Written by Jennifer Li '26
Edited by Anusha Srinivasan '24
At the age of six, Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL), the most common form of blood cancer found in children. While ALL normally responds well to chemotherapy in pediatric patients, Emily proved to be an exception: after twenty-two months of intermittent chemotherapy, she continued to relapse, eventually exhausting all approved treatment options [7].
In a stroke of luck and perfect timing, the Children’s Hospital of Philadelphia was in the early stages for a clinical trial in Chimeric Antigen Receptor (CAR) T-Cell Therapy, and received approval to treat their first relapsing ALL pediatric patient.
Emily made a full recovery, emerging as the first pediatric patient to be cured of acute lymphoblastic leukemia through CAR T-cell therapy. Today, she celebrates ten years cancer-free, and is a strong advocate for cancer research and innovation [2].
Emily’s story brought CAR T-Cell Therapy to the forefront of research in immunotherapy. With over 60 years of history, research in T-Cell immunotherapy had been persistent yet slow-growing. Indeed, the Children’s Hospital of Philadelphia’s clinical trial came at a time when research in gene therapy was nearing failure: Emily’s survival gives insight to the incremental, cyclic nature of the scientific process, as well as the underlying dedication, patience, and chance leading to her survival.
Beginning in 1989, Israeli immunologists Zelig Eshhar and Gideon Gross developed the first engineered chimeric antigen receptor (CAR) T-cell. To create these specialized cells, the genetic material from two or more genes were combined to create a single protein with properties derived from each of the original molecules [3]. Hence the term “chimeric,” referring to the union of separate functional parts to create a new, hybrid protein.
The motivating factor was the potential for this engineered receptor protein to recognize and target cancer cells specific to an individual patient. In the case of CAR T-Cells, this specialized protein is expressed as a receptor on the cell surface which recognizes and binds to specific antigens[3]. These first-generation CARs faced early challenges: researchers found that they did not persist in the body, and were not yet clinically effective.
More headway was made in 1998, when Dr. Sadelain and colleagues found that introducing a co-stimulatory molecule increased the lifespan of these molecules, allowing them to remain active in the human body [3]. This led to the development of second generation CARs in 2002, which were demonstrated to be effective in recognizing and eliminating prostate cancer cells in the laboratory.
Figure 1: Treatment Using CAR-T Cell Therapy
With this, researchers established the feasibility of CAR T-Cell therapy. The Children’s Hospital of Philadelphia’s clinical trial was the first in a series of successes leading to the 2017 Food and Drug Administration (FDA) recognition of CAR T-Cell Therapy as a curative option for patients with advanced leukemias and lymphomas.
Today, the FDA has granted approvals to six CAR T-Cell therapies – all of which target blood cancers [1]. Regardless of which therapy is used, the treatment and manufacturing processes are the same. T-Cells are first harvested by passing a patient’s blood through a machine which separates the various components. The collected T-Cells are then incubated with a viral vector, a benign, modified virus which attaches to the immune cells and introduces the genetic material encoding the chimeric antigen receptor (CAR). As cells multiply, this introduced genetic material is maintained, and the chimeric antigen receptor is expressed on the cell surface. The cells are then frozen, shipped back to the hospital, and infused into the patient, where they will seek out and eliminate malignant cells [4].
Once inside the body, CAR T-Cells are there to stay. Any new cells created by means of CAR T-Cell division also contains the modified genetic material, and can remain circulating in the blood. Any new cancer cells expressing the target antigen would be promptly destroyed, rendering CAR T-Cell Therapy a potential “one-time curative therapy” [6].
Nevertheless, this targeted form of immunotherapy is still in the early stages of development: there is large room for improvement in the cancer subtypes eligible for treatment. Moving forward, researchers are working towards fine-tuning CAR T-Cell Therapy for treatment of leukemias and lymphomas, as well as applying the therapy to solid tumors [8].
