  at the Marriott Long Wharf Hotel in Boston.

I’ll highlight some of our favorite novel targets during my talk entitled The Next Wave of Immune Checkpoint Targets, at 2pm on August 11th.

Also, I’ll be live tweeting the conference which also features Michael Postow from Memorial Sloan Kettering Cancer Center, Vijay Kuchroo from Harvard Medical School, Dmitry Gabrilovich from the Wistar Institute, Agenus, Peregrine Pharmaceuticals, Compugen, F-star, Pelican Therapeutics, Lion Biotechnologies, Quest Pharmatech, arGen-X and other academic groups and biotechs.

I’ve been told you can register at the door (ask for the discount registration!) and just walk on in, or go to http://www.imvacs.com/Immunomodulatory-Antibodies-Cancer/ for more information.

Finally, follow me @PDRennert for updates throughout the day tomorrow and Tuesday.

Gilead and the silly spat over Solvadi pricing

Dear readers and clients of sugarconebiotech.com,

Sunday’s NY Times did us the favor of moving the discussion about Sovaldi from treatment of HCV to HCV cure (nyti.ms/1tHcFIw). It’s about time…

We present a compelling report from Dr. Paul De Santis on the valuation and future of Gilead Sciences (GILD): Alpha BioPharma Evidence-Driven Rebuttal to Morgan and Goldman, Summary & Marketing Report.

On the heals of their impressive quarterly earnings and heading toward a transformative year, Gilead faces fundamental issues. Dr. De Santis uses comprehensive and relentless analysis, deeply vetted, to trace the paths Gilead may take, and argues that bearish analyses from Morgan Stanley, Goldman Sachs and others have led the Street to fundamentally undervalue this innovative, aggressive and ultimately triumphant company.

In the full report Dr. De Santis covers critical topics including

      M&A:  GILD will have the capacity to repurchase their entire market cap by 2020.

      HCV PRICING: Sovaldi pricing pressure will ease as the discussion shifts to cost per cure, not cost per treatment. Further, the emerging HCV competition (MRK, BMY, ABBV) has little incentive to discount price – consensus forecastsrely on premium pricing.

      HCV, EMERGING MARKETS: Sovaldi has first mover advantage in 26 Emerging Markets. The pricing model/methodology presented in this report was confirmed by GILD management – no sell-side firm has put together such a comprehensive model on E.M. 

      PIPELINE: Gilead will leverage $100B in FCF to accelerate their transformation into a premier Oncology franchise

      SUSTAINABILITY: As we’ve seen in other chronic diseases (MS, RA) the arrival of transformative therapies will drive market expansion over many years

If you maintain or trade positions in GILD, it’s competitors, partners or takeover targets I kindly suggest you acquire his detailed 145 page report. Pricing and download information are available directly from Dr. De Santis at drpauldesantis@alphabiopharmaadvisers.com. In addition to the report Dr. De Santis will send you real-time updates from the critical upcoming medical conferences (ASH, the AASLD Liver conference, CHEST, and ESMO) and important updates related to GILD and its’ competition through year-end.

We support this report based on the very high quality and content and our respect for the work of Dr. De Santis and his firm AlphaBioPharma.

To be fair, we are also long GILD.