I will try and start to try and answer your question and hope it helps. I think that first it is very common for people when evaluating forest for the trees. I try an make things as simple as possible. If you cannot get past step one, step 2 will not work(or at least with any consistency). More to my point. solid tumors mutate a lot. 2 biopsies of the same tumor from different sites can look quite different. For instance targeted therapy tries to hit one target on the tumor that is common. Some targets(antigens) are more common than others, so if you make a targeted therapy for that antigen that is more common you will probably get a better response rate. That is why you might see such dramatic shrinkage in a tumor with targeted therapy. If it is present on 99% of the cells at the time of treatment the radiologically the tumor will disappear. We know that usually does not happen pathologically though. That 1% that remains(usually it is a lot more, and rarely in is completely killed) is even more anaplastic and does not carry the antigen for that therapy and grows back with vengance. Then you are lucky if something else works. With nonspecific immune stimulating drugs like PD-1 the response rate in a crude sense is based on the tumors ability to not suppress it's activation. 75% of the time it can, in most of the other 25% it eventually does. Then it will never work again. I believe the response rates will never be very high because you cannot get around the above. We have not even talked about side effects(I have had dozens of patients on PD-1 and CTLA which is similar that I shared with a medical oncologist at UCSF and life is not fun for most).
Now lets talk about immunotherapy for a little. The only thing smart enough to keep up with cancer and it's ability to mutate is the immune system. We will never be as smart as it is. One of them main problems if not the main problem is the ability of cancer to shut it down. The original vaccines did not work well enough because even though multiple personalized antigens were given the immune system of the patient was not stimulated. That is why it only worked on a few percent(but boy could it work and be sustained). DCVAX is the only company I have ever seen that deals with this issue. It in essence turns on the immune system even if it is shut off. It not only turns it on but turns it on at it's source. It attacks the cancer through multiple antigens, many probably that we don't even know. Once the system is turned on it can feed off of itself and make new T-cells to attack the cells that mutate and change there profile. For something or someone not to be hypocritical what is said one day has to be in the same belief system that is said next week, next year, or 2 weeks ago. If you look at the way the cancer is attacked in immunotherapy it is so different than targeted therapy, that is why you don't get this sudden(often short lived massive shrinkage). The immune system is ramped up and is attacking from multiple angles, in a sense keeping up with the tumor in a race making it's presence chronic rather than terminal. As we learn more we may see shrinkage faster or more tumors disappear(dosage changes, better activation, more frequent activation). What I am saying is when I look at all of the data and science it all just fits together, no 2 thoughts do not align. There are things they don't know, steps that are happening that we don't see yet. All of us who believe in it hope they have connected enough of the steps to get this to work well enough to help people and be perfected as we learn more. Fighting cancer with our immune system is the only way, I know it. I will try and write a little more about my thoughts on immunotherapy as the days go on. I am an call and am getting called to the OR. I really do hope I am helping and not wasting anyones time. I really believe you cannot make this too complicated, the big picture should tell you what the right direction is.
Thanks(sorry about any typing errors, was trying to get this done fast)
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