By FILIP CVETKO in Science — May 29, 2022

CAR-T: Using biotechnology to reengineer our immune systems

Autologous chimeric antigen receptor T-cell therapy or CAR-T cell therapy in short is a type of cancer treatment in which we try to extract the T cells from a person's blood, and reengineer them by adding a novel gene that codes for a chimeric antigen receptor to match the tumor antigen. After that, we wish to multiply the cells and finally inject them back into the same person, hopefully eradicating the neoplasm with this newly forged army of hungry T-cells.

This technology, however, is far from new. It was hatched way back in 1987 when the first CAR-T cell was created. It was a start, but far from great. The researchers failed to replicate the cells in significant quantities so they could be used in clinical applications. In the late 1990s, however, methods were developed to successfully replicate the cells and in 2011 the first promising results showed complete remission in patients with chronic lymphocytic leukemia (CLL). The same was discovered nearly simultaneously in patients with acute lymphoblastic leukemia (ALL), where nearly 90 % of patients showed a complete and rapid response.

The most notable year for CAR-T was 2017 when tisagenlecleucel (Kymriah) was approved by U.S. FDA for the treatment of children and young adults with acute lymphoblastic leukemia (ALL). Roughly thereafter axicabtagene ciloleucel (Yescarta) was approved for treating patients with relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) and other rare large B-cell lymphomas. European Medicines Agency (EMA) also approved both of these novel treatments in mid-2018.

But how does it really work?

CAR-T cell with labeled parts of the chimeric antigen receptor (CAR).

Chimeric antigen receptors are composed of scFV, which in the current industry applications recognizes only CD19 protein on the surface of all B-cell neoplasms, but in theory could be modified for any other surface antigen. Because CD19 is an integral part of the normal human B-cells, no immune response will be mounted towards this protein without additional help. This is why we engineer a CAR protein, which mounts a response against this protein because we want to destroy the cells expressing this protein, which in the case of neoplasms is mostly cancer cells. However, many healthy cells will be eradicated alongside as well, but this is the risk we are sometimes willing to make, depending on the expected benefit and side effects of individual treatment.

And how does the patient experience this?

Usually, the first step is to determine whether the patient is a candidate for such treatment and if no objections are found T-cells are harvested from a patient's blood, and re-engineered with an additional DNA sequence from an adenovirus, enabling the transcription of a CAR protein. Then, the T-cells are rapidly replicated a hundredfold. This, otherwise complex procedure, takes only from a few days to a couple of weeks. Meanwhile, the patient undergoes preconditioning chemotherapy and is only after infused back with the modified CAR T-cells.

On the practical side...

Which patients are eligibile for CAR-T therapy?

They should have adequate organ function and performance status to tolerate the therapy.
Currently, CAR-T has been studied only in patients with advanced relapsed or refractory malignancy. Efficacy as a first line treatment has not yet been studied.
Have tumors that are positive for the CAR target (i.e. CD19).
Have an adequate number of T cells for collection.
Do not have an active infection (Hepatitis B, Hepatitis C, HIV ...)
Do not have certain relevant comorbidities (cardiovascular, neurologic, or immune disorders)

CAR-T vs allo-HSCT (stem cell transplant)

If a patient achieves complete remission with conventional treatment for acute lymphoblastic leukemia (ALL), the standard treatment is to proceed with allogeneic HSCT, however, this is not always necessary if the patient has also undergone CAR-T treatment. In other words, CAR-T therapies can in some cases reduce the need for stem cell transplants, especially in Non-Hodgkin's lymphoma.

What are some side effects of CAR-T treatment?

Cytokine release syndrome (CRS) is a systemic inflammatory response due to high circulating levels of cytokines, released from activated CAR-T cells. Patients usually report flu-like symptoms, high fever, and tachycardia in the first 1 to 3 weeks after cell infusion and can even progress to organ failure, a need for ventilatory support, and supportive care in the ICU. Severe CRS is usually treated by the use of anti-IL-6 (tocilizumab) and corticosteroids.
Neurotoxicity has often been observed in clinical trials, but the mechanism is not yet known. Corticosteroids and anti-epileptic medication may help in mitigating the symptoms.
B-cell aplasia can occur due to damage to the normal, healthy B-cells. Patients can be treated with immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis.