You are completely correct in that tumor antigens are heterogenous and several studies have shown that not 100% of cells in the tumor express a given antigen. For ex, this paper outlines that in a clinical trial with a CAR against a tumor antigen (mutant EGFR), some tumors were as low as 6% mutant EGFR. (http://stm.sciencemag.org/content/9/399/eaaa0984/tab-pdf). Several earlier clinical trails of transgenic TCR or cancer vaccine have proven ineffective and perhaps the tumor heterogeneity is partly to blame (along with a immunosuppressive tumor environment)

However, your question is complex because the antigen-based immunotherapies have several mechanisms of action distinct from just that antigen. For example, there is a process of 'antigen spreading' or 'epitope spreading' which can occur as you prime the immune system against the tumor. This occurs either through re-activation of suppressed/dysfunctional T cells or through enhanced tumor lysis and subsequence macrophage/DC phagocytosis and presentation of more tumor antigens. Such a phenomenon is documented for example with a BiTE antibody immunotherapy against the tumor antigen WT1 (http://www.nature.com/nbt/journal/v33/n10/full/nbt.3349.html). Therefore, even if your target is not expressed on all tumor cells, there is the possibility that you activate the immune system against other tumor antigens and ideally turn the tide against the tumor.

Hope this helps!

Dear Aran Chang, thanks for the response.

I agree with you on many of the points; my question remains same as reoccurrence is the main problem in the tumor therapy.

So at first point, there is an antigen loss which is discussed in this paper http://www.sciencedirect.com/science/article/pii/S0304383514006181

The second one is after reoccurrence http://www.jimmunol.org/content/189/2/767.short there is almost no antigen expressed.

Coming on to your point as very less antigen expressing cells can also generate sufficient immune response with the help of other mechanisms, how useful it can be because it is an alternative mechanism, not direct and can easily be shadowed by tumor suppressive environment. Immunotherapy usually is not treating the tumor in a single dose need to multiple doses; the possibility that it can activate the immune system against other tumor antigens remains very low. Please share more related ideas, would be interesting to discuss.

Thanks for sharing the related articles and knowledge.

Hope I can get more discussion on this aspect.

lmmunotherapy has been a hopeful technique to avoid fatal chemotherapy and radiation, which both create tumor-stem-cells out of or normal stem cells existing for every tissue in our body. Unfortunately, as you correctly observed, immunothrapy is rather complicated and not successful kn every case.

Therefore Intried othercsays of treatment. Using the yin-ang-neutralization method by Dr. Alfred Schneider, I induced apoptose-reaction in all tumorcells resuling in a two to three decades diminuation of tumorcells per session. Meanwhile Dr. Schneider has updated the method resulting in an immediate reprogramming of all tumorcells into normal tissuecells. I made successful treatments during the last year and it would be fruitful to use the method on a larger scale and compare it with the conventual methods.

Dear Dr. Hans thanking you very much for the valuable information. Is it possible to get more information or Paper link (if published) about Dr. Schneider's work?

It is going to revolutionize the cancer immunotherapy if utilized correctly.

Thanking you very much for sharing your knowledge and expertise on this platform.

Hope we get more valuable information about this topic in this thread.

Unfortiunately Dr. Schneider did not yet write a publication. He has no internet homepage and no email address or facebook etc. He courses were declining, because his argumentation with quantum physics they could no longer follow.Since about 5 years he does not offer anycourses. I see him about twice each year to get his newest findings, which are really revolutionary. Since about one year he transferrs the energetic informations on infusion-fluids. I do not know the exact procedure. I have really phantastic success of treatment wit his energized  infusion fluids. It harmonizes people fromthe quantum level to the highest spiritual dimensions.

After an in fusion all bone-marrow white blood cells are reprogrammend so that they produce abtibodies which never react with personel proteins. Therefore allergic reactions are no longer possible. and all auto-immune-diseases are immediately stopped. Furthermore if present all cancer cells are reprogrammed to normal tissue cells. If the patients suffered already from chemotherapy or radiation, the thus induced tumor-stemm-cells are reprogrammen to normal stemm-cells. In all cases I made this treatment it was fully successful.

I myself deveolped a diagnostic sytem by using yijing chinese charakters for the hexagrams. I found they are extremely sensitive means to detec diseases and to follow succes of treatment. See my  article in the addenda.

Dear Dr. Hans,

Thanks for sharing your paper, although I don’t have any idea how yin-and-neutralization can reprogram tumor cells into healthy cells.

I request you to convince Dr. Schneider to publish related data or exact correlation which will allow new scientist to work on these areas if there is any scientific evidence proved.

Thanks for sharing your report about the hexagrams and diagnostics, I request you also to publish few more articles related to mechanisms which will help young clinicians and scientists.

As far as my question related to immunotherapy is concerned, we still cannot reach on any conclusion,

I call for other cancer biologist and scientists to share their thoughts on the current issue, please.

Yes I know; some more details shold be published. Unfortunately Dr.Schneider has resigned and I doubt he will publish. I work with his systems for more than ten years very sucessfully. Sofar I could not convince kollegues in uiversitxy to test and verify or falsify my tresults, with  the few patients I have ther are no big studies beeing made, I personally do not have the resouces. the whol procedure is blocked by pharmaceutical lobbies who fear for their incomes.

Dear Prashant,

Back to your original discussion, yes antigen loss and tumor micro-environment are both major roadblocks for immunotherapy. A good example is that thus far, direct antigen cancer vaccines targeting single tumor antigens (MAGE, WT1, NY-ESO1, have not shown dramatic therapeutic efficacy.  https://www.ncbi.nlm.nih.gov/pubmed/27058246

Even with engineered CAR T cells, it has been observed that antigen-negative relapse happens in about 30% of patients. https://www.jci.org/articles/view/87366

The reason why Checkpoint inhibitors work effectively in a subset of patients (along with several other reasons being studied) could be that checkpoint inhibition releases the brakes on a polyclonal immune response and therefore the immune system is targeting several antigens, not just the 1 or 2 that cancer vaccines use. This is suggested in observations where relapse after checkpoint inhibition occurs in tumors which have lost B2M and therefore have lost the ability to present antigen.  http://www.nejm.org/doi/full/10.1056/NEJMoa1604958#t=article

Therefore, certain cancer immunotherapies (CAR T cells, checkpoint blockade etc) have already proven to be effective in clinical trials, but relapse does occur due to antigen loss, and thus they can still be improved.

It will be interesting to see what clinical trials show in the next few years combining immunotherapies with other drugs that have synergistic mechanisms of actions.

In this article we have tried to find most of the mechanisms involved .There are many unexplored questions, Hope we can further investigate other aspects also.

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