January 2015, Vol. 2, No. 1
CAR T-Cell Therapy Achieves High Rate of Remission in Pediatric Relapsed/Refractory ALL
Administration of T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) persist over the long term and induce durable remissions in children with relapsed/refractory acute lymphocytic leukemia (ALL).
Complete responses were achieved in 92% of recipients of CTL109 cells who were enrolled in a phase 1/2a study, reported Stephan A. Grupp, MD, PhD.
In July 2014, CTL019 received breakthrough therapy designation from the FDA for its potential as a treatment for pediatric and adult patients with relapsed/refractory ALL.
The CAR process uses genetically engineered T cells to target cancer, explained Grupp, director of translational research, The Childrenâ€™s Hospital of Philadelphia. â€śThe idea is that we have to collect T cells from each patient, so this is very much an individualized therapy,â€ť he said. â€śWe collect these T cells by apheresis. We bring them to the lab where we genetically engineer them using a lentiviral vector, which is an inactivated form of HIV, which retains the ability to genetically modify the T cells.â€ť The genetic modification allows the expression of a CAR protein on the surface of the T cell. The T-cell receptor gains this new recognition capability through the CAR protein, which allows interaction with the cancer cell, with the intent of killing it. It also allows activation of the T cell, which causes significant proliferation.
More than 130 patients at the University of Pennsylvania and The Childrenâ€™s Hospital of Philadelphia have been treated with CTL019, encompassing ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Gruppâ€™s report focused on 39 pediatric patients with relapsed, treatment-resistant ALL who received treatment with CTL019 at a median 3.6Ă—106 cells/kg over 1 to 3 days. One week prior to treatment with CTL019, 87% of patients received lymphodepleting chemotherapy.
A complete response was achieved in 36 patients (92%) 28 days after a T-cell infusion. There have been 10 relapses, half related to disappearance of the engineered T cells (CD19-positive relapse) and half related to antigen escape (CD19-negative relapse). Forty percent of patients who relapsed with CD19 disease after achieving complete response were also refractory to prior treatment with blinatumomab.
Median follow-up has been 6 months, but 15 patients have been followed for 1 year or longer, with the longest being 31 months. Only 3 patients have subsequently gone on to stem cell transplantation.
Response seems to be independent of the disease burden, said Grupp. In patients with >50% bone marrow blasts by minimal residual disease, the overall response rate was 82%, similar to the response rate of 88% in patients with >5% blasts.
The significant risk of treatment is cytokine release syndrome, with a higher likelihood in patients with high disease burden, although all patients experience some degree of cytokine release syndrome at peak T-cell expansion. â€śPatients who have <50% bone marrow blasts essentially do not have significant degrees of cytokine release syndrome,â€ť he said.
Persistence of the cells is key, he indicated. â€śAbout two-thirds of the patients retain their T cells for 6 months or longer,â€ť Grupp said. â€śItâ€™s a key point in terms of maintaining remission in these patients.â€ť
Duration of response has been favorable: 76% of the patients remain in remission if they are in remission at 6 months. The event-free survival rate at 6 months is 70%, and the overall survival is 75%.
Immune Checkpoint Blockades: The Future of Cancer Therapy
Using the bodyâ€™s own defenses to kill cancer may sound like the realm of science fiction. However, in the keynote lecture presented at the 2015 Gastrointestinal Cancers Symposium, T cells and antibodies were shown adept at recognizing and targeting antigens created by tumor mutations as they evolve within patients. â€śThe [ Read More ]
Immunotherapy Attacks Minimum Residual Disease in ALL; Leads to High Rate of Complete Response
An antibody that recruits T cells to attack minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) who are in remission can prevent full relapse. No MRD was detected in 78% of patients treated with blinatumomab, a bispecific T-cell engager antibody construct, with nearly all complete responses occurring [ Read More ]