A Phase I/II Study Evaluating SJCAR19 (CD19-Specific CAR Engineered Autologous T-Cells) in Pediatric and Young Adult Patients ≤ 21 Years of Age With Relapsed or Refractory CD19+ Acute Lymphoblastic Leukemia (SJCAR19)
Why was this study done?
Acute lymphoblastic leukemia (ALL) is a type of blood and bone marrow cancer. For some patients, cancer may come back after treatment or not respond well to treatment. This is known as relapsed/refractory ALL.
SJCAR19 is a research study that tests how well a type of immunotherapy works to treat relapsed/refractory ALL in patients younger than 21 years old. Chimeric antigen receptor (CAR) T cell therapy uses the patient’s immune cells (T cells) to fight cancer. The health care team collects T cells directly from patients. Scientists in the lab change the T cells slightly so that they recognize a protein marker (CD19) found on the surface of ALL cancer cells. These modified SJCAR19 cells recognize the cancer cells and may help kill them better.
The study’s main goals were to:
- Find out the largest and safest dose of SJCAR19 for children and young adults
- Learn how long the SJCAR19 cells last in their bodies
- Detect any side effects from using SJCAR19
- Learn how well SJCAR19 can treat the cancer
When was this study done?
The study opened in July 2018 and is still open.
What did the study consist of?
The study has 3 parts:
- Collection: Scientists use apheresis to collect the part of the patient’s blood that contains T cells.
- Manufacturing: In the lab, the researchers change the patient’s T cells to help them recognize and kill cancer better. These changed cells are known as SJCAR19.
- Treatment: Researchers give patients chemotherapy (chemo) to help prepare the patient’s immune system for the infusion. The chemo helps the SJCAR19 cells grow and work better. After chemo, the researchers give patients an infusion of their own, manufactured SJCAR19 cells.
- During the first part of the dosing study (known as phase 1), the first group of patients gets the lowest dose of SJCAR19 cells. If this dose is safe, the researchers slowly increase the dose for each new group of patients. The process continues until they find the highest dose that is safe.
- After phase 1 of the study, all subsequent patients will receive the highest, safe dose during phase II.
Researchers follow patients before, during, and after treatment to better understand how well the treatment works and any side effects. The scientists conduct tests to see how long the SJCAR19 cells stay in patients’ bodies and monitor for any side effects. They also ask patients questions about their quality of life. Treatment and follow-up take about 1 year. Scientists will then follow patients for 15 years to find out if they have long-term side effects.
What did we learn from this study?
The scientists studied 12 patients in phase 1 of the trial. They found that:
- The patients tolerated their treatment well, with expected side effects. Six patients had cytokine release syndrome and 3 had neurotoxicity.
- Of the 12 patients treated on the study, after study treatment 9 had no disease in their bone marrow. The treatment worked well.
- Patients with more advanced disease before SJCAR19 treatment had more side effects. These patients also had a lower response to treatment.
- Scientists studied how the SJCAR19 cells grew in the patients’ bodies after their cell infusion (treatment). The scientists found that some subsets of T cells grew more than other (known as CD8+ cells).
- Following the SJCAR19 treatment, some patients went on to get bone marrow transplants. These patients had good responses to their transplants.
- Lab studies showed that a type of CAR T cell, called CD19-CARCD7-, was better at stopping tumor growth than similar CD19-CAR cells. Scientists then looked at genetic details from SJCAR19 cells produced for patients in this study. They found a subset of T cells (CD19-CARCD7lo) remained in the patients’ bodies after their infusion. Patients who had a better response to therapy tended to have higher numbers of these cells.
- Scientists compared the genetic features of the SJCAR19 cells before and after infusion into patients. They found a type of cell (TIGIT+, CD62Llo, CD27-) that was better at killing cancer cells. This type of cell was able to kill leukemia cells longer than other types of cells.
- SJCAR19 cells lose their ability to kill cancer over time (known as exhaustion). Scientists studied how this exhaustion happened, and found a process known as DNA methylation was involved.
What are the next research steps as a result of this study?
Scientists will treat more patients in the phase 2 study to better understand how this treatment works and to look for side effects of the treatment. Researchers need to learn ways to improve how well CD19 CAR T cells work, including ways to make them last longer in the patient’s body. A subset of T cells, CARCD7-, may have greater antitumor activity. These cells show promise for future cell therapy treatments.
The methods used by scientists in these studies helped identify cells that kill cancer well. This information can help scientists make more effective CAR T products. Understanding why CAR T cells lose their ability to kill (exhaustion) can provide clues on how to prevent this process. This information will help scientists improve CAR T-cell products.
How does this study affect my child?
Every childhood cancer survivor should have long-term follow-up care. Please speak with your St. Jude doctor about specific guidelines for your child.
For more information
Please talk with your child’s St. Jude doctor about questions or concerns you have as a result of this study.
Publications generated from this study:
Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Talleur A, Qudiemat A, Métais JY, Langfitt D, Mamcarz E, Crawford JC, Huang S, Cheng C, Hurley C, Madden R, Sharma A, Suliman AY, Srinivasan A, Velasquez MP, Obeng EA, Willis CM, Akel S, Karol SE, Inaba H, Bragg A, Zheng W, Zhou S, Schell S, Tuggle-Brown M, Cullins D, Patil SL, Li Y, Thomas PG, Zebley C, Youngblood BA, Pui CH, Lockey T, Geiger TL, Meagher MM, Triplett BM, Gottschalk S. Blood Adv. 2022 Apr 21.
Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies. Freiwan A, Zoine JT, Crawford JC, Vaidya A, Schattgen SA, Myers JA, Patil SL, Khanlari M, Inaba H, Klco JM, Mullighan CG, Krenciute G, Chockley PJ, Naik S, Langfitt DM, Mamonkin M, Obeng EA, Thomas PG, Gottschalk S, Velasquez MP. Blood. 2022 Dec 22;140(25):2684-2696.
Common trajectories of highly effective CD19-specific CAR T cells identified by endogenous T-cell receptor lineages. Wilson TL, Kim H, Chou CH, Langfitt D, Mettelman RC, Minervina AA, Allen EK, Métais JY, Pogorelyy MV, Riberdy JM, Velasquez MP, Kottapalli P, Trivedi S, Olsen SR, Lockey T, Willis C, Meagher MM, Triplett BM, Talleur AC, Gottschalk S, Crawford JC, Thomas PG. Cancer Discov. 2022 Sep 2;12(9):2098-2119.
CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia. Zebley CC, Brown C, Mi T, Fan Y, Alli S, Boi S, Galletti G, Lugli E, Langfitt D, Metais JY, Lockey T, Meagher M, Triplett B, Talleur AC, Gottschalk S, Youngblood B. Cell Rep. 2021 Nov 30;37(9):110079.
Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity..Prinzing B, Zebley CC, Petersen CT, Fan Y, Anido AA, Yi Z, Nguyen P, Houke H, Bell M, Haydar D, Brown C, Boi SK, Alli S, Crawford JC, Riberdy JM, Park JJ, Zhou S, Velasquez MP, DeRenzo C, Lazzarotto CR, Tsai SQ, Vogel P, Pruett-Miller SM, Langfitt DM, Gottschalk S, Youngblood B, Krenciute G Sci Transl Med. 2021 Nov 17;13(620):eabh0272. Epub 2021 Nov 17