Talk:Cancer immunotherapy

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Introductory sentences

Cancer Immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease.

This is an incorrect generalisation, and as such should not be part of the opening paragraph, if TK inhibitors and radioimmunotherapy are classed as part of cancer immunotherapy, rather than as targeted therapy. Whilst immune stimulation is a strategy, this is emphatically not the technique used by most of the commercial monoclonals used today eg the tyrosine kinase inhibitors such as Herceptin, Cetuximab, which interfere with the ErbB family. Nor is it the mode of action of the radioconjugates such as Zevalin, or Bexxar. Jellytussle 20:12, 11 May 2006 (UTC)

It is confusing to classify Mabs, TK inhibitors and radioimmunotherapy as immunotherapies, it is more correct to refer to these therapies as targeted therapies. Jellytussle above makes the correct argument that immune stimulation is not the mechanism used by most commercial mabs, but then draws the wrong conclusion. Immunotherapy or more specifically, active immunotherapies, to exploit the immune system's potential to discern healthy from diseased tissue, has been the focus of researchers for nearly 3 decades. SInce the above mentioned targeted therapies do not use the immune mechanism, this supports the arguments to discuss these therapies in a separate "Targeted Therapies" section.

I think the nuance is that Immunotherapies have not yet been commercialized despite decades of research and promising pre-clincal results due to failure in the clinic. This is correct and I feel it is appropriate to discuss reasons for failure in the clinic and possible strategies to deal with (and learn from) these failures. DoctorCancer (talk) 01:46, 11 April 2011 (UTC)

Immune modifiers

It is generally accecpted that cancer immunotherapy refers to the use of monoclonal antibodies in the treatment of cancer, so I have removed references to IL-2, artificial T cell receptors, Imiquimod and vaccines. They would be more approiately placed in an article on immune modification or immune modifiers.

The problem is that this makes the opening paragraph even more irrelevant. I think it is instructive to look at a respectable and authoritative source for a good summary of definitions. This is taken from the Cancer Research UK website:

"Immunotherapy

In the 1850s, doctors in Germany noticed that patients' tumours would occasionally shrink if their tumour became infected. This observation led to the idea that the body's immune system could be harnessed and made to fight cancer.

Around the same time, doctors throughout Europe, encouraged by the success of Edward Jenner's smallpox vaccine, attempted to make a 'cancer vaccine' by injecting patients with crude extracts of tumours from other cancer patients. These treatments were largely ineffective, but the field of 'immunotherapy' was born.

Initial progress on immunotherapy was slow, and over a hundred years' work in the laboratory yielded little success in actual cancer treatment. This all changed when in 1975, Georges Köhler and César Milstein, working in Cambridge, discovered how to make synthetic antibodies.

Their discovery, coupled with an ever-increasing understanding of the immune system, has led to a variety of treatments and strategies that use the immune system to tackle cancer. Some, such as the antibody-based breast cancer drug Herceptin, are now used routinely to treat cancer patients.

Immunotherapy can be local or systemic.

Local immunotherapy delivers the treatment to the affected area. For example, the BCG vaccine can be injected into the bladder to treat bladder cancer, as it causes inflammation that can cause the tumour to shrink.

Systemic therapy treats the whole body and is useful for targeting cancer that may have spread. In the 1980s, scientists at the Cancer Research UK Medical Oncology Unit at the Christie Hospital in Manchester showed that the protein interferon alpha could cause tumours to shrink in patients with low-grade lymphoma. Interferon is now used to treat several different types of cancer.

Immunotherapy can also be non-specific or targeted.

Non-specific immunotherapy works by boosting the body's immune system in general, so that its natural cancer-killing activity is enhanced. Both of the examples of local and systemic therapies (above) are also examples of non-specific immunotherapy.

Targeted immunotherapy is designed to make the immune system specifically kill cancer cells. The following types of targeted immunotherapy are available or are in development:

Antibody-based therapies

Antibodies are proteins produced by the immune system. A type of white blood cell called a B-cell produces them in response to an infection. Normally, antibodies stick to foreign objects in the body and label them for destruction. Researchers have been trying to make antibodies that will attach themselves only to cancer cells. This can be useful in four ways.

   * It can stop the cancer from growing by stopping other essential 'growth factors' from sticking to it.
   * It can 'tag' the cancer for destruction by the immune system.
   * If cancer drugs or radioactive particles are attached to the antibody, it can deliver them directly to the cancer cell without harming the rest of your body.
   * An enzyme (a type of protein that can promote chemical reactions) can be attached to an antibody, and then given to a patient along with a chemical that can be turned into a powerful drug by the enzyme. This directs the drug to the cancer, and minimise side effects. This process is known as Antibody-directed Enzyme/Pro-drug Therapy (ADEPT).

Several antibody-based therapies are available, including the breast cancer drug Herceptin."

Jellytussle 23:47, 30 May 2006 (UTC)

Yes, Immunotherapy is a very ambigious name, as many immunological-based techniques are employed in cancer treatment. Monoclonal antibody therapy is a very distinct and high profile treatment, so it requires its own article. Maybe we should rename this article with something more specific and use "Immunotherapy" as an all encompasing aricle on immunological-based treatments in cancer. --Cellpath 01:17, 3 June 2006 (UTC)

ErbB2

Other kinds of tumor cells display cell surface receptors that are rare or absent on the surfaces of healthy cells, and which are responsible for activating cellular signaling pathways that cause the unregulated growth and division of the tumor cell. Examples include ErbB2, a constitutively active cell surface receptor that is produced at abnormally high levels on the surface of appromimately 30% of breast cancer tumor cells. Such breast cancer is known a Her-2 positive breast cancer, and is treated with Herceptin.

