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…

4 thoughts on “Lion Biotechnologies and TIL therapy for melanoma

  1. re “The presence of TILs is correlated with improved survival at least in some indications.” do you have a reference for this (and other?) sub-categorisation(s) in determining survival please?

  2. Many thanks for the search term, changing it a bit (eg “HLA” gives a July paper, or just no qualification) suggests quite a minefield of sub-categories to affect small sample-size trials it seems (to the lay observer).