From his June 28 Biotech Stock Mailbag. Bold emphasis is mine, as is bold underlined.
"Before I address a specific question about NewLink Genetics (NLNK), I want to lay down a bifurcated position on cancer immunotherapy in general.
Position No. 1: Until I see convincing evidence of efficacy (successful phase III studies, FDA approvals) I am extremely skeptical of any company taking the "vaccine" approach to targeting cancer cells. I define a cancer vaccine as any therapy made up of tumor cells (autologous or patient specific), antigens or other immune-boosting agents designed to provoke the body's immune system to mount an attack on specific types of cancer cells.
Who's in this cancer vaccine group? Dendreon (DNDN), of course. Provenge is approved, but it's a fluke and a commercial disappointment. The list of companies with failed cancer vaccines is much longer -- Cell Genesys, Genitope, Favrille, Oncothyreon (ONTY), Antigenics (AGEN), CancerVax, etc.
Despite a lot of convincing evidence debunking the vaccine approach to cancer immunotherapy, tiny biotech companies push ahead -- NewLink, Galena Biopharma (GALE), Vical (VICL), Northwest Biotherapeutics (NWBO), ImmunoCellular Therapeutics (IMUC). I'm not a believer. I'll be happy to admit my error if/when one of these companies produces boffo clinical data. I just don't see that happening anytime soon.
Position No. 2: The anti-PD1/PDL1 approach to cancer immunotherapy works. These therapies turn off a cloaking device used by cancer cells to hide from a patient's immune system. One way cancer cells grow is by donning molecular camouflage which tricks the immune system into thinking they're normal, healthy cells. The anti-PD1/PDL1 (and anti-CTLA4) drugs turn off cancer's cloaking device. Without the protective camo, the immune system attacks cancer cells as foreign and deadly.
I just came back from the ASCO annual meeting where Bristol-Myers Squibb (BMY), Merck (MRK) and Roche (RHHBY) presented a lot of astounding clinical data on their respective anti-PD1/PDL-1 therapies. This is the positive direction in which the cancer immunotherapy field is headed. By comparison, cancer vaccine developers are driving into a dead end.
Back to NewLink and its pancreatic cancer vaccine known as HyperAcute Pancreaa, or algenpantucel-L. Results from an interim analysis of an ongoing phase III study are expected soon. [The official guidance is mid-year.]
This interim analysis is fundamentally meaningless. At best, it's another biotech catalyst for biotech traders to trade around.
The most likely outcome of the interim analysis -- to be conducted after half of the expected number of deaths have occurred -- will be a determination to continue the study with final results ready next year. The bar to stop the study early for efficacy is really high -- estimated at a 45% improvement in overall survival for HyperAcute Pancreas relative to the control arm, according to NewLink.
Notably, NewLink is not conducting a futility analysis concurrent with the early look at overall survival. A futility analysis determines whether an experimental drug is unlikely to confer a benefit relative to control.
In other words, NewLink only wants to know if HyperAcute Pancreas works so well that victory can be declared early. The company doesn't want to know -- and will not learn -- if the vaccine has no chance of succeeding.
Unfortunately, this half-blind approach to clinical trials is standard operating procedure for cancer vaccine developers."Feuerstein's Position No. 1: "I define a cancer vaccine as any therapy made up of tumor cells (autologous or patient specific), antigens or other immune-boosting agents designed to provoke the body's immune system to mount an attack on specific types of cancer cells." ➟➟➟ Throwing around labels, like a cancer vaccine (or the Holy Grail of cancer, among other labels), very often poorly describes what you are trying to describe because you've used a poor label, you aren't using it "fully properly," or you don't fully understand the label you are using.
Let's start with Provectus' Society for Immunotherapy of Cancer (SITC) poster, where the company concluded the immuno-chemoablative response to PV-10 is tantamount to “in situ vaccination.”
PV-10 is not made up of tumor cells, antigens or other immune-boosting agents. It stimulates the immune system by virtue of the very large quantity of relevant and specific antigens the chemoablative properties of the drug facilitate and thus enable to be expressed. I suppose if we're being intellectually honest, PV-10 could be viewed as an immune-boosting agent, depending on what you mean or intend to mean by "boosting."
I don't think the company calls PV-10 a cancer vaccine, although Moffitt might, but I think they might consider it "vaccine-like" in how it stimulates the immune system.
From Wikipedia: "A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters."
The bold emphasis above is mine. PV-10, while not being the agent in the context of the verbiage above, does indeed stimulate the immune system. PV-10's chemoablative properties enable the creation of thousands of "agents" -- the very large quantity of relevant and specific antigens created after PV-10 is administered intralesionally into tumors -- that then are (i) recognized by the immune system as foreign, (ii) are remembered by the immune system, and thus (iii) easily recognized and destroyed by the immune system when they are later encountered.
Words matter. "Provoke" does not fully equal "stimulate."
Feuerstein's Position No. 2: "These therapies turn off a cloaking device used by cancer cells to hide from a patient's immune system." ➟➟➟ Anti-PD-1s/PDL-1s are the next wave of interesting immunotherapy agents, but that is neither the full sum nor the end of the story.
PV-10 triggers immune cell mediation, which is natural, after initial chemoablation occurs. Again, words matter. "Turn off"/"turn on" are artificial, as in doing something artificial to the immune system (and thus, as Craig would say, to Mother Nature). PV-10 harnesses/employ/stimulates the immune system in a manner that, said colloquially, allows Mother Nature to do what she does best.