Novartis has highlighted new research from members of the faculty at the University of Pennsylvania's Perelman School of Medicine (Penn) on the investigational chimeric antigen receptor (CAR) therapy, CTL019. Several studies being presented at the American Society of Hematology (ASH) annual meeting add to the scientific understanding of CTL019 in the treatment of acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL) and build on earlier research findings.

"These data reflect a significant advance in our understanding of the novel, investigational CAR therapy, CTL019, which shows potential for advancing the treatment of patients with ALL and CLL," said Hervé Hoppenot, president, Novartis Oncology. "We are committed, through our collaboration with Penn, to expand the clinical trials of CTL019 to include as many patients as soon as possible."

Highlights of the presentations include findings that 19 of 22 paediatric patients with ALL (86 per cent) experienced complete remissions. The first paediatric patient treated with the protocol remains in remission 20 months later. Five paediatric patients have relapsed, including one whose tests revealed new tumour cells that do not express the CD19 protein targeted by the reprogrammed cells. Additionally, all five of the first adult ALL patients treated to date have experienced complete remissions, the longest of which continues six months after treatment. One adult patient subsequently underwent a bone marrow transplant and remains in remission. Another adult patient relapsed after three months with disease that also tested negative for the CD19 protein.

In studies of adult patients with CLL, 15 of 32 adult patients (47 per cent) responded to the therapy, with seven of those experiencing a complete remission of their disease. These results are derived from a completed pilot study of 14 CLL patients and results to date of the first 18 patients in a phase II, dose-optimization trial. Separately, investigators observed in vivo expansion of CTL019 cells in all patients who achieved a complete response. This was followed by contraction and, in all but one patient, ongoing stable persistence of the reprogrammed T cells.

Novartis and Penn have an exclusive global agreement to research, develop and commercialize personalized CAR T cell therapies for the treatment of cancers. Novartis holds the worldwide rights to CARs developed through the collaboration for all cancer indications, including the lead programme CTL019 (also known as CART19). This innovative collaboration has expanded to include multiple CART programmes now in discovery and pre-clinical research phases for both hematological cancers and solid tumours.

"This strong collaboration with Novartis, combined with our exciting new research, has brought us closer to making CTL019 available for children and adults who have no other effective treatment options," said Carl H June, MD, director of Translational Research and professor of Pathology and Laboratory Medicine in the University of Pennsylvania's Abramson Cancer Centre and Perelman School of Medicine. "These CTL019 data at ASH reinforce that CAR therapy has the potential to change the treatment paradigm for those suffering from various types of leukaemia."

CTL019 is an investigational, personalized T cell therapy, which was pioneered by Carl June and his team at Penn. In a CTL019 treatment cycle, immune cells (T cells) are drawn from a patient's blood. Then, using CAR technology, the T cells are reprogrammed to "hunt" cancer cells that express specific proteins, called CD19. When the T cells are re-introduced into the patient's blood, the cells proliferate and bind to the targeted cancer cells and destroy them. CD19 is associated with a number of B-cell malignancies including ALL, CLL, diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma.

In a study evaluating CTL019 for the treatment of children and adults with relapsed/refractory ALL, paediatric patients (n=22) received a targeted T cell dose range of 107 to 108 cells/kg with a transduction efficiency (TE) of 11-45 per cent and adult patients (n=5) received a target dose of 5x109 total cells split over three days with a TE of 6-31 per cent. The study found that 19 of 22 pediatric patients with ALL (86 per cent) experienced complete remissions and all five of the first adult ALL patients treated have thus far experienced complete remissions. There were no infusional toxicities greater than Grade 2, although five patients developed fevers within 24 hours of infusion and did not receive planned subsequent infusions of CTL019 cells.

In studies of adult patients with CLL, 15 of 32 adult patients (47%) responded to the therapy, with seven of those experiencing a complete remission of their disease. These results are derived from a completed pilot study of 14 CLL patients and results to date of the first 18 patients in a phase II, dose-optimization trial. In the pilot study of CTL019 for the treatment of adult patients (n=14; median age=67) with relapsed/refractory CLL, the target dose of cells administered to patients was 5x109 mononuclear cells with an expected TE of 10-40% (total CTL019 dose 5x108 - 2x109 total cells)[2]. The Phase II dose optimization study of two doses of CTL019 cells in patients with relapsed/refractory CLL (n=27; median age=63 years) was conducted to better define an optimal CTL019 cell dose following results from the initial pilot study. In this ongoing trial, patients were randomly assigned to receive either 5x108 vs. 5x107 transduced CTL019 cells. Results thus far from 18 patients in the study are being presented. A preliminary analysis through July 15, 2013 showed that in 10 adult patients, 20% of patients (n=2) achieved a complete response (CR) and 20% a partial response, for an overall response rate of 40% (n=4).

Finally, a separate study evaluating functional persistence, trafficking and bioactivity of CTL019 cells in patients treated with CTL019 determined that CTL019 holds the potential to effectively target CD19-positive malignancy. In all patients who achieved CR, in vivo expansion of CTL019 cells was observed followed by contraction and in all but one patient, ongoing stable persistence of engineered cells, elimination of tumor B cells and ongoing B cell aplasia in blood and marrow at all evaluated time points (minimum 3 months, maximum ongoing at 35 months).

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

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