Given that immunotherapy will be a hot topic at the BioPharm America™ partnering conference this September, we asked BioMedtracker to provide an update on the space. Below is a brief synopsis followed by a link to their full report:
Robert Jeng, BioMedtracker
Perhaps no other recent topic in oncology has generated as much excitement as the immunotherapies. PD-1s, checkpoint inhibitors, CAR-T, and DC therapies – all have become common fare for those following cancer drug development. Indeed, “Cancer Immunotherapy” was voted the Science Breakthrough of the Year for 2013 (Science, Vol. 342, no. 6165) and MD Anderson promoted immunotherapies as part of their ambitious Moon Shots program. And attendees at the recent 2014 American Association for Cancer Research witnessed a flood of immunotherapy sessions first-hand.
Immunotherapies in oncology have actually been around for decades, including the use of cytokines and immunomodulatory agents that had a general stimulatory effect on the immune system. Targeted monoclonal antibodies also are technically immunotherapies. However, the renewed interest in immunotherapies has primarily been driven by a few promising new classes that are the focus of this report.
The immune system is a complex defense mechanism against foreign particles, but it often fails to recognize cancer cells. Nevertheless, the idea of stimulating the immune system to better attack cancer cells has long been attractive because of the special properties an immunotherapy could provide including high specificity against tumor cells and a uniquely long-lasting response (immunologic memory).
Therapies that modulate the immune system have, of course, been common in other disease areas, particularly autoimmune disorders. Even cancer immunotherapies in the broader sense have been available for decades including general immunomodulators (e.g. cytokines), and targeted antibody biologics that block specific oncogenic pathways but that also stimulate immune responses against the targeted tumor cells (e.g. Avastin, Herceptin). Indeed, most therapies that result in lysed tumor cells likely stimulate at least some immune response to tumor specific antigens that are released as a secondary mechanism.
However, the more recent identification of novel mechanisms that cancer cells use to actively avoid immune detection (e.g. immune checkpoints) as well as emergence of new technologies to manipulate immune cells have ignited a new wave of interest and drug development in immunotherapies. And, so far, the early clinical signs are promising, particularly for PD-1s which are demonstrating the long durability characteristic of an endogenous immune response in several tumor types.
Two next-generation immunotherapies have already reached the market with the FDA approval of Provenge (sipuleucel-T; DNDN) for prostate cancer in 2010 marking the start of the current era of immunotherapies. Provenge is a complex cell therapy that was remarkable as the first targeted prostate cancer therapy in the castration-refractory setting to demonstrate a survival advantage (Jevtana [cabazitaxel, SNY] also showed a survival benefit around the same time but is more similar to a traditional chemotherapy). Although Provenge has achieved limited commercial success due to a variety of factors (including the rapid arrival of strong traditional-drug competitors), its development did set the stage for the current generation of immunotherapies, including addressing the issue of extending overall survival (OS) without extending progression-free survival (PFS) that may be common to many immunotherapies due to the lag time required for an immune response to develop.
Following Provenge was the approval of Yervoy (ipilimumab, BMY) for melanoma in 2011. Yervoy is an inhibitor of the CTLA-4 immune checkpoint. Checkpoint inhibitors are some of the most promising immunotherapies in development (especially PD-1s), with several large companies developing drugs in this space including Bristol-Myers Squibb, Roche, and Merck. These inhibitors attack endogenous immune controls that some tumors co-opt to suppress immune attacks against them. In addition to the CTLA-4 checkpoint, other checkpoints have been identified including the Programmed Death checkpoint (PD, or PD-1), TIM3 (T-cell Immunoglobulin and Mucin domain 3), and LAG3 (Lymphocyte-activation gene or CD223).
It is worth noting that because of the broad definition of immunotherapies, some companies are trying to inflate interest in their more traditional drugs by associating them with the more novel immunotherapies. Thus, those following the field must be cautious about understanding the actual mechanism behind new drugs in the space. One example is Provectus Biopharmaceuticals (PVCT). Its lead drug, PV-10, is a formulation of the small molecule, rose bengal, which has been long been used as a biological stain. Although the specific mechanism of action to kill tumor cells is not entirely clear, PV-10 is believed to accumulate in the lysosomes of rapidly growing tumor cells and cause cell lysis. However, more recently, the company has been promoting a tumor specific immune response associated with PV-10 that is most likely a secondary effect of lysing tumor cells (see 2013 AACR poster #1248 and 2013 PLOS One publication, DOI: 10.1371/journal.pone.0068561).
Another example is Peregrine Pharmaceuticals (PPHM) and its promotion of bavituximab. Early in its development, the company described the mechanism of action primarily through targeting of exposed phosphatidylserine (PS) on tumor cell surfaces. Now, however, the company is proposing a more detailed mechanism involving immune signaling to macrophages by PS. While macrophage polarization and tumor-specific immune response could very well be a part of PS signaling, it also could be an effect of a more intense effort to measure immune responses which could likely be identified with many oncotherapies.
For more information on BioMedTracker please visit www.biomedtracker.com
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