Ironically ErbB2 is expressed variably in a variety of normal tissues(ref: Press, M.F., C. Cordon-Cardo, and D.J. Slamon, Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene, 1990. 5(7): p. 953-62. ), and in developing and diseased myocardium (3 Refs : Zhao, Y.Y., et al., Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem, 1998. 273(17): p. 10261-9. Fuchs, I.B., et al., Analysis of HER2 and HER4 in human myocardium to clarify the cardiotoxicity of trastuzumab (Herceptin). Breast Cancer Res Treat, 2003. 82(1): p. 23-8. Uray, I.P., et al., Left ventricular unloading alters receptor tyrosine kinase expression in the failing human heart. J Heart Lung Transplant, 2002. 21(7): p. 771-82.) and is therefore a poor example of a tumour specific antigen. Jellytussle 02:47, 31 May 2006 (UTC)

OK fixed that, it's untrue.

Her-2 is found in many cell types and tissues, but it is only overexpressed in 
some types of cancer, and that's the critical thing with Herceptin.

--Cellpath 01:17, 3 June 2006 (UTC)

Cancer vaccines and TLR9 agonists

Apart from the intro there isn't much on cancer vaccines. Needs summary here ?

No mention of TLR9 agonists eg "Prostate Cancer: Genes, Environment, Immunity and the use of Immunotherapy: TLR9 Agonist in Immunotherapy" 2008 but I think this would be a whole new category here. Rod57 (talk) 03:53, 20 January 2010 (UTC)

GD2

GD2 seems only mentioned in the Intro section. Presumably this should be moved to a new section further down the article ? Rod57 (talk) 04:28, 20 January 2010 (UTC)

Natural Products

This section contains information on the immune effects of various mushroom, most not clearly related to clinical medicine, with no mention of clinical studies etc, particularly with respect to cancer treatment. One product is mentioned as being "commercially available in Australia" which means very little if one can buy it over the counter from a health food shop. Propose delete the entire section unless it can be seriously beefed up.Jellytussle (talk) 15:34, 10 August 2011 (UTC)

German article

has material should probably be here, especially the history section which appears to be completely absent here. 72.228.177.92 (talk) 10:32, 12 January 2012 (UTC)

Does using antibodies to target a therapeutic count as an immunotherapy.

Under Advances it says "Another strategy is to deliver a lethal radioactive dose directly to the target cell, which has been utilized in the case of the Zevalin therapeutic. A third strategy is to deliver a lethal chemical dose to the target, as used in the Mylotarg therapeutic"
but since that doesn't affect the host immune system shouldn't we exclude these ? They seem to be targeted therapys as mentioned above. - Rod57 (talk) 12:27, 11 April 2013 (UTC)

Adoptive T Cell Therapy

Hi Alexbrn, You removed some content on the cancer immunotherapy article regarding new information by the National Cancer Institute, National Institute of Health, and Science Magazine/Journal, with the stated reason that WP:MEDRS was violated. These sources are very reliable, and many more sources on the subject are available with a quick google search. You seem to be a valuable member of the wikipedia community, have edited many articles, and I believe I saw that you are a cancer survivor yourself. My family has been affected by cancer as well. I'm confused why you wouldn't want information regarding one of the most promising avenues of cancer immunotherapy treatment added to the cancer immunotherapy article. Thx Whodat2112 (talk) 15:27, 10 May 2014 (UTC)

The problem is the text is asserting some claims ("can mount a response") and implying efficacy through results ("majority of patients ... went in to complete remission") when the underlying sourcing is not strong enough to support such claims and implications. The sources are:

1. a news item from NIH - which carefully qualifies its wording ("The research provides evidence that this immune response can be harnessed for therapeutic benefit in patients, according to the scientists")
2. an earlier news update from NIH, again properly caveated ("These are small clinical trials, their lead investigators cautioned, and much more research is needed")
3. primary studies from Science (we should not use primary studies)

I think we could support a statement such as "As of 2014, clinical trials for ACT are underway, and preliminary results are promising" sourced to the NIH news items perhaps. Much more would be undue and we shouldn't be jumping to conclusions for which there isn't solid evidence as accepted & reported good medical sources. Alexbrn ^{talk|contribs|COI} 15:49, 10 May 2014 (UTC)

Alexbrn, you make a good point, but it's important to remember that these are two separate subjects you are referring to. For the study of CAR T Cell therapy on ALL patients, I was actually understating the results. The actual result was an 89 percent complete remission for the 27 patients that were studied (22 children and 5 adults), of which the majority of patients are still in complete remission. These results were published about 1 year ago and can be verified by many reliable secondary sources such as The American Society of Hematology and the American Society of Clinical Oncology:

http://www.hematology.org/Newsroom/Press-Releases/2013/1322.aspx

http://www.ascopost.com/issues/january-15,-2014/mounting-success-in-trials-of-genetically-engineered-t-cells-to-treat-leukemias-and-lymphomas.aspx

For the study on Personalized ACT starting with whole-exome sequencing to target TIL's, this is a very recent discovery that CAR T Cell Therapy can be used to target epithelial cancers. Besides the NCI, NIH, and Science Magazine Primary sources, I can offer secondary sources such as webmd, the wall street journal, and fiercebiotech:

http://www.webmd.com/cancer/news/20140508/one-womans-cancer-battle-highlights-promise-of-new-treatment

http://online.wsj.com/news/articles/SB10001424052702303701304579550101737391142?mod=WSJ_LatestHeadlines&mg=reno64-

wsj&url=http%3A%2F%2Fonline.wsj.com%2Farticle%2FSB10001424052702303701304579550101737391142.html%3Fmod%3DWSJ_LatestHeadlines

http://www.fiercebiotech.com/story/new-immunotherapy-uses-patients-cells-attack-tumors/2014-05-09

