Researchers at Children’s Hospital of Philadelphia (CHOP) have shown that modifying a chimeric antigen receptor (CAR) to look more “human” is a safe approach with high response rates and lasting remissions in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). The results of the phase 1 study testing this potential treatment were published recently in the Journal of Clinical Oncology.
CAR T-cell therapy involves engineering a patient’s T cells to express a CAR that targets a protein on the surface of cancer cells, thus harnessing the power of the patient’s own immune system to fight the disease. When targeting CD19, a surface marker of malignant B cells, this immunotherapy has transformed the treatment of B-ALL that has resisted or failed therapy, with response rates as high as 93% and durable responses in many cases for a disease that was once considered incurable.
However, as many as 50% of patients who undergo this treatment eventually relapse, either due to loss of CAR T-cell persistence, which allows any residual leukemia to spread, or escape from CAR T-cell killing. One hypothesis as to why patients lose CAR T-cell persistence is that most CARs in clinical development contain a domain derived from mouse monoclonal antibodies. The patients might end up rejecting the treatment because their bodies see it as “non-human.”
To bypass this issue and potentially improve persistence, the CHOP researchers developed a CAR containing a “humanized” anti-CD19 domain, modifying it so that it looked as if it had been derived from a human cell line rather than a mouse model. Using this huCART19, the researchers assessed the safety, feasibility, persistence, and efficacy of this treatment in 74 children and young adults with relapsed or refractory B-ALL, including patients previously treated with CAR T cells who lost T cell persistence.
The research team found that huCART19 was safe and effective, particularly in B-ALL patients who had not received CAR T-cell therapy treatment previously, with 100% of those patients experiencing complete remissions. At one and two years after treatment, the probability of remaining disease free was 84% and 74%, respectively. Among patients who had previously received CAR T treatment, 64% saw a response, with a probability of remaining relapse free of 74% and 58% at one and two years after treatment.
“These results show that humanized CART19 is an encouraging option for retreatment in a difficult-to-treat population,” said Shannon L. Maude, MD, PhD, an attending physician in the Cancer Center at CHOP and senior author of the study. “We are continuing to analyze the effectiveness of this approach in a phase 2 trial, which is ongoing.”
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Researchers at Children’s Hospital of Philadelphia (CHOP) have shown that modifying a chimeric antigen receptor (CAR) to look more “human” is a safe approach with high response rates and lasting remissions in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). The results of the phase 1 study testing this potential treatment were published recently in the Journal of Clinical Oncology.
CAR T-cell therapy involves engineering a patient’s T cells to express a CAR that targets a protein on the surface of cancer cells, thus harnessing the power of the patient’s own immune system to fight the disease. When targeting CD19, a surface marker of malignant B cells, this immunotherapy has transformed the treatment of B-ALL that has resisted or failed therapy, with response rates as high as 93% and durable responses in many cases for a disease that was once considered incurable.
However, as many as 50% of patients who undergo this treatment eventually relapse, either due to loss of CAR T-cell persistence, which allows any residual leukemia to spread, or escape from CAR T-cell killing. One hypothesis as to why patients lose CAR T-cell persistence is that most CARs in clinical development contain a domain derived from mouse monoclonal antibodies. The patients might end up rejecting the treatment because their bodies see it as “non-human.”
To bypass this issue and potentially improve persistence, the CHOP researchers developed a CAR containing a “humanized” anti-CD19 domain, modifying it so that it looked as if it had been derived from a human cell line rather than a mouse model. Using this huCART19, the researchers assessed the safety, feasibility, persistence, and efficacy of this treatment in 74 children and young adults with relapsed or refractory B-ALL, including patients previously treated with CAR T cells who lost T cell persistence.
The research team found that huCART19 was safe and effective, particularly in B-ALL patients who had not received CAR T-cell therapy treatment previously, with 100% of those patients experiencing complete remissions. At one and two years after treatment, the probability of remaining disease free was 84% and 74%, respectively. Among patients who had previously received CAR T treatment, 64% saw a response, with a probability of remaining relapse free of 74% and 58% at one and two years after treatment.
“These results show that humanized CART19 is an encouraging option for retreatment in a difficult-to-treat population,” said Shannon L. Maude, MD, PhD, an attending physician in the Cancer Center at CHOP and senior author of the study. “We are continuing to analyze the effectiveness of this approach in a phase 2 trial, which is ongoing.”
Learn more about CHOP’s Cancer Immunotherapy Program.
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