Game changers in pediatric cancer

CAR T cells transformative in ALL

A variety of different types of immunotherapy have been tested in patients with pediatric cancers. In general, immunotherapy has proved less effective than in adult cancers, possibly because of the lower tumor mutation burden in pediatric cancers, which means there are likely fewer cancer antigens to provoke an anti-tumor immune response.

There are notable exceptions among the disappointments, however, and most exciting is the development of chimeric antigen receptor (CAR) T cells. CAR T cells fall into a category of immunotherapy known as adoptive cell therapy (ACT), in which immune cells are harvested from a patient and grown outside the body to increase their numbers before being reinfused into the patient.

In the case of CAR T-cell therapy, the cells are genetically engineered to express a CAR that endows them with tumor-targeting capabilities. To date, the development of CAR T cells has focused on the use of the CD19 antigen as a target, which is highly expressed on a variety of B-cell malignancies, including several of the most common forms of pediatric cancer. ASCO shined the spotlight on CAR T-cell therapy this year, naming it the Advance of the Year for 2018, saying that the treatment is “poised to transform childhood ALL.”¹⁹

Two CD19-targeted CAR T-cell therapies – tisagenlecleucel and axicabtagene ciloleucel – were brought to market in 2017. Only tisagenlecleucel is approved in the pediatric ALL population, however, having been awarded approval for the treatment of patients aged up to 25 years whose disease is refractory to or relapsed after receiving at least 2 prior therapies. In the pivotal trial, complete responses were observed in more than 60% of patients.²⁰ Clinical trials of both CAR T-cell therapies in pediatric ALL and non-Hodgkin lymphoma are ongoing (Table 3).

CD19 has also proven to be a promising target for other forms of immunotherapy, including a new type of antibody known as a bispecific T-cell engager (BiTE). In 2014, blinatumomab became the first BiTE to receive regulatory approval, for the treatment of adult patients with relapsed/refractory ALL. Blinatumomab also targets the CD3 protein on T cells and helps to bring cancer cells and cytotoxic immune cells into close enough proximity that an immunological synapse can be formed between the two, facilitating tumor cell killing.²¹

In 2016, the approved indication was expanded into the pediatric population based on the results of a phase 1/2 study in which the safety and efficacy of blinatumomab were evaluated in 93 pediatric patients with relapsed/refractory ALL. Among the 70 patients who received the recommended dose of 5µg/m² a day for the first 7 days, followed by 15µg/m² a day thereafter, 51% achieved complete remission within the first 2 cycles, 52% of whom achieved minimal residual disease (MRD).²² Most recently, the FDA expanded the indication for blinatumomab to include patients (both adults and children) who are in remission, but MRD positive.²³Despite the dramatic responses, many patients relapse after treatment with CD19-targeted CAR T cells, and researchers have uncovered numerous mechanisms of resistance. Among them is the loss of the CD19 antigen on the surface of target cells, such that a CD19-positive tumor becomes CD19-negative after treatment, driving relapse.^24-26Several strategies for overcoming CD19-negative relapse are already being investigated, including the development of CD22-targeted CAR T cells and bispecific CAR T cells that target both CD19 and CD22. The results of a first-in-human trial of anti-CD22 CAR T-cell therapy were recently published. Among 21 pediatric and adult patients with relapsed/refractory B-cell ALL who were treated with either 3 x 10⁵ cells/kg, 1 x 10⁶ cells/kg, or 3 x 10⁶ cells/kg, complete responses were observed in 57%.²⁷

Results from 15 pediatric patients enrolled in a trial evaluating CD22-targeted CAR T cells as salvage therapy for those who relapse after CD19-targeted CAR T cell therapy were presented at the recent Congress of the European Hematology Association in Stockholm, Sweden. Patients who had undergone a stem cell transplant received the CAR T cells at a dose of 0.9 x 10⁵ cell/kg and those who had not undergone a transplant received a dose of 8.2 x 10⁵ cells/kg. At 30 days after CAR T cell infusion, the CR rate was 80% and the treatment was well tolerated.²⁸