In this time of war and problems domestically, we should highlight one ray of hope in the cancer arena, a new therapeutic approach with broad-based potential and already bearing fruit. I am grateful to my good friend Jonathan Harrison who reviewed this article for me to ensure its accuracy, so any errors are Jon’s (just kidding!).
Recently, Grand Rounds in Medicine at Columbia was by Michel Saidelin of Memorial Sloan-Kettering Cancer Center on CAR-T cell therapy. I heard about this therapy for years but never understood it. Here was a lecture by one of the world’s foremost experts for non-oncologists, so I hoped it would be simple enough so I could grasp the fundamentals. After the speaker said, “Thank you for that kind introduction,“ I did not understand more than 10% of what he said. But let me say that it is the newest and perhaps most promising form of immunological therapy.
Chimeric antigen receptor T-cells are T lymphocytes that have been genetically modified to express a receptor on the surface of the T-cell that forces the cell to bind to and kill a target cell. They combine the antigen recognition function and the T-cell activation function onto the same protein. Basically, these CARs can direct T-cells against any target—different types of cancer, lupus, rheumatoid arthritis, etc. In the fight against cancer, T-cells are harvested from cancer patients and the CARs are used to genetically target them against the cancer cells. They are programmed to target a specific antigen on the cancer cell’s surface so that the CAR-T cells will attack only the cancer cells and not healthy cells.
In other immunotherapies, we have used monoclonal antibodies produced by B-cells against antigens on tumor cells in a similar fashion. However, antibodies are proteins that have a short life expectancy and so must be repeatedly re-infused. In contrast, CAR-T cells, after being sensitized against an antigen, are infused into patients and act as a “living drug” attacking the tumor cells. This activation causes them to proliferate and become cytotoxic.
The first CAR-T cells were produced in 1987 in Japan by Yoshihisa Kuwana at Fujita University, and almost simultaneously at Weizmann Institute in Israel by Zelig Eshhar. Eshhar was born in 1941, earned his undergraduate and master’s degrees in biochemistry from Hebrew University, and his PhD in immunology from the Weizmann Institute where he joined the faculty. The first clinical application of these entities was in treatment of various leukemias and non-Hodgkin lymphoma. The first adult patient to receive CAR-T cell therapy was William Ludwig at the University of Pennsylvania in 2010 for refractory chronic lymphocytic leukemia under Dr. Carl June. He remained in complete remission for over 10 years until dying from COVID in 2021.
The first treatment approved by the FDA was in 2017 against the antigen CD19 found on B-cells; this led to the treatment of B-cell derived cancers, such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Other leukemia/lymphoma antigens have also been targeted, as well as the BCMA antigen in multiple myeloma. The result has been effective treatments for various leukemias/lymphomas, and multiple myeloma. As of April 2023, six CAR-T cell therapies have been FDA-approved. In contrast, it has been difficult to identify suitable antigens on solid tumors; this is currently an active area of research.
Several problems remain under vigorous investigation. One is the duration of efficacy for this treatment. While the initial response rate to CAR-T cell therapy is extremely high, and there is no need for ongoing treatment as is the case for most chemotherapeutic modalities, the duration of treatment may be a problem. It may last for multiple months or even years, but the beneficial effect may then peter out or the CAR-T cells may suffer from exhaustion. How to prolong the effect is under investigation.
The treatment may also engender several types of toxicity. These include cytokine release syndrome, which occurs in 15-20% of patients. It causes severe symptoms, such as fever, fatigue, myalgias, and cardiac dysfunction; it is usually ameliorated by corticosteroids. Increased experience with its management has mostly eliminated any significant degree of mortality. There is also a form of neurotoxicity that occurs in conjunction with CAR-T cell therapy, which resembles cerebral edema. It is manifest by lethargy/malaise and speech difficulty. It appears that the severity of the toxicities is proportional or correlates with the pre-treatment tumor burden, so a higher tumor burden results in worse adverse effects. Thus, it may be advantageous to utilize CAR-T cell therapy with reduced or smaller tumor burdens either by initiating treatment earlier in the disease course, or by debulking the tumor prior to infusion.
Progress is being made daily on almost every aspect of this therapy, including the diseases against which it will be targeted, the efficacy of treatment, its duration, and reduction in the toxicity profile. Application of this modality to solid tumors has been particularly challenging. The lack of success reflects the absence of tumor-specific antigen targets and tumor microenvironments which are immunosuppressive. Also important is the methodology for production of the CAR-T cells, which contributes to the high cost. A treatment can cost upwards of half a million dollars just for the CAR-T cell manufacturing and not including hospital stays and medical care.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