If you feel that either of these discoveries are not established enough to put in the Adoptive T Cell Therapy Section, I would be happy to put them in the "New and Future Immunotherapies Section". Please let me know how you would like me to proceed when you get a chance. Whodat2112 (talk) 18:30, 10 May 2014 (UTC)

Alexbrn, I added the sentence you suggested "As of 2014, clinical trials for ACT are underway, and preliminary results are promising." and sourced the NIH and NCI references. I'm ok with this compromise to describe the state of ACT clinical trials, but I think we are still missing important info about the discovery that ACT which starts with whole-exome sequencing has the potential to work on epithelial cancers, which is a major breakthrough in our understanding of ACT's potential in cancer treatment beyond just blood based cancers. I'm open to your thoughts though. Whodat2112 (talk) 21:07, 10 May 2014 (UTC)

Removing antibodies that do not activate the immune system

The following antibodies mentioned in this article appear to work by mechanisms other than activation of the immune system:

• Bevacizumab – inhibits angiogenesis
• Brentuximab vedotin – prevents cell division by disrupting microtubules
• Cetuximab – EGFR antagonist
• Gemtuzumab ozogamicin – antibody/cytotoxic warhead conjugate
• Ibritumomab tiuxetan – antibody/radioisotope chelator conjugate
• Tositumomab iodine tositumomab regimen – antibody/radioisotope chelator conjugate
• Trastuzumab – HER2 receptor antagonist

Hence they do not appear relevant to this article but would be relevant for Monoclonal antibody therapy. Am I missing something? Boghog (talk) 12:31, 26 June 2015 (UTC)

I have gone ahead and removed the above list of antibodies from this article. Boghog (talk) 05:20, 30 June 2015 (UTC)

Just saw this. Instead of "activate the immune system", the inclusion criterion should be "involved in ci". Lfstevens (talk) 15:00, 1 August 2015 (UTC)

I agree that "activate" may be too restrictive but "involved in" is too broad. Would "restore or enhance the immune system" be better? Regardless of the definition, the list of antibodies above are not generally thought of as cancer immunotherapy agents. Boghog (talk) 15:13, 1 August 2015 (UTC)

That wouldn't include the checkpoint inhibitors discussed below, would it? It shouldn't be about the immune system, it should be about antibody therapies. Lfstevens (talk) 19:38, 2 August 2015 (UTC)

It would include the checkpoint inhibitors discussed below. Cancer immunotherapy drugs include both small molecules (see for example PMID 26228631) and biologics (e.g., antibodies). Not all cancer immunotherapy agents are antibodies and not all antibody based anticancer drugs are immunomodulatory. Boghog (talk) 20:05, 2 August 2015 (UTC)

Below are a couple of definitions. None mention antibodies specifically:

• "Immunotherapy: Using the Immune System to Treat Cancer - National Cancer Institute". National Cancer Institute. Retrieved 3 August 2015. Immunotherapies are treatments that restore or enhance the immune system's ability to fight cancer.
• "What is cancer immunotherapy?". American Cancer Society. Retrieved 3 August 2015. Immunotherapy is treatment that uses certain parts of a person's immune system to fight diseases such as cancer. ... Immunotherapy includes treatments that work in different ways. Some boost the body's immune system in a very general way. Others help train the immune system to attack cancer cells specifically.
• "Understanding Immunotherapy". Cancer.Net. Retrieved 3 August 2015. Immunotherapy, also called biologic therapy, is a type of cancer treatment designed to boost the body's natural defenses to fight the cancer. ... There are several types of immunotherapy, including monoclonal antibodies, non-specific immunotherapies, and cancer vaccines.

Boghog (talk) 08:49, 3 August 2015 (UTC)

Proposed split out of the Immune checkpoint blockade section

The Immune checkpoint blockade section could start new article. Could call it checkpoint inhibitor therapy ? Possibly also split out PD-1 inhibitor since there are other types of Immune checkpoint blockade - see Immune checkpoint. - Rod57 (talk) 18:56, 22 June 2016 (UTC)

I don't have any objections in starting new articles based on the material from immune checkpoints, but I think a fairly detailed description of this strategy should remain in the parent cancer immunotherapy article because of the high importance of checkpoints within the field. As a practical matter, I also think this section would need to be expanded significantly in order to have enough material to justify one or more new articles. Boghog (talk) 08:09, 24 June 2016 (UTC)

Worth a new article, but this one isn't so big yet that it is urgent. This topic is becoming huge, so getting articles set up now will mean less drama down the line. Lfstevens (talk) 15:01, 24 June 2016 (UTC)

@Lfstevens: Done, see Checkpoint inhibitor therapy for the page I've copied over. I will keep the under construction tag on the page over the next day or two here while I get some time to work on this page. Shaded0 (talk) 18:48, 16 August 2017 (UTC)

New content on mouse study

Lfstevens has been doing some great work on IT across several articles; this is something that really needed doing, so thanks for that!

This content however is UNDUE on a single mouse study

Combined therapy

In 2015 a study on mice with an aggressive form of melanoma, simultaneously applied antibody therapy, activating the innate immune system and adoptive cell transfer, stimulating the adaptive immune system. A signaling molecule called IL-2 generated both types of immune responses. Building on earlier attempts to use the molecule, the research extended IL-2's duration in the bloodstream by fusing to to part of an antibody molecule. The study concluded that a weekly dose of IL-2 with antibodies could stop tumor growth.

