PracticeUpdate: Haematology & Oncology

CONFERENCE COVERAGE 18

Complete remissions with anti-CD22 CAR-T in childrenwith relapsed/ refractory ALL C hildren and young adults with relapsed or refractory acute lymphoblastic leukaemia who lymphoblastic leukaemia and had previously undergone at least one al- logeneic stem cell transplant.

Gene therapymay improve quality of life for haemophilia patients P atients with haemophilia B, who are unable to produce factor IX, began producing factor IX at sufficient levels after receiving a single infusion of the investigational gene therapy product SPK-9001, finds preliminary data of an ongoing phase 1/2 trial. Katherine A. High, MD, of Spark Therapeutics, Inc. Philadelphia, Pennsylvania, explained that the standard of care for haemophilia B requires patients to self-administer intravenous infusions of laboratory-produced factor IX at regular intervals, typically once to twice a week. Factor IX levels fluctuate widely, and patients may need to limit their activities to avoid breakthrough bleeding when their factor IX levels are low. The ongoing trial involves seven previously treated adult patients with an extremely deficient, baseline factor IX < 2%. Twelve weeks after SPK-9001 infusion, patients showed factor IX levels of 20–40%, and an overall average of 32%, sufficiently close to normal (at least 50% in healthy adults). Maintaining a minimum level of 12% prevents minor, chronic joint bleeding, a common cause of disa- bility in patients with haemophilia. SPK-9001 uses an inactive adenovirus vector that delivers a small section of DNA that, when stabilised in the patient’s hepatocytes, allows the body to produce factor IX. Factor IX levels achieved with SPK-9001 to date have been sufficient to allow patients to engage in normal daily activities without the need for factor IX infusions. Though none of the seven participants have required in- fusions of factor IX concentrates to prevent bleeding, one precautionary infusion was needed due to a suspected ankle bleed 2 days after administration of SPK-9001. In addition, six patients reported increased physical activity and improved quality of life. Dr High said, “One of the potential innovations with gene therapy for haemophilia B, compared to factor IX infu- sions, is that once patients establish a stable factor activity level, they may remain at that level for an extended time. “At factor IX levels attained in the study, patients with haemophilia do not have to worry about bleeding. Most normal activities of daily living should be open to them. The therapy could mean a potential paradigm shift in the treatment of haemophilia.” One participant suffered an autoimmune response and needed corticosteroids. Despite the immune response and decline in factor IX activity level, this patient has not experienced any bleeds or required replacement factor IX. Dr High concluded that the results show the highest and most consistent levels of factor IX production of any gene therapy tested to date. Dr High and colleagues plan to continue to track patient outcomes for at least 5 years.

received chimeric antigen receptor (CAR) T cell therapy targeting the CD22 protein on the leukocyte sur- face, appeared to mount a clinical response and in some cases achieved remission. The early findings of a phase 1 clinical trial were reported at ASH 2016. Terry J. Fry, MD, of the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, ex- plained that a team from the Pediatric Oncology Branch of the National Can- cer Institute of the National Institutes of Health genetically altered patients’ own T cells to track down and kill cancer cells expressing CD22. The study was the first to evaluate this new target of immunotherapy in humans, and provides a first glimpse into how patients who already received CAR-T therapy directed at a different antigen, CD19, might fare when given a second immunotherapy. The first three patients treated at the second dose level attained complete remission with no evidence of residual disease. Based on these initial results, Dr Fry and coinvestigators treated additional patients (16 in total) and found that eight of the 10 patients attained com- plete remission when treated at the top dose levels. Dr Fry said, “We’ve been able to show that you can give a second CAR-T therapy directed against a different an- tigen and it will be safe and effective.” Dr Fry said the result adds to the notion that a single antigen-directed CAR-T immunotherapy probably won’t be sufficient for long-term durable remis- sions in many patients. It points to the potential for bispecific targeting. The trial included 16 patients with relapsed or treatment-resistant acute lymphoblastic leukaemia who were either CAR-T naïve or previously treated with anti-CD19 CAR-T cells and/or blinatumomab therapy and had relapsed with CD19-negative disease. Patients ranged in age from 7–22 years of age. All had CD22-positive acute

The majority of treated patients had re- lapsed after earlier anti-CD19 CAR-T cell therapy before entering the trial. Researchers then collected T cells from eligible patients and modified them to recognise and bind to CD22. Patients then received an infusion of these enhanced cells and were evalu- ated for response and adverse effects after an average of 28 days. The trial is continuing to accrue pa- tients, and these early results raise new questions about how anti-CD22 CAR-T therapy might best be used. For example, whether it is better to wait for relapse after initial CAR-T therapy, or to pre-empt relapse by co-treating it. Dr Fry and the team plan to investi- gate combined use of anti-CD19 and CD22 CAR-T targeting approaches with the hypothesis that combined therapy will raise the likelihood of sustained remission.

PracticeUpdate Editorial Team

PracticeUpdate Editorial Team

© ASH 2016

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY