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Adoptive Cell Transfer and Chimeric Antigen Receptors
Chimeras love eating ponies and attacking cancer cells.
My Little Pony, Hasbro.
Throughout the past few decades, treatment options for cancer have continually changed and expanded. Though surgery, chemotherapy, and radiation therapy have been around since at least the 1940s, they all have very substantial limitations that have always forced researchers to continually strive towards new and better cancer therapies. For example, though chemotherapy could kill cancer cells through a cytotoxic treatment, it would also kill healthy cells and lead to a number of undesirable side effects. Targeted drugs, such as monoclonal antibodies directed at specific tumor antigens, made a big impact on how cancers were treated in that they could attack transformed cells while leaving the healthy cells alone. However, these were still limited in that the treatments were very specific to a particular tumor cell type, and thus could only treat certain cancers (and sometimes, only very rare cancers).

Cancer Research Institute.
The next generation of cancer treatment is immunotherapy. The major benefit of immunotherapy is that it is not tailored to a specific type of cancer, since it essentially uses the body's own immune system to combat cancer. We'll be discussing immune checkpoint blockade (and one of our new product lines, GoInVivo™) in another blog, however this post will focus on another type of immune therapy, called adoptive cell transfer, also known as ACT.

What’s in a name? – Apparently there’s a lot of information in the generic name of targeted therapies.
Vanderbilt-Ingram Cancer Center.
The first major driving force to treating cancers through ACT was the discovery in the mid 1960s that immune cells were responsible for tissue transplant rejection, or graft-versus-host disease (GVHD). Thinking that they could try to train the transplanted immune cells to attack cancer cells, scientists transferred lymphocytes into a rat with carcinogen-induced sarcoma. Indeed, the transferred lymphocytes were able to inhibit tumor growth. During this time, scientists were mainly limited to cells that could be taken from one animal and directly placed into another animal, but this changed over the next few decades, particularly after the discovery of IL-2 and its ability to help expand T cells in vitro prior to (and during) its injection into the host, amplifying the anti-tumor response from transfer.

Although some people would rather give to T.B.A., GVHD is a serious problem with transplants.
Arrested Development, Fox.
It was also discovered that chemotherapy and immunosuppression prior to ACT increased efficacy in these transfers, not only because of the two-pronged treatment of tumors, but also because of the elimination of old immune cells that were no longer effective at destroying tumor cells. Though all of these were incremental improvements, another treatment method of modifying these cells has been evolving and is just beginning to come to maturity.

In the 1980s, Dr. Zelig Eshhar and his lab thought of the idea of altering immune cells prior to adoptive transfer so that they could more specifically target tumor cells. To do this, they transfected a patient's own T cells with special T cell receptors that are engineered to be specific to a tumor antigen. These special T cell receptors were called chimeric antigen receptors, or CARs. CARs have a single-chain variable fragment (scFv), which is derived from the part of an antibody that is specific to an antigen. Attached to the scFv is a signaling peptide on one end, which directs the protein to the ER, and on the other end, a transmembrane domain and an endodomain, which transmits activation signals, most commonly through a CD3ζ component. Just like your smartphone, CARs have had steady improvements, leading to 2nd and 3rd generation CARs that help their T cells proliferate better or survive better after transfer by adding additional chimeric subunits, such as OX40 and CD28 into the endodomain.

Schematic of a CAR and modifications made over different generations of CARs. Wikipedia.
So far, many of the most promising results using CAR-transfected ACT have been observed in liquid tumors, where the cancer does not originate from a specific location, but instead a single cell type throughout the blood. One example is ALL, acute lymphoblastic leukemia, where CAR T cells engineered to target CD19, a major B cell maker, were able to wipeout cancer in 90% of the patients treated in that study1. Clinical trials have begun for treatment of other leukemias and lymphomas, and have recently even been used to treat solid tumors, such as prostate cancer and even pancreatic cancer.

Liquid tumors fear the Ultimate Chimera.
Super Smash Bros. Brawl, Nintendo.
Transferring large amounts of overactive immune cells does have some negative consequences. A subset of patients experience an adverse effect that has been termed the "cytokine storm", in which transferred cells release huge amounts of cytokines, sending the patient into shock and, in at least some cases, eventually leading to death2. Even with this huge caveat, companies like Juno Therapeutics and Novartis had no problem raising funds and getting the public on board with the therapeutic promise of these treatments. Even though work still has to be done, CAR therapy has come a long way and will continue to improve, harnessing the body's own immune system to fight off cancer. Let us know if you have any thoughts about CAR therapy by contacting us at tech@biolegend.com.
References:
  1. CAR T Cells in Leukemia Trial, New England Journal of Medicine
  2. Case Report of Serious Adverse Event Following T Cell Administration, Molecular Therapy
  3. CAR T-Cell Therapy, Cancer.gov

I’ve never seen the original, but I can only assume that it’s a fantastic movie.
Sony Pictures.
Contributed by Ed Chen, PhD.
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