T cells were the most important component of the anti-tumor response induced by the antibody-IL-2 combination. They combination of IL-2-induced cells and cytokines with the antibody treatment allowed T cells to attack more effectively. Neutrophils that react strongly to foreign invaders entering the body through a cut or other injury were also important. Adoptively transferred T cells that targeted the tumor were more effective when delivered with an antibody and IL-2. In 80 to 90% of the mice, tumors disappeared completely. Tumor cells that were re-injected into the mice months after the original treatment were killed by the immune system, preventing new tumors from forming. More generally IL-2 bound to antibodies that did not target a protein on the tumor cell surface, still halted or slowed tumor growth.

References

There is a lot of media hype around IT (per the sources here) and we need to go really, really lightly on that stuff, per WP:MEDREV which explicitly talks about this. Jytdog (talk) 00:24, 10 April 2016 (UTC)

While I'm always open to revision and compression, I see this bit as complying with the cited policy, which gives an example of how to treat important new material. The material does not contradict earlier, validated results and positions the new info as the result of a single study (rather than proclaiming a new "fact"), alerting users to the possibility that a second study might disagree. Lfstevens (talk) 17:42, 10 April 2016 (UTC)

the issue with putting a ton of weight on any mouse study (but especially in cancer) is that what happens in humans is almost entirely uncorrelated with what happens in mice. We have cured cancer in mice ten thousand times over. it's important in the development process as a go/no-go check -- if it doesn't work in mice, there is not much point going forward - but that's about it. see this article from the 1998 (!) LA Times for example. that was hype over angiostatin which never became a drug (anti-VEGF drugs have become super important, of course) Jytdog (talk) 17:58, 10 April 2016 (UTC)

But the language drew no implications for human health. And it's in the research section. And it's a variation on other material in the research section. Lfstevens (talk) 21:54, 10 April 2016 (UTC)

This whole article exists because it is about treating cancer in people and readers want to understand this whole IT thing. The research section exists because people want to understand what is going on with bringing more treatments, and sure some of the science too. But research is exactly where a lot of hype comes into Wikipedia. Here is the example I beat to death -- remember that scientist who published work showing that if you shake cells (really!) you could turn them into stem cells? There was huge media hype around that. And yep, people rushed to add content based on the hyped primary source to WP. (Note the edit date, and the date the paper came out) only to delete it later when the paper was retracted. We should not be jerking the public around like that no matter how "exciting" the research result is. There is no reason to do that - we have no deadline here. (We actually have an article on the whole mess Stimulus-triggered acquisition of pluripotency) In my view it is great to have "research direction" sections in articles about diseases and treatments but they should be high level and based on reviews, and identify challenges as well as progress, not be blow-by-blow, focusing in on this hyped paper or that one.... Jytdog (talk) 23:30, 10 April 2016 (UTC)

History does not mention Coley's toxins

History includes "Towards the end of the 19th century Emil von Behring and Shibasaburō Kitasato discovered that injecting animals with diphtheria toxin produced blood serum with antitoxins to it." with no reference or explanation of how it relates to cancer immunotherapy. (Could someone improve it ?) - Coley's toxins, in use (in humans) 1893 to 1963 (USA), to 1990 (Germany) seem as/more relevant. - Any objection to a brief mention of Coley's toxins in the History section ? - Rod57 (talk) 13:00, 27 May 2016 (UTC)
And also this review mentions it. - Rod57 (talk) 11:56, 2 July 2016 (UTC)

Some of History not clear - may relate to wider definition of scope

History says "In 1997 rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; alemtuzumab (2001), ofatumumab (2009) and ipilimumab (2011)." but it is not clear if any of these relate to 'cancer immunotherapy' (which is modification of the immune response, NOT the mere use of antibodies) - Rod57 (talk) 21:48, 12 June 2016 (UTC)

... Looks like (from comments above) that some prior editors had a wider definition of Cancer immunotherapy but the excess content has not yet been purged. Any objections to eg that "In 1997 ..." sentence being removed ? - Rod57 (talk) 21:57, 12 June 2016 (UTC)

Isn't the question not whether the sentence should be removed but whether the 11 antibodies were for cancer immunotherapy? Lfstevens (talk) 07:21, 13 June 2016 (UTC)

To answer the question, one needs to look at the mechanism/mode of action. Cancer immunotherapy is the simulation of the immune system to treat cancer. In contrast, the first three agents mentioned target cancers where the origin of the cancer is immune system itself. By directly killing malignant immune cells, this mechanism is opposite of how cancer immunotherapy is usually defined. The fourth agent, ipilimumab, is a legitimate cancer immunotherapy agent.

• rituximab – kills B cells, basically an anti-inflammatory agent (anti CD20)
• alemtuzumab – kills lymphocytes (anti CD20)
• ofatumumab – kills lymphocytes (anti CD20)
• ipilimumab – activates the immune system (anti CTLA-4)

ipilimumab was first approved in 2011. Interferon alfa could also be consider a cancer immunotherapy agent (stimulates B cells) and was approved in 1986. Boghog (talk) 11:42, 13 June 2016 (UTC)

Hmm. This is more complicated than I thought. According to PMID 20350658, the mechanism of destruction of B cells by rituximab is unknown. However one of the proposed mechanism is antibody-dependent cell-mediated cytotoxicity. If this is the mechanism, then rituximab can legitimately be called a cancer immunotherapy agent. Boghog (talk) 17:49, 15 June 2016 (UTC)

When we're sure we could include rituximab; until then perhaps we should only mention ipilimumab ? - Rod57 (talk) 12:09, 2 July 2016 (UTC)

Jan 2016 review could be useful

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential. Jan 2016 looks useful. - Rod57 (talk) 12:05, 2 July 2016 (UTC)

Proposed merge with Cancer immunology - rejected

It has been proposed that this cancer immunotherapy be merged with cancer immunology.

