Novartis and the University of Pennsylvania's Perelman School of Medicine (Penn) announced preliminary results from two pilot clinical trials published in The New England Journal of Medicine (NEJM) evaluating the efficacy and safety of CTL019 in patients with relapsed/refractory acute lymphoblastic leukaemia (r/r ALL). The studies, conducted by Penn, demonstrated that 27 of 30 paediatric and adult patients, or 90 per cent, experienced complete remissions with the investigational chimeric antigen receptor (CAR) therapy CTL019.

"These interim results, which supported the recent FDA Breakthrough Therapy designation, reinforce the potential CTL019 has as a life-saving therapy for patients with relapsed/refractory ALL," said Usman Azam, Global Head, Cell & Gene Therapies Unit, Novartis Pharmaceuticals. "These studies are another promising development in CTL019's history. With each new CTL019 milestone, we are one step closer to potentially offering these seriously ill patients an additional treatment option."

These data build on earlier research findings and are part of two pilot clinical studies that demonstrated sustained remissions of up to two years in paediatric and adult patients with r/r ALL. Median follow-up was just over six months, with event-free survival of 67 per cent and overall survival of 78 per cent. Probability of six-month CTL019 persistence was 68 per cent and CTL019-modified T cells were detectable in the blood by flow cytometry for up to 11 months. Sustained remissions were seen in 15 patients and were associated with CAR T cell persistence and B cell aplasia. Updated results have been submitted for presentation at a medical congress taking place later in 2014.

"We are excited by these results, which indicated how effective CTL019 may be in fighting ALL, a leading cause of childhood cancer deaths," said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Paediatrics in the Perelman School of Medicine at the University of Pennsylvania and director of Translational Research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia (CHOP), where 25 paediatric patients were treated in the study cohort. "This represents the largest experience to date of CD19-CAR T cells and demonstrates the ability of this approach to achieve sustained complete responses in a patient population with few other treatment options. We are especially hopeful for those patients who remain in remission for 1-2 years without further therapy."  

In July 2014, the FDA designated CTL019 as a Breakthrough Therapy under the Penn IND, which is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint.

Novartis holds the worldwide rights to CARs developed through the collaboration with Penn for all cancer indications, including the lead programme, CTL019.

Twenty-five patients enrolled in the paediatric pilot trial at CHOP and 5 patients enrolled in the adult pilot trial at Penn from April 2012 to February 2014. The patients were infused with autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.7-20.6x106 CTL019 cells/kg. The study found that 27 of 30 paediatric and adult patients with r/r ALL (90 per cent) experienced complete remissions, including two blinatumomab-refractory patients and 15 with prior stem cell transplant.

Of the 27 patients who achieved a complete remission, five went off-study for alternate therapy, three of whom proceeded to allogeneic SCT in remission. Fifteen patients remain in remission with a median follow-up of seven months. Sustained remissions were achieved up to two years with six-month event-free survival 67 per cent (95 per cent CI, 51 per cent to 88 per cent) and overall survival 78 per cent (95 per cent CI, 65 per cent to 95 per cent). The probability of six-month CTL019 persistence was 68 per cent (95 per cent CI, 50 to 92 per cent) and relapse-free B cell aplasia was 73 per cent (95 per cent CI, 57 to 97 per cent). CTL019-modified T cells were detectable in the blood by flow cytometry for up to 11 months, and CTL019 sequences remained detectable by quantitative PCR (Q-PCR) in patients with sustained remissions for up to two years.

All patients experienced cytokine release syndrome (CRS). Of the 30 patients, 74 per cent (n=22) experienced mild to moderate CRS. Severe CRS, seen in 27 per cent of patients (n=8), was associated with higher disease burden and effectively treated with the IL-6 receptor antibody tocilizumab. Several patients experienced neurologic toxicities, which fully resolved without further intervention or apparent long-term implications.

CTL019 uses CAR technology to reprogram a patient's own T cells to "hunt" cancer cells that express specific proteins, called CD19. After they have been reprogrammed, the T cells (now called CTL019) are re-introduced into the patient's blood; they proliferate and bind to the targeted CD19+ cancer cells and destroy them.

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.

Acute lymphoblastic leukaemia (ALL) is the most common cancer diagnosed in children, representing approximately 25 per cent of cancer diagnoses among children younger than 15 years, according to data published in 2013. It can also occur in adults. ALL is a type of cancer in which the bone marrow makes too many abnormal white blood cells (lymphocytes). ALL usually gets worse quickly if it is not treated and can be fatal within a few months; therefore, it is critical for patients to start treatment soon after diagnosis. Patients with relapsed ALL experience ALL cells returning in the marrow and a decrease in normal blood cells following their remission. Patients with refractory ALL still have leukaemia cells in their bone marrow following treatment.