On the face of it, the phrase “chimeric antigen receptors” (CARs for short) might not sound particularly exciting. But as Clive Gray, Professor of Immunology in the Division of Molecular Biology and Human Genetics at Stellenbosch University tells Spotlight, there is a lot more to this new class of immunotherapies than immediately meets the eye.

For one thing, the name is derived from a fantastical hybrid monster in Greek mythology called the Chimaera — often depicted as having two heads, one of a goat and one of a lion. In The Iliad Homer describes the being as “A mingled monster of no mortal kind, Behind, a dragon’s fiery tail was spread, A goat’s rough body bore a lion’s head, Her pitchy nostrils flaky flames expire, Her gaping throat emits infernal fire.”

As Gray explains, the word chimaeric or chimeric comes from the word Chimaera.

Photograph of the Chimera of Arezzo, Etruscan bronze statue. (Photo: Sailko/distributed under the GNU Free Documentation License version 1.2./Spotlight)

The connection lies in the fact that, as with the mythical beast, CARs are assembled from parts one wouldn’t normally expect to see together. Rather than a goat’s body with a lion’s head, however, CARs are made up of at least two distantly related genetic “arms” that code for recognising parts of the body’s immune system that would never be found together naturally. These CARs are then used therapeutically to treat disease.  

As Gray points out, “a chimeric antigen receptor is completely artificial and is made in very specialised laboratories.” 

He explains that so far there are at least 80 to 90 different CARs that recognise targets in the body and that are being used to treat people with different cancers. “They are proven to be really, really useful immunotherapeutic tools,” he says. 

While new CARs are being developed all the time to try to treat different diseases, the field where it has shown the most success is in cancer, according to Gray. As a cancer treatment, he describes CARs as a razor-sharp treatment, because they specifically target cancer cells and eliminate them. Chemotherapeutic drugs, on the other hand, although effective, are a much blunter treatment because many other cells in the body are killed besides the cancer cells. 

How it works

The “A” in CARs stands for antigen. Antigens can be thought of as any substance that the immune system mounts a response against. In more technical language, Gray explains that an antigen is a very small part of a protein derived from a pathogen or a tumour and is presented by a unique set of inherited molecules that are inherited equally from both parents and are able to be directors of the immune system’s T-cells. As we will see, the T-cell bit is important. 

Dr Katherine Antel, a clinical haematologist from South Africa currently conducting research at the Dana-Farber Cancer Institute at Harvard University in the United States, tells Spotlight that CAR therapy involves taking an antigen receptor specific to a diseased cell, like a cancer cell, and putting that receptor into an immune system cell. 

These modified cells are then used to “train” the person’s immune system, according to Antel, to go and find the antigen and kill the cell that is expressing that specific antigen, in this case, a cancer cell expressing an antigen unique to the cancer. 

“The chimeric antigen receptor would fit perfectly onto the antigen that’s on the cancer itself and would go and bind to that [cell]. And then there would be a number of downstream signals that would enable the cell that’s now bound to that antigen to kill that cell,” she says. 

She adds that while T-cells are the most common cells used for CAR therapy, known as CAR T-cells, other immune system cells known as NK cells can also be used. 

Potential as HIV treatment

While it is unclear whether CARs will ever be a safe and effective treatment for HIV, some in the HIV world think there is potential. During a session at this year’s Conference on Retroviruses and Opportunistic Infection (CROI) Dr James Hoxie, a Professor of Medicine in the Haematology-Oncology Division at the University of Pennsylvania, classified CARs as an exciting scientific advance with a potentially high impact for HIV and other fields.

“I can think of few areas that are as breath-taking as this one, specifically because it has led to cures of acute leukaemia, chronic lymphocytic leukaemia, and non-Hodgkin’s lymphoma,” Hoxie says.  

Achieving the same kind of success in treating HIV with CARs will however not be easy. That is because HIV presents an additional complexity.

“What we’re doing with the CAR T-cells is allowing the therapy or the CAR intervention to cause proliferation of HIV specific T-cells which allows these HIV specific T-cells to recognise the HIV infected targets,” Gray explains. “The downside of this approach is that you’re also going to cause a proliferation of CD4 cells, which are targets for HIV. So, you then have to render the CD4 cell resistant to HIV, so it becomes really complicated.”

