CAR T cell therapy is being extensively used in Oncology. During this process, cells from an individual are modified outside the individual to create modified cells. Those modified cells could also be "antibodies to self antigens". Once such a group of cells are created and when transfused back onto the individual could have DISASTROUS consequences.
It could either be that an entire organ may be attacked by the autoimmune process.
Kindly add your comments.
Thanks
Hello Aradhana Rani
You may refer to the article attached below. This review describes the toxicities caused by CAR T-cells and reviews the published approaches used to manage toxicities.
Article Toxicities of chimeric antigen receptor T cells: Recognition...
Toxicities caused by CAR T-cells are diverse and not fully understood. Management requires vigilant monitoring, aggressive supportive treatments, and, in some cases, intensive care. Administering immunosuppressive agents to decrease toxicity is an evolving practice. Overall improvement in the field of CAR T-cell therapies could be achieved by improving the management of CAR T-cell toxicity.
Best.
Hi Malcolm Nobre , Thank you for highlighting, this already published work by Brudno et al.
When we know that a therapy is toxic, why would we not eliminate the source of the toxicity (in this case CAR T cell therapy). Managing the toxic effects of CAR T cells, will only toxify the protected human micro and macro-environment even more.
It must be about "a stitch in time saves nine", which means if you sort out a problem immediately it may save a lot of extra work later (reference for the connotation of "a stitch in time saves nine" was taken from https://languages.oup.com/google-dictionary-en/). The other option is ONLY that, naive researchers continue with CAR T cell therapy, only to know in the end that ALL THEIR WORK WAS WORTHLESS.
Thanking you and with kind regards
Aradhana
Dear Aradhana Rani
I would like to draw your attention to the article attached below.
Article A brief history of CAR-T cells: from laboratory to the bedside
First engineered T-cell with chimeric molecule was developed in 1989– 1993 by Israeli immunologists Zelig Eshhar and Gideon Gross. These first-generation CARs were not yet clinically effective.
Then, over the next thirty years, CARs were immunologically and technologically modernized and sophisticated as first, second, third, and currently fourth generation, depending on their composition. The second-generation CARs had improved antitumor activity of T cells: improved T-cell proliferation, resistance to apoptosis, cytokine secretion, and in vivo persistence. The third-generation CARs, in comparison with second-generation CARs, had improved effector functions and in vivo persistence. Fourth-generation CARs, the so-called TRUCKs (CAR redirected T cells that deliver a transgenic product to the targeted tumor tissue) or armored CARs, present further enhancement in antitumoral potency, cytokine activity, and costimulatory ligands and enzymes that can degrade the extracellular matrix in solid tumors.
Why would we not eliminate the source of the toxicity (in this case CAR T cell therapy)?
Further enhancement in the safety of CAR-T cell therapy can be obtained with the so-called smart T cells, which is under investigation. Finally, new engineering modalities, based on the use of targeted nucleases like clustered regularly interspaced short palindromic repeats (CRISPR), may further enhance the efficacy and safety of CAR-T cells.
Naive researchers continue with CAR T cell therapy, only to know in the end that ALL THEIR WORK WAS WORTHLESS.
Sorry! I disagree with you on this point. AFTER YEARS OF PAINSTAKING RESEARCH, CAR T-cell therapies have entered the mainstream of cancer treatment.
Like all cancer treatments, CAR T-cell therapies can cause severe side effects. One of the most frequent and serious side effects is cytokine release syndrome (CRS). Ironically, CRS is considered an "on-target" effect of CAR T-cell therapy, that is, its presence demonstrates that T cells are at work in the body. Generally, patients with the most extensive amount of cancer in their bodies are more likely to experience severe CRS from CAR T cells.
In many patients, mild forms of CRS can be managed with standard supportive therapies, including steroids. And as researchers have gained more experience with CAR T-cell therapy, they've discovered ways to better manage the more serious cases of CRS.
Researchers have also begun to rethink the source of immune cells for CAR T-cell therapies by using T cells collected not from patients, but from healthy donors.
For the off-the-shelf CAR T cells now being tested in small clinical trials, gene-editing technologies like TALON and CRISPR are being used to induce the donated T cells to produce CARs.
Other off-the-shelf CARs also use a different type of immune cell, called natural killer (NK) cells. Much of this research is still in its early days, but some CAR NK cell therapies are already being tested in small clinical trials.
Several research groups are using nanotechnology and mRNA-based approaches that allow CAR T cells to be created inside the body.
Thank you for the phrase "a stitch in time saves nine". It sounds good, but does not apply to scientific research, especially when scientists work hard to find new treatments for dreaded diseases. We (scientific community) need to move one step at a time. As I already mentioned, new engineering modalities, based on the use of targeted nucleases like CRISPR, may further enhance the efficacy and safety of CAR-T cells.
Regards,
Malcolm Nobre
Dear Aradhana Rani!
The issue you raised is relevant and very serious. Developers of chimeric antigens for T-cell technology do not hide the dangers of using these cells, which often cause a lethal cytokine storm. Nevertheless, there are positive results. But there are less dangerous and more effective options for using the body's own cells to kill cancer. In addition to T-cells, our unique body has other effective immunocompetent cells. You can get acquainted with anti-cancer cellular processes on my page - see articles and projects.