In this respect, researchers are faced with a number of distinct challenges. The tumor microenvironment, for instance, is uniquely hostile to immune system activity [8]. This immunosuppressive property lessens the anticancer activity of immunotherapies such as CAR T-Cells introduced into the body. Moreover, malignant tissues are characterized by an increase in expression and density of the extracellular matrix (ECM) [8]. This rigid network of proteins and other molecules wraps tightly around cancer cells, hampering the ability for CAR T-Cells to reach their target. To counter these hurdles, scientists are engineering T-Cells to regulate the activity of ECM degrading enzymes, and have seen some improvement [5].
A decade after the Children’s Hospital of Philadelphia’s breakthrough case, using CAR T-Cell therapy as treatment for blood cancers is now seen as the “low-hanging fruit” T-Cell therapies [6] . As scientists move towards treatments of more complex malignancies, CAR T-Cell therapy remains at the forefront of research in immunotherapy.
References
1. Car T cells: Engineering immune cells to treat cancer [Internet]. National Cancer Institute. National Institutes of Health; [cited 2022Nov13]. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
2. The Children's Hospital of Philadelphia. Emily Whitehead, first pediatric patient to receive car T-cell therapy, celebrates cure 10 years later [Internet]. Children's Hospital of Philadelphia. The Children's Hospital of Philadelphia; 2022 [cited 2022Nov13]. Available from: https://www.chop.edu/news/emily-whitehead-first-pediatric-patient-receive-car-t-cell-therapy-celebrates-cure-10-years
3. Eshhar Z. From the Mouse Cage to human therapy: A personal perspective of the emergence of T-bodies/chimeric antigen receptor T cells [Internet]. Human gene therapy. U.S. National Library of Medicine; 2014 [cited 2022Nov13]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174423/
4. Facebook.com/bioinformantworldwide. History of CAR-T cell therapy spans 60+ years [Internet]. BioInformant. 2022 [cited 2022Nov13]. Available from: https://bioinformant.com/history-of-car-t-cell-therapy/#:~:text=In%201987%2C%20the%20first%20chimeric,to%20home%20in%20on%20tumors.
5. Marofi F, Achmad H, Bokov D, Abdelbasset WK, Alsadoon Z, Chupradit S, et al. Hurdles to breakthrough in car T cell therapy of solid tumors - stem cell research & therapy [Internet]. BioMed Central. BioMed Central; 2022 [cited 2022Nov13]. Available from: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-022-02819-x
6. Notman N. A decade of CAR-T cell therapy [Internet]. Chemistry World. Chemistry World; 2022 [cited 2022Nov13]. Available from: https://www.chemistryworld.com/features/a-decade-of-car-t-cell-therapy/4015337.article
7. Rosenbaum L, Author AffiliationsDr. Rosenbaum is a national correspondent for the Journal. Tragedy, perseverance, and chance - the story of Car-T therapy: Nejm [Internet]. New England Journal of Medicine. [cited 2022Nov13]. Available from: https://www.nejm.org/doi/full/10.1056/NEJMp1711886
8. Study of Penn Patients with Decade-Long Leukemia Remissions after CAR T Cell Therapy Reveals New Details About Persistence of Personalized “Living Drug” Cells [Internet]. Pennmedicine.org. [cited 2022Nov13]. Available from: https://www.pennmedicine.org/news/news-releases/2022/february/study-of-penn-patients-with-decade-long-leukemia-remissions-after-car-t-cell-therapy
9. T cell [Internet]. Encyclopædia Britannica. Encyclopædia Britannica, inc.; [cited 2022Nov13]. Available from: https://www.britannica.com/science/T-cell
Image: CAR T-Cell Therapy [Internet]. Baylor Scott & White Health. Baylor Scott & White Health; [cited 2022Nov13]. Available from: https://www.bswhealth.med/Pages/departments/hematology-oncology/leukemia-lymphoma-myeloma/car-t-cell-therapy.aspx
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