Jim Riley, a professor of microbiology at the University of Pennsylvania, presented preliminary data at CROI about an ongoing clinical trial using CAR T-cells to target HIV cells. An excellent  write-up on HIV i-Base summarised the study as using CAR T-cells designed to target HIV infected cells “in combination with CD4 T cells that have been genetically modified to block expression of the CCR5 receptor.” Blocking the CCR5 receptor on a CD4 T cell prevents HIV from entering the cell.

Riley shared data from eight participants, where half started ATI (analytical treatment interruption) the day after the infusions and the other half received ATI eight weeks after the infusion. Everyone in the first group experienced viral rebound and had to restart ART before the end of the 16 week-ATI. While people in the second group were able to complete the 16-week ATI, as viral loads did increase but then decreased again. 

According to HIV i-Base, Riley’s research group has another CAR T-cell design they’re planning to trial, an enhanced CAR T-cell that “includes the co-stimulatory molecules 4-1BB and CD28 and, in animal models, showed increased proliferative potential and activity”.

The research being done by Riley and others is still very much at an early experimental stage. The ClinicalTrials.gov database currently lists only six clinical trials containing the search terms HIV and CARs, although one of these studies are looking at HIV-Associated Aggressive B-Cell Non-Hodgkin Lymphoma.

For now, antiretroviral therapy remains the only proven way to suppress HIV and to help people living with HIV to stay healthy.

Next frontiers in cancer

While CARs have already shown very impressive results in the treatment of cancer, there is a lot more research to be done and still a lot more potential.

Antel says that at the moment the indications for where CAR T-cell therapy can be used are for certain types of blood cancer. 

According to the National Cancer Institute’s website, the FDA has approved six CAR T-cell therapies to date, for use in treating acute lymphoblastic leukaemia (ALL), B-cell non-Hodgkin lymphoma, B-cell lymphoma, follicular lymphoma (FL), Mantle cell lymphoma and multiple myeloma. 

“There’s a lot of research at the moment using them for solid tumours, but there are a number of limitations. One of the main problems is that it’s quite difficult to get these cells back into a solid tumour space. But…with the cancer cells circulating in the blood or in the bone marrow it’s much easier for the T-cells to get [to it],” Antel explains. 

How are CARs manufactured?

Antel explains that CAR T-cells to treat cancer are currently manufactured using the patient’s own T-cells in order to prevent graph versus host disease. She uses the example of the CD19 CAR T-cells, used to treat leukaemia and lymphoma (one example is diffuse large B cell lymphoma).

She says that the patient’s T-cells are extracted using a plasmapheresis, similar to the process of donating platelets. The T-cells are then genetically engineered in a lab using a lentiviral backbone, which allows the cells to be engineered to express a receptor that, in this case, binds to the CD-19 antigen. This same receptor signals to the body’s T-cells to kill the abnormal cells. 

The genetically modified T-cell then has the CAR on its surface, according to Antel. 

These cells are then multiplied and are infused back into the patient after they’ve had chemotherapy to deplete the remaining T-cells in their body. This is normally done as an inpatient procedure, with the patient in hospital for two to four weeks. The whole process can take around six weeks. 

But this process can cause a cytokine storm in the patient’s body, where the T-cells release interleukins and other pro-inflammatory proteins, which can cause a number of side effects, says Antel, including neurotoxicity. But this problem can be combated by monitoring the patient and giving them drugs to suppress the inflammation. 

She adds that the amount of time the CAR T-cells stay active in a patient’s body after infusion is variable and depends on the antigen. 

“Unfortunately, in myeloma, we tend to see that these T-cells disappear around a year or up to two years [after infusion], which is a problem because that’s frequently then when patients relapse,” she says. 

“[For] the CD19 CARs that are used for leukaemia and lymphoma the T-cells last longer and that’s probably because they’re exposed to the antigen more frequently,” she explains. 

Antel is hoping to come back to South Africa and carry on with her research on using NK cells to produce antibodies to fight myeloma; and work with clinicians and researchers to find ways to make CAR-T therapy accessible to patients in South Africa. 

“I hope that despite the high costs we can find a way to creatively do this [in South Africa], to offer this to patients. We have excellent clinicians who are ready to treat patients with CAR-T cells but need to find ways to manufacture them and bring down costs radically to make it accessible,” she says. DM/MC

This article was published by Spotlight — health journalism in the public interest