Best regards,
professor Andrei Ostanin
Hi Malcolm Nobre,
Thank you. Since you sent me a review worth reading, it would be so good to see you write a review on "Adenoviruses" and how their misuse could lead to mutations in the long run.
With regards to CAR T cells, Sir Andrei Ostanin , I like to differ. I do not believe in "first creating a dinosaur and then trying to control the dinosaur".
Kind regards
Aradhana
Dear Aradhana Rani!
YOU misunderstood me. I don't support "dinosaur". I do not want to offend other scientists and their developments. But I am amazed at the scientific community, which is confidently going to a dead end. T cells cannot penetrate deep into the tumor. Therefore, colleagues come up with various chimerical nonsense. This is very similar to the joke about the fly that beats herself to the glass when there is an open window nearby. Asking why? The fly replies that any can fly through an open window, but she is special . The human body is a unique creation that has a lot of alternative options for solving any problem. If we talk about cancer, then there are very effective blood granulocytes - eosinophils, which successfully cope with the destruction of cancer cells. They are simply not enough to solve the problem. We have learned to raise their level to the required level in a controlled in vivo mode. Doctors are afraid of this word - eosinophil. A lot of diagnoses are associated with this word. He was undeservedly turned into an enemy. There is nothing superfluous in our body. Managing these cells is certainly not easy. But the result is worth it. We have learned how to destroy all cancer cells in stage IV patients with a complete lesion of the lymphatic system. If a person's immunity is set up correctly, then you can live with this diagnosis for a very long time and happily without suffering.
The cause of cancer is immunodeficiency.
Best regards,
professor Andrei Ostanin
The key question of oncoimmunology, as always, is the tumor antigen that we choose as the target of the immune response. It can be an autoantigen (tumor-associated antigen) or a neoantigen (tumor-specific antigen) expressed as a result of a mutation. CAR therapy as it is - yes, it can be dangerous because it targets tumor-associated antigens, which are self-antigens. The risk may be minimal, for example, if tumor-associated antigen is normally expressed only in placental cells and CAR therapy is used to treat a postmenopausal woman. I think that the risks will be minimized if TCRs specific to neoantigen peptides are used for CAR therapy. In this case, we will get a variant of passive immunotherapy, which will be performed by T-lymphocytes.
Hi Dmitry B. Kazansky ,
Thank you for adding onto the discussion. However, we are deviating from the facts about CAR T cell therapy. CAR T cell therapy relies on EDUCATING our "supposedly" T lymphocytes only to target the cancerous cells. However, it is during this process of EDUCATING OUR immune cells "by force" to behave in a certain way, that leads to "ERRONEOUS transcription" events. These newly educated "T lymphocytes" when sent back into the same individual, CANNOT be recognised as "SELF" any longer. The CAR T cell therapy is thus essentially, more like an "NEW ORGAN TRANSPLANTED" into the same individual. The individual undergoing CAR T cell therapy will have multiple organ failures (to various extents), because the ORGAN being transplanted is a "NEW T lymphocyte" and lymphocytes travel into all organs of the body.
Kind regards
Aradhana
Dear Aradhana, by this way any T lymphocyte can be recognized as non self and "new organ transplanted" because it expresses unic TCR protein sequences. Moreover, new T lymphocytes are regularly formed during intrathymic development. During immune response respective clones of lymphocytes undergo multiplication and travel into all organs of the body. However, this does not result in multiple organ failures.
Dear Dmitry B. Kazansky ,
Thank you. I am amazed at your reply. You do understand about the repertoire of antigens that could be presented by lymphocytes, due to infections. However, the difference between the repertoire being expressed in vivo and in vitro, when challenged by an infection, are very different. In an in-vitro scenario, will T lymphocytes live on, and express unic TCR protein sequences???
During CAR T cell therapy, an individuals lymphocyte is taken out from his OWN BODY and the EDUCATION of lymphocytes are done OUTSIDE of that individuals body.
Thus, CAR T cell therapy is a MODE to KILL an individual.
Kind regards
Aradhana
"In an in-vitro scenario, will T lymphocytes live on, and express unic TCR protein sequences???" - Yes.
"During CAR T cell therapy, an individuals lymphocyte is taken out from his OWN BODY and the EDUCATION of lymphocytes are done OUTSIDE of that individuals body." - Does not matter. It seems, you need to read carefully, what is "education" of T lymphocytes for CAR-therapy and technics used.
"Thus, CAR T cell therapy is a MODE to KILL an individual" - :-)
Hi Dmitry B. Kazansky ,
You answered yes to this question: "In an in-vitro scenario, will T lymphocytes live on, and express unic TCR protein sequences???" - Yes.
Please explain how? and and under which circumstances? In my experience, in the "in-vitro scenario" any invasion ( example: culture under unsterile conditions), finally leads to the death of all the cells in the culture.
I thought, I had to tell you "does not matter", since you just do not understand, why the CAR T cell therapy is a wrong idea propagated by novices in human immunology.
Thanks and kind regards
Aradhana
Dear Aradhana, "any invasion (example: culture under unsterile conditions)" cannot be a subject of discussion in a professional environment. First you need to learn how to work sterile.
Dear Sir Dmitry B. Kazansky , This article is a really good one.
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016 Jun 30;127(26):3321-30. doi: 10.1182/blood-2016-04-703751. Epub 2016 May 20. PMID: 27207799; PMCID: PMC4929924.