January 2015, Vol. 2, No. 1

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CAR T-Cell Therapy Achieves High Rate of Remission in Pediatric Relapsed/Refractory ALL

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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 Children’s Hospital of Philadelphia. “The idea is that we have to collect T cells from each patient, so this is very much an individualized therapy,” he said. “We 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.” 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 Children’s Hospital of Philadelphia have been treated with CTL019, encompassing ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Grupp’s report focused on 39 pediatric patients with relapsed, treatment-resistant ALL who received treatment with CTL019 at a median 3.6×106 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. “Patients who have <50% bone marrow blasts essentially do not have significant degrees of cytokine release syndrome,” he said.

Persistence of the cells is key, he indicated. “About two-thirds of the patients retain their T cells for 6 months or longer,” Grupp said. “It’s a key point in terms of maintaining remission in these patients.”

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%.

Uncategorized - February 18, 2015

Immune Checkpoint Blockades: The Future of Cancer Therapy

Using the body’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. “The [ Read More ]

Uncategorized - February 18, 2015

PD-1 Inhibitor–Based Immunotherapy the Newest Breakthrough in Hodgkin Lymphoma

Two PD-1 inhibitors – the investigational drug nivolumab and the recently approved pembro­lizumab – produced dramatic responses in patients with Hodgkin lymphoma in phase 1 clinical trials. Complete or partial responses were reported by up to 87% of patients who had exhausted other treatment options, providing solid evidence that targeting [ Read More ]