Oppose : the 'ology' is about what happens without immunotherapy. The therapy is about modifying the behaviour of the immune system to treat cancer. Best IMO to keep the two separate (but cross referenced), both will grow. - Rod57 (talk) 14:26, 25 November 2016 (UTC)

Comment – I am removing this malformed proposal that did not include a rationale. Boghog (talk) 16:32, 25 November 2016 (UTC)

cancer immunogene therapy

The following was added in these diffs; this is all sourced to primary sources by the subject being described - we need secondary sources saying this. As it stands this is WP:OR and WP:UNDUE:

Cancer immunogene therapy was introduced by Jerzy Trojan and colleagues in 1993, applying a subcutaneous injection of autologous cancer cells transfected with vector expressing antisense IGF-I RNA,; the clinical trial of glioblastoma was approved by NIH n˚ 1602, and FDA in 1994. The modified strategy using anti – gene (antisense / triple helix) anti IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial - n˚ 635 and 636; the clinical protocol was conducted by J. Trojan through the Collaborative NATO Science Program (USA, France, Poland n˚ LST 980517) and later in Colombia. This cell-based immunotherapy has proven to be efficient, strengthening anti-tumor immune response (TCD8, TCD28) and apoptotic phenomena. Promising results were obtained in personalized treatments of glioblastoma, prostate, ovary, uterus, liver and colon cancer.

References

-- Jytdog (talk) 23:54, 2 January 2017 (UTC)

Promotional content about

User:Mjenik you are adding content that is unsupported by its source, and that is promotional. A paper published on Y date about X, cannot itself be a source for X being first on Y date. That is WP:OR. The content is explicitly promotional as well, in violation of the WP:PROMO policy. Jytdog (talk) 14:50, 17 October 2017 (UTC)

User:Jytdog I am adding the first paper who presents an anticancer CAR-T cell. http://www.pnas.org/content/86/24/10024.full.pdf You can look also at this patent. http://www.google.com/patents/US7741465 As I see I am not violating any policy as I am not doing promotion but I am recognizing the merit of the pioneers of the CAR. Whats would it be the way of claiming X was the first on Y date ? What more evidence should I bring ? I am showing a very very early journal publication https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2149517/. You will not find anyone from before. I assure you. I am also showing you here a patent from those dates. These team also developed the first ScFv on that moment. But this is another discussion.

Please allow the content to be there. They deserve the credit. — Preceding unsigned comment added by Mjenik (talk • contribs) 16:48, 17 October 2017 (UTC)

The content is WP:OR. You are claiming that these are "first" but we need secondary sources that actually say what is first. Also patents are not reliable sources in WP - they are specifically mentioned in WP:USERGENERATED. Jytdog (talk) 15:10, 22 October 2017 (UTC)

@Mjenik: Wikipedia is an encyclopedia, a tertiary source, that is written primarily as summaries of secondary sources. We have to be very careful about the use of primary sources, and not use them to make claims that are not directly made in reliable sources. There is also no concept of deserving credit here, other than where it is derived as a summary of good quality, published, independent, secondary sources. So you will either need to find such a source to verify directly a claim of "invention" or "first publication", or settle for a more neutral description of Gross and Eshhar's work. I would tentatively suggest that in the middle of the History section, you may be justified in adding something along the lines of:

• Research by Gross and Eshhar, et al, in 1989 on chimeric T-cell receptor genes demonstrated some anti-tumour specificity and led to a US patent.

@Jytdog: Would that be sufficiently neutral? Is it significant enough to be included in the late 1980s part of History per WP:DUE?

References

--RexxS (talk) 17:30, 22 October 2017 (UTC)

In my view without secondary sources it is UNDUE. Jytdog (talk) 17:39, 22 October 2017 (UTC)

Dear @Jytdog: , @RexxS: and reviewers, thank you. Here are two quite valuable secondary sources. Carl June writes "The concept of introducing into a cytotoxic T-cell hybridoma the genetic material for an antibody recognizing a model antigen (a hapten, 2,4,6-trinitrophenyl) was described in 1989 by Gross, Waks, and Eshhar" and "The above basic science advances demonstrated that it was possible to redirect T-cell signaling to an antigen of choice and independent of MHC restrictions. In their seminal work, Gross et al. (9) concluded that ‘construction of chimeric T-cell receptors with anti-tumor specificity will enable testing of the feasibility of this approach in combating human tumors.’ " on.

Steve Rosenberg writes "CARs were pioneered by Gross and colleagues in the late 1980s (45) and can be constructed by linking the variable regions of the antibody heavy and light chains to intracellular signaling chains such as CD3-zeta ..." on. Mjenik (talk) 12:47, 23 October 2017 (UTC)

User:Jytdog, these both look like ideal sources under WP:MEDRS (and "who did what in which year" isn't even WP:Biomedical information anyway, but high-quality academic sources are welcome everywhere). Are you satisfied that these sources support the claim?

