OncoSec Medical Inc (ONCSQ)

[cameron12x]

This is just an opinion, but an informed one:

The presence of PD1/PDL1 expression in the tumor has been shown to be NOT a reliable indicator of efficacy (of the PD/L1 checkpoint blockade antibodies).

In the EARLY days of the trials, investigators *thought* it was potentially a reliable marker. Then, they started noticing patients were responding to the checkpoint blockade antibodies even though the biopsied tumors did NOT contain PD1/PDL1.

Basically, the immune system is highly complex. PD1/PDL1 expression can come and go. It depends when you one is actually measuring expression on the tumor.

The $1m question is whether or not combining Immunopulse + PD1 will result in significant synergies. My bet is yes.

I dug around Stanford University's research website and found the following:
http://www.nejm.org/doi/full/10.1056/NEJMc1203984

As you can see, just introducing radiation therapy to a single tumor can make checkpoint blockade suddenly work (where it was not working before). They got so excited that they even started a clinical trial combining the two:
http://clinicaltrials.gov/ct2/show/NCT01769222

Now, take this observation one step further. Go ask all the radiation oncologists how many times they have seen the "immunopulse effect" where zapping just one or two tumors can cause systemic antitumor effect. Very very few, if any will tell you they've seen it. The point here is that if simple radiation can cause dramatic response to checkpoint blockade, it is a reasonable, if not a strong bet, that combining Immunopulse with checkpoint blockade will result in this combination synergy, perhaps more apparent, at higher rates.

The scientific rationale is all there -- zapping a tumor with immunopulse causes immediate attraction of Tcells. Tcells attack the tumor, leading to an "in situ vaccine effect". These Tcells go on to attack other tumors throughout the body. However, tumors have highly immunosuppressive defensive mechanisms. That's where the PD1 checkpoint blockade comes in -- to remove these defenses.

My bet is we truly will see a shockingly high synergistic rate of responses to PD1 with Immunopulse. Furthermore, other alternatives such as radiation, vaccines may not be as good as Immunopulse because of the following:

1) Immunopulse DNA plasmids result in *constant* secretion of IL12 -- this creates a "constant vaccine" like effect. Imaging if you have to vaccinate a person (or irradiate) every minute. 24x7.

2) Electroporation causes transient intense inflammation. This is highly beneficial in generating the needed immune response. You can research something called cryo-ablation (or cryoablation). Many investigators have observed a transient systemic anti-cancer effect -- just like immunopulse -- from cryo-ablation. However, this effect is very temporary and nowhere as apparent as Immunopulse. The point is that the transient inflammation is very beneficial.

3) IL12 has been tried in the past (systemic infusions). However, it failed. Why? One reason posited was IL12 causes upregulation of "Bad stuff" like Tregs. You see, the immune system is highly complex will all sorts of checks & balances. These checks exist to prevent bad stuff from happening like auto-immune diseases (where your own Tcells attack your healthy tissue). IL12 has been shown to cause Tregs to initially decrease increase. This promotes the beneficial antitumor effects. However, after some time, Tregs may re-increase to prevent autoimmune type symptoms. This is one explanation for the countless "failed" immunotherapies from the 80s, 90s, and even today. This is where checkpoint blockade comes in. Checkpoint blockade (PD1) prevents Tregs from eventually stopping the anti-tumor effects of IL-12.