Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia

Abstract

BACKGROUND Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor–modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. METHODS We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×106 to 20.6×106 CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. RESULTS A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab. CONCLUSIONS Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.)

Perspectives of Fc engineered antibodies in CD19 targeting immunotherapies in pediatric B-cell precursor acute lymphoblastic leukemia

“…1A). 2 , 23-24 For generation of autologous CAR T cells, T cells are isolated, expanded ex vivo, and transduced with the CD19 specific CAR construct using viral transduction methods, and re-infused into the patient. Costimulatory domains included in the CAR were shown to be necessary to achieve CAR T cell expansion in the patient and for long persistence, which provides ongoing control of the disease.…”

“…Tisagenlecleucel (CTL019) for the treatment of children and young adults with BCP-ALL that is refractory or in second or later relapse and axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. 24-27 It is important to note that also CD22 specific CAR T cells have recently proven effective in BCP-ALL and may, in the future, provide another valid treatment option for infants and children. 28 …”

“…2 , 21 , 24 , 27 These toxicities include cytokine release syndrome (CRS), seizures and encephalopathy. In addition, CD19 CAR T cell therapy may be associated with long-term B cell aplasia.…”

“…In addition, CD19 CAR T cell therapy may be associated with long-term B cell aplasia. 2 , 24 Blinatumomab has the disadvantage that its molecule size is only 55 kDa, which results in unfavorable pharmacokinetic properties with a fast clearance from the blood and the body and an elimination half-life of approximately 2 hours. 2 , 29 Thus, blinatumomab treatment requires continuous infusion over several weeks in each cycle requiring special equipment and training of patients and health professionals.…”

Recent advances in T‐cell immunotherapy for haematological malignancies

“…(Rooney et al 2014, Sadelain 2015, Vonderheide and June 2014) Indeed, this is an exciting time in the field of T-cell immunotherapy with in vitro discoveries paving the way for bench-to-bedside translation and resulting in remarkable clinical responses in a variety of haematological malignancies. In particular, adoptively transferred T-cells genetically modified to express CD19 CARs have shown great promise (Davila et al 2014, Lee et al 2015, Maude et al 2014), although some haematological malignancies remain recalcitrant. For these tumours, combination immunotherapeutic approaches are being investigated and may prove beneficial.…”