On a related point, I want to welcome User:Sebjaeger, who changed a different historical claim, and to ask: Why the sudden interest in the history of cancer immunotherapy? Is there something going on in the real world (a "history of immunotherapy" conference, maybe?) that relates to this subject, or is it just a coincidence? WhatamIdoing (talk) 15:14, 23 October 2017 (UTC)

The interest is probably sparked by the 1st FDA approval of a CAR-T therapy - success has many fathers! Jytdog (talk) 15:19, 23 October 2017 (UTC)

@Jytdog: User:WhatamIdoing also asked if you are satisfied with these sources supporting the claim. Regards Mjenik (talk) 16:35, 23 October 2017 (UTC)

@Jytdog: Also , a success like this deserves the mention of those fathers and what they did for it. That's the purpose of the "History" section , isn't it ? In this way I'm pointing the pioneer inventors of the CAR-T cells as far as on 1989. Mjenik (talk) 16:41, 23 October 2017 (UTC)

The purpose of the history section is not to promote anybody in particular but to summarize the history as described in independent, reliable, secondary sources. I have not had time to review the sources provided by WAID yet, nor to determine if they support the claim. I will do soon. Jytdog (talk) 17:55, 23 October 2017 (UTC)

Here you have one of the second sources by Steven Rosenberg https://snag.gy/HgDJ0o.jpg Mjenik (talk) 11:54, 25 October 2017 (UTC)

Here you have other second source by Carl June https://snag.gy/gjD0uH.jpg Mjenik (talk) 12:02, 25 October 2017 (UTC)

history section

Seeing the total absence of a history section in the article, I read the comment below, and inserted a brief history section that comes entirely from NIH PMC (freely available medical journal articles). Feel free to improve it, but deleting the entire history is absurd. Immunotherapy itself is not a new invention; the history goes back more than 4,000 years.<end of what I'm typing, someone else typed what is below.>

moved here as this is built from primary sources and editors are spatting over how to build content from primary sources which is never resolveable.

This needs to be done over based on independent (in other words, not written by the person who is claiming they were very important) secondary sources.

History

Immunotherapy for the treatment of cancer has been utilized throughout history, with the earliest report in 2600 BC, by Egyptian pharaoh Imhotep who had a poultice, followed by incision, to facilitate the development of infection in the desired location and cause regression of the tumour. In 13th century, St. Peregrine is reported to have experienced spontaneous regression of tumor, after the tumor became infected. In the 18th and 19th centuries, deliberate infection of tumors were a standard treatment, where surgical wounds were left open to facilitate the development of infection. Throughout the time period, physicians reported successful treatment of cancer by exposing the tumor to infection including the report of French physician Dussosoy who covered an ulcerated breast carcinoma with gangrenous discharge soaked clothe, resulting in disappearance of tumor. Observations of a relationship between infection and cancer regression date back to at least the 18th century.

Modern Immunotherapy began in 1796 when Edward Jenner produced the first vaccine involving immunisation with cowpox to prevent smallpox. Towards the end of the 19th century Emil von Behring and Shibasaburō Kitasato discovered that injecting animals with diphtheria toxin produced blood serum with antitoxins to it.

Dr. William Coley, father of modern oncological immunotherapy, pioneered the treatment of cancer with immunotherapy based on bacterial vaccination with Coley's Toxins. He developed a treatment based on provoking an immune response to bacteria. In 1968 a protein related to his work was identified and called tumor necrosis factor-alpha.

Paul Ehrlich's research gave rise to the "magic bullet" concept; using antibodies to specifically target a disease. The production of pure monoclonal antibodies for therapeutic use became available in 1975 when Georges J. F. Köhler and Cesar Milstein produced hybridoma technology.

Immune cell therapy for cancer was introduced by Steven Rosenberg and colleagues. In the late 1980s, they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer who underwent different types of active specific immunotherapy.

In 1987, cytotoxic T-lymphocyte antigen 4, or CTLA-4 was identified by Pierre Golstein and colleagues. In 1996, Allison showed that antibodies against CTLA-4 allowed the immune system to destroy tumors in mice. In 1999, biotech firm Medarex acquired rights to the antibody. In 2010, Bristol-Myers Squibb, who acquired Medarex in 2009, reported that patients with metastatic melanoma lived an average of 10 months on the antibody, versus 6 months without it. It was the first time any treatment had extended life in advanced melanoma in a randomized trial.

In the early 1990s, a Tasuku Honjo and colleagues discovered a molecule expressed in dying T cells, which they called programmed death 1, or PD-1 and which they recognized as another disabler of T cells. An antibody that targeted PD-1 was developed and by 2008 produced remission in multiple subjects across multiple cancer types. In 2013, clinicians reported that across 300 patients tumors shrunk by about half or more in 31% of those with melanoma, 29% with kidney cancer and 17% with lung cancer.

In 1997 rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; alemtuzumab (2001), ofatumumab (2009) and ipilimumab (2011).

In 2003 cytokines such as interleukin were administered. The adverse effects of intravenously administered cytokines led to the extraction, in vitro expansion against a tumour antigen and reinjection of the cells with appropriate stimulatory cytokines.

However, with both anti–CTLA-4 and anti–PD-1, some tumors continued to grow before vanishing months later. Some patients kept responding after the antibody had been discontinued. Some patients, developed side effects including inflammation of the colon or of the pituitary gland.

The first cell-based immunotherapy cancer vaccine, sipuleucel-T, was approved in 2010 for the treatment of prostate cancer.

After success harvesting T cells from tumors, expanding them in the lab and reinfusing them into patients reduced tumors, in 2010, Steven Rosenberg announced the feasibility of chimeric antigen receptor (CAR) therapy, invented on 1989 by Gideon Gross and Zelig Eshhar [1][2]. This technique is a personalized treatment that involves genetically modifying each patient's T cells to target tumor cells. It produced complete remission in a majority of leukemia patients, although some later relapsed.

By mid 2016 the FDA had approved one PD-L1 inhibitor (atezolizumab) and two PD-1 inhibitors (nivolumab and pembrolizumab).

