Yesterday’s U.S. Food and Drug Administration’s (FDA) approval of the immunotherapy drug, CTL019 (tisagenlecleucel-T | Kymriah®; Novartis), for treatment of childhood Acute Lymphoblastic Leukemia (ALL), was a milestone in medicine, good news for patients, and a promising precursor for those involved in developing novel anticancer drugs.
Although the approved use of the chimeric antigen receptor or CAR-T,–for advanced leukemia in children and young adults up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse—is relatively narrow in scope, it opens the door for a new era in cancer therapeutics.
FDA Commissioner Scott Gottlieb, MD, summed this up when he said that “[With this approval], we’re entering a new frontier in medical innovation … with the ability to reprogram a patient’s own cells to attack a deadly cancer,… [holding out] the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”
This therapy is not only the first approval for the use of genetically modified autologous T-cell immunotherapy as a treatment for cancer, it’s also an important validation of technical advances under way in the field of cellular immunotherapy. Furthermore, this approval validates the importance of similar lifesaving cellular immunotherapies currently being developed and tested in pre-clinical and clinical trials.
ALL is a cancer of the bone marrow and blood in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer. In the U.S. the incidence of new cases of pediatric ALL is approximately 3,100 in children and adolescents per year. Approximately 25% of these pediatric patients are younger than 15 years of age.
While the number of new cases may seem relatively low, the disease represents a major unmet medical need for children and young adults with this serious disease. 
Although Acute Lymphoblastic Leukemia can be of either T or B cell origin, approximately 80%-85% of all cases are of B-cell origin. Current treatment for de novo or relapsed B-cell in pediatric ALL and young adult ALL, includes combinations of chemotherapy, radiation therapy, and hematopoietic stem cell transplantation or HSCT, and is risk-based. 
Mode of Action
CAR-T cell therapy works differently than other currently available small molecular or biologic therapies. One of its unique features is that each dose of the therapy is manufactured for each individual patient, using the patient’s own T-cells, a type of white blood cell known as lymphocytes.
During the treatment process, T-cells are drawn from a patient’s blood and “reprogrammed” in the laboratory to create T-cells that are genetically modified or coded with a new gene that contains a specific protein (a chimeric antigen receptor or CAR) to “hunt” the patient’s cancer cells and other B-cells expressing a particular antigen called CD19 on the surface.
After being reprogrammed, the T-cells (now called CTL019) are re-introduced–infused back into the patient–where they proliferate and bind to the targeted CD19+ cancer cells and kill the targeted tumor cells.
The results are truly remarkable. A multicenter trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL demonstrated the safety and efficacy of CTL019. The treatment resulted in an overall remission (OR) of 83% within 3 months (95% confidence interval [CI]: 68.6, 91.4; p<0.0001). [a]
It’s a start
As the executive editor of Onco’Zine, The Onco’Zine Brief and ADC Review | Journal of Antibody-drug Conjugates, I’m convinced that the approval received earlier this week is just the first step of what will soon be many new immunotherapy-based treatments for a variety of cancers.
While regulatory approvals are indeed important, they’re just the beginning. More work—from early, pre-clinical, clinical and beyond–is still ahead of us.
The safety, availability, and affordability of these new immunotherapies can be–and should be–improved. But to achieve these goals we need an increase in partnerships with industry, more corporate investments, and sustained and increased government funding. And the cost factor also has to addressed: Novartis has priced the therapy at U.S. $475,000, making it one of the most expensive cancer treatments in the world. However, the company also agreed with the US Centers for Medicare & Medicaid Services or CMS, that patients who do not respond to its therapy won’t be charged. In this unprecedented approach, the efficacy of the drug is directly related to costs of treatment.
This increased collaboration and funding will allow us to make further investments in key fundamental research as well as the development of research findings into how the immune system interacts with cancer, and to pursue advances in cell-engineering techniques that can accelerate clinical trials, making these innovative therapies available to more patients.
To that end various NCI-designated centers and others research institutes are currently testing new experimental T-cell therapies for breast cancer, leukemia, lymphoma, lung cancer, Merkel cell carcinoma and mesothelioma.
Let’s hope these interventions prove as fruitful as the one for ALL.
[a] Evidence of the clinical efficacy of CTL019 (tisagenlecleucel) is primarily based on data from the pivotal, single-arm, international, multicenter, Phase-II Study B2202, which utilized CTL019 manufactured in accordance with the Novartis manufacturing process (with 63 patients worldwide receiving U.S.-manufactured product and 5 patients from the European Union (EU) receiving EU-manufactured product).
Last editorial review: August 31, 2017
Featured Image: Medical anatomy Illustration. White blood cell. Courtesy: © 2017 Fotolia. Used with permission.
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