It is 7 o’clock in the evening. 45-year-old Jane Doe is rushed to the ER with a fever, rapid heart rate, shallow rapid breathing, low blood pressure and nausea. She receives saline to improve blood pressure, but improvements are minimal. Laboratory tests return negative for infection and liver and kidney injury. Jane is treated with multiple vasopressors to raise blood pressure and an antagonist for human interleukin-6 (IL-6) receptor. She is diagnosed with severe Cytokine Release Syndrome (CRS). Jane was aware she might experience CRS, as it is a side-effect of an experimental “living drug” with which she is treated. Jane is a participant in a clinical trial that is testing the efficacy of chimeric antigen receptor (CAR)-T cells in treating patients with aggressive persistent non-Hodgkin’s Lymphoma, a type of blood cancer. This completely hypothetical patient scenario was inspired by a case-study presented by the American Society of Hematology and the ZUMA-1 clinical trial affiliated with Kite Pharma.
Jane has Diffuse Large B-Cell Lymphoma (DLBCL), a type of non-Hodgkin’s Lymphoma (a collective term for a range of blood cancers). She has undergone multiple rounds of radiation and chemotherapy to kill off the cancerous cells, but every time the cancer returned. For a patient like Jane, further treatment plans are limited. A clinical trial may be one of few remaining options for a potentially effective treatment. This hypothetical clinical trial uses CAR-T cell immunotherapy. CAR-T cells are T cells that have been modified and engineered to express a synthetic receptor that is specific for the patient’s cancer cells. The clinical trial that inspired this hypothetical scenario is the one run by Kite Pharma, which used a CAR-T cell treatment called axicabtagene ciloleucel (Yescarta™). The trial’s success led to the FDA-approval of Yescarta™ as a CAR-T immunotherapy drug.


What is CAR-T cell immunotherapy?

In short, it is a therapy that makes a person’s own immune cells become better at targeting their specific cancer cells, hence “immuno”-therapy. The personalized nature of this approach minimizes the number of foreign introductions into the patient’s body. This is important, because the body is very sensitive to foreign entities and can generate reactions to them, but the intensity of which can be life-threatening. What makes CAR-T cells in cancer therapy revolutionary, besides their personalization to each patient, is their viability. CAR-T cells will multiply and reside for lengthy periods in the patient’s system, acting like a long-term, continuous anticancer surveillance system.

CAR-T cell immunotherapy has been most successful against blood cancers. Scientists have also been attempting to use CAR-T cells as an immunotherapy against solid tumours, but these cancers are proving more difficult to treat. One reason is that solid tumour cells perform “immune evasion” more frequently than soluble forms; they more frequently change their cell surface proteins, the targets of CAR-T cells, making them more difficult to recognize and treat. Also, the microenvironment in which solid tumours grow can be immunosuppressive; the cells, proteins and molecules present near the tumours “fight off” immune response, hindering the access and function of cells like CAR-T cells. Nonetheless, research is ongoing to develop successful CAR-T immunotherapy for solid tumours.


How are CAR-T cells made, and how do they function?

To begin their production, T cells are isolated from the patient’s blood. Then, genes containing the CAR construct are inserted into the T cells via viral (introduction of a gene using a virus that is incapable of dividing) or non-viral (genetic recombination techniques) methods. The engineered cells are grown in a nourishing media that promotes their expansion in number, before being prepared for injection and re-administered into the patient.

CAR is a synthetic cell receptor made up of two domains: a recognition domain and a response domain. The recognition domain is highly synthetic: while normally, the recognition domain of a native T-cell receptor (TCR) recognizes MHC (a native cell receptor) complexed with a short, linear protein strand, the CAR recognition domain resembles the that of an antibody that can directly bind a single cancer antigen in the absence of MHC. Interestingly, the CAR response domain resembles that of a TCR and leads to cytotoxicity. Hence, CAR-T cells partially mimic B cells by using their antibody-like receptors to locate cancer cells that may have decreased the number of MHC receptors on their cell surface to evade the native T-cell recognition system, but also resemble cytotoxic T cells by directly killing cancer cells upon recognition.


What are the risks associated with CAR-T immunotherapy?

Jane Doe was admitted into the ER with severe CRS, a high-risk side effect of CAR-T immunotherapy. CRS is a widespread inflammatory response caused by the high levels of cytokines released during CAR-T immunotherapy. CRS varies in severity, with severity dictating the appropriate treatment. The treatment of Jane’s severe CRS involved an IL-6 receptor antagonist to prevent the action of IL-6, a cytokine that promotes inflammatory symptoms.

Another high-risk side effect of CAR-T immunotherapy is neurotoxicity. For instance, IL-6 can cross the blood-brain-barrier, and once in the brain, IL-6 can alter the inflammatory status of the brain tissue, leading to damage. Neurotoxicity is also variable in severity, and that dictates the appropriate treatments.


What is the history of CAR-T immunotherapy?

It was not until 1986 that the potential of a patient’s own T-cells for cancer therapy was unveiled, through the work of Steven Rosenberg and colleagues. Ever since, it was a speedy journey to CAR-T cell therapy, accomplishing so much in only a few decades. First generation CAR-T were developed as early as 1993. These cells are characterized by only having the CAR domain. First generation CAR-T cells did not live long and needed supplementation with cytokines, inflammatory signaling proteins, to efficiently kill tumor cells. Therefore, in the second generation of CAR-T cells, a co-stimulatory domain was added to help produce enough cytokines to sustain themselves and improve longevity; after seeing its increased survival, multiple co-stimulatory domains were included in the third generation. Finally, fourth generation CAR-T cells were made to release soluble proteins that can activate other immune cells and components to help target the tumor, decreasing the ability of tumour cells to escape immune response. Scientists are now trying to engineer CAR-T cells that have molecular “ON and OFF” switches, so practitioners can better control CAR-T cell action within the patients.

The challenges of CAR-T immunotherapy are not solely health-related; its highly personalized nature comes with limitations in its production and commercialization. The manufacture of CAR-T cells is a highly complex process, involving many procedures that must be executed by trained professionals. The required equipment, professionals and hospital care render it a costly therapy, with its prices often exceeding $400,000 per patient. Significant financial investment is required in health institutions involved in CAR-T cell therapy and clinical trials. However, increasing interest in CAR-T cell immunotherapy renders moderate investments insufficient to neutralize the financial burden. Unless an effective financial plan is constructed, the financial burden CAR-T cell therapy poses may drive health systems to reconsider the worth of this immunotherapy in the context of consequent monetary deficits.

CAR-T cell cancer therapy is a beautiful example of the power of scientific knowledge. Years of effort and dedication have allowed the scientific field to construct a sophisticated, complex, and revolutionary cancer therapy that takes every patient uniquely into consideration. It is true that CAR-T cell immunotherapy requires further developments, particularly in its prospective commercialization, to make it a more accessible and standard treatment. Nonetheless, the growing interest in this state-of-the-art cancer immunotherapy will guide healthcare and scientific systems to familiarize themselves with its side-effects and properties for enhanced clinical outcome and expanded clinical use.


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Kawther Nemrish

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