References

-- Jytdog (talk) 20:38, 26 October 2017 (UTC)

Dear User:Jytdog , I believe the last paragraph can be improved. This is related to the other claim we have been discussing (https://en.wikipedia.org/wiki/Talk:Cancer_immunotherapy#Promotional_content_about). The paragraph is saying "... in 2010, Steven Rosenberg announced chimeric antigen receptor therapy, or CAR therapy." . But we have been talking about the announcement of CAR-T cells for cancer. I believe what Steven Rosenberg achieved on 2010 is the claiming of the usability and proved clinical potential of anticancer CAR-T cell therapy for human. But the sentence like it's there looks as Rossenberg inventing alone on that year CAR-T cells or CAR-T cells anticancer therapies. And it is clear when looking at the papers that anticancer CAR-T cells therapies was thought as early as in 1989 by Gross and Eshhar. Rosenberg worked to bring them to the clinical field, and that is out of discussion. Mjenik (talk) 10:08, 29 October 2017 (UTC)

You have made it absolutely clear, WITH NO DOUBT WHATSOEVER, what you want to see. If you want to accelerate the re-introduction of this content (of course including the content about Gross and Eshhar) the best thing for you to do would be to propose a rewrite of the section above, based on secondary sources, in a new section below. I am trying to get to back to this but other things keep coming up. In the meantime please stop WP:BLUDGEONing this page. Jytdog (talk) 16:35, 30 October 2017 (UTC)

proposed rewrite of the history section

This is how the section looked like before going off but with the addition of a sentence to mention the invention of the CAR on late 80s. Of course this fact is supported by citations of respected secondary sources.

History

Immunotherapy for the treatment of cancer has been utilized throughout history, with the earliest report in 2600 BC, by Egyptian pharaoh Imhotep who had a poultice, followed by incision, to facilitate the development of infection in the desired location and cause regression of the tumour. In 13th century, St. Peregrine is reported to have experienced spontaneous regression of tumor, after the tumor became infected. In the 18th and 19th centuries, deliberate infection of tumors were a standard treatment, where surgical wounds were left open to facilitate the development of infection. Throughout the time period, physicians reported successful treatment of cancer by exposing the tumor to infection including the report of French physician Dussosoy who covered an ulcerated breast carcinoma with gangrenous discharge soaked clothe, resulting in disappearance of tumor. Observations of a relationship between infection and cancer regression date back to at least the 18th century.

Modern Immunotherapy began in 1796 when Edward Jenner produced the first vaccine involving immunisation with cowpox to prevent smallpox. Towards the end of the 19th century Emil von Behring and Shibasaburō Kitasato discovered that injecting animals with diphtheria toxin produced blood serum with antitoxins to it.

Dr. William Coley, father of modern oncological immunotherapy, pioneered the treatment of cancer with immunotherapy based on bacterial vaccination with Coley's Toxins. He developed a treatment based on provoking an immune response to bacteria. In 1968 a protein related to his work was identified and called tumor necrosis factor-alpha.

Paul Ehrlich's research gave rise to the "magic bullet" concept; using antibodies to specifically target a disease. The production of pure monoclonal antibodies for therapeutic use became available in 1975 when Georges J. F. Köhler and Cesar Milstein produced hybridoma technology.

Immune cell therapy for cancer was introduced by Steven Rosenberg and colleagues. In the late 1980s, they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer who underwent different types of active specific immunotherapy.

In 1987, cytotoxic T-lymphocyte antigen 4, or CTLA-4 was identified by Pierre Golstein and colleagues. In 1996, Allison showed that antibodies against CTLA-4 allowed the immune system to destroy tumors in mice. In 1999, biotech firm Medarex acquired rights to the antibody. In 2010, Bristol-Myers Squibb, who acquired Medarex in 2009, reported that patients with metastatic melanoma lived an average of 10 months on the antibody, versus 6 months without it. It was the first time any treatment had extended life in advanced melanoma in a randomized trial.

In the early 1990s, a Tasuku Honjo and colleagues discovered a molecule expressed in dying T cells, which they called programmed death 1, or PD-1 and which they recognized as another disabler of T cells. An antibody that targeted PD-1 was developed and by 2008 produced remission in multiple subjects across multiple cancer types. In 2013, clinicians reported that across 300 patients tumors shrunk by about half or more in 31% of those with melanoma, 29% with kidney cancer and 17% with lung cancer.

In 1997 rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; alemtuzumab (2001), ofatumumab (2009) and ipilimumab (2011).

In 2003 cytokines such as interleukin were administered. The adverse effects of intravenously administered cytokines led to the extraction, in vitro expansion against a tumour antigen and reinjection of the cells with appropriate stimulatory cytokines.

However, with both anti–CTLA-4 and anti–PD-1, some tumors continued to grow before vanishing months later. Some patients kept responding after the antibody had been discontinued. Some patients, developed side effects including inflammation of the colon or of the pituitary gland.

The first cell-based immunotherapy cancer vaccine, sipuleucel-T, was approved in 2010 for the treatment of prostate cancer.

After success harvesting T cells from tumors, expanding them in the lab and reinfusing them into patients reduced tumors, in 2010, Steven Rosenberg announced the feasibility of chimeric antigen receptor (CAR) therapy, invented on 1989 by Gideon Gross and Zelig Eshhar . This technique is a personalized treatment that involves genetically modifying each patient's T cells to target tumor cells. It produced complete remission in a majority of leukemia patients, although some later relapsed.

By mid 2016 the FDA had approved one PD-L1 inhibitor (atezolizumab) and two PD-1 inhibitors (nivolumab and pembrolizumab).

References

Anti-CD47 therapy section

I rewrote the outdated anti-CD47 therapy section. I used primary sources and assume this was the reason the new author, Jytdog, didn't like it and deleted the whole paragraph leaving just one sentence. I wonder if it is not too little. I feel like at least the most important parts could have been left there and the sources just replaced from primary ones to reviews. Jan Kuzmik (talk) 20:20, 1 March 2018 (UTC) — Preceding unsigned comment added by Jan Kuzmik (talk • contribs) 20:18, 1 March 2018 (UTC)

BCG (Bacillus Calmette–Guérin)

Why isn't the BCG vaccine (Bacillus Calmette–Guérin) listed here? It is a live vaccine containing Mycobacterium bovis used to protect against tuberculosis, but it has also been (very successfully) used as immunotherapy treatment for bladder cancer since the 1970s. I'm not sure which category, if any, it would fit into in this article, otherwise I'd add it. 2602:304:1064:8429:99F8:11E3:B8CC:2619 (talk) 15:02, 18 May 2020 (UTC)

Categories

I'm not entirely sure the categorization of active or passive is really necessary or useful. I've found multiple different definitions for active vs passive, and different classifications of what each agent is considered (see discussion here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350348/). I've made edits based on what I perceived as the distinguishing features of active vs passive, but would be interested to see if perhaps we should skip this section entirely and just focus on the different sub-types of immunotherapy. Quokkarobocop (talk) — Preceding undated comment added 04:17, 1 December 2020 (UTC)

I re-titled this section to be "Types and Categories" and added a bulleted list of NCI's type classification at the start of this section, since it's more high-level. Info was obtained from their website, which I cited. I page-linked each of the NCI's types to relevant Wikipedia articles or sub-sections.

Regarding the "active vs passive" categorization, that seems like a more technical classification of different types of therapy. It's relevant, but perhaps not as interesting as the listing of different types. I included your citation as well as this one which points to a different section of the NCI website.

Btw, the 'History' section needs work. At present it's only ancient history – no info about more recent biotech-era developments. SteveChervitzTrutane (talk) 08:15, 14 October 2023 (UTC)

Lifestyle

Lifestyle is the biggest factor in determining the state of the immune system. Yet it is not even mentioned. This is pathetic... 192.0.202.25 (talk) 05:32, 24 October 2023 (UTC)

Copyright problem removed

Prior content in this article duplicated one or more previously published sources. The material was copied from: https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/what-is-immunotherapy.html. Copied or closely paraphrased material has been rewritten or removed and must not be restored, unless it is duly released under a compatible license. (For more information, please see "using copyrighted works from others" if you are not the copyright holder of this material, or "donating copyrighted materials" if you are.)

For legal reasons, we cannot accept copyrighted text or images borrowed from other web sites or published material; such additions will be deleted. Contributors may use copyrighted publications as a source of information, and, if allowed under fair use, may copy sentences and phrases, provided they are included in quotation marks and referenced properly. The material may also be rewritten, provided it does not infringe on the copyright of the original or plagiarize from that source. Therefore, such paraphrased portions must provide their source. Please see our guideline on non-free text for how to properly implement limited quotations of copyrighted text. Wikipedia takes copyright violations very seriously, and persistent violators will be blocked from editing. While we appreciate contributions, we must require all contributors to understand and comply with these policies. Thank you. begocc ^questions? 12:50, 12 April 2024 (UTC)

very confusing structure of article- needs clean up

Came here via rediect of immune checkpoint inhibitors (ICIs), in order to update. Found it mentioned right at the beginning in the introduction, but then only buried under research ! Why on earth ? They are no longer research only. There are even numerous less important single sentence sections crammed in above. The initial outline does not fit with what follows. Also, "Combination immunotherapy" is nothing but immune checkpoint inhibitors combination, belongs there. Animal experiments, even if they are worth mentioning should be under the respective child- pages. Wuerzele (talk) 17:35, 21 April 2024 (UTC)

I agree that the organization of this article is a mess. One solution would be to move:

• 7.2 Anti-CD47 therapy
• 7.3 Anti-GD2 antibodies
• 7.4 Immune checkpoints

to:

• To 4.2 Mechanism of action

I never liked the term "antibody therapy". It is a modality that encompasses a lot of different mechanisms including checkpoint inhibitors. Some of these mechanisms could also be targeted by small molecules including immune checkpoints. None of these small molecules have as yet been approved for use, but several are in clinical trials. Boghog (talk) 19:49, 21 April 2024 (UTC)

Thanks for your reply, Boghog. Since you didnt ping me, I unfortunately didnt see it before I made my clean up edits. Which molecules do you refer to when you say "None of these small molecules have as yet been approved for use"? Certainly not immune checkpoint inhibitors, as they are approved and now widely prescribed for various malignant tumors, so much so that concerns about their use during pregnancy have emerged and been studied (maternal, fetal, or newborn complications).

I agree 7.2 Anti-CD47 therapy and 7.3 Anti-GD2 antibodies should be moved under Mechanism of action. I think that adoptive T-cell therapy should be moved out of research section as well: tisagenlecleucel and axicabtagene ciloleucel were FDA approved 7 yrs ago. Turns out most sources on this page are no longer up todate, from 2017/18.--Wuerzele (talk) 20:00, 21 April 2024 (UTC)

Thanks for reorganizing the article, Wuerzele. It looks much better. The approved checkpoint inhibitors are not small molecules. They are all antibodies. However there are several small molecule checkpoint inhibitors that are in development. I am just questioning the appropriateness of the term "antibody therapy" since small molecules can target the same mechanisms. Boghog (talk) 20:18, 21 April 2024 (UTC)