Sarah K. Tasian, MD, discusses the success of CAR T-cell therapy, as well as novel agents and immunotherapies that appear promising in the treatment of children with leukemia.
Sarah K. Tasian, MD
The historic FDA approval of tisagenlecleucel (Kymriah) marked the beginning of a new era of personalized medicine in hematologic malignancies, especially for select pediatric patients.
This CD19-directed chimeric antigen receptor (CAR) T-cell therapy was approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. This indication also signified an advance for the treatment of pediatric leukemia, a field in which drug development is slow.
Research is now being conducted with CAR T-cell therapy in pediatric acute myeloid leukemia (AML), with a possibility for a clinical trial opening over the next year.
In an interview with OncLive, Sarah K. Tasian, MD, an attending physician and assistant professor of pediatrics in the Division of Oncology at Children’s Hospital of Philadelphia, discussed the success of CAR T-cell therapy, as well as novel agents and immunotherapies that appear promising in the treatment of children with leukemia.Tasian: The approval of CD19-redirected CAR T cells for children with B-ALL is a historic landmark. Several institutions across the country, including CHOP and the University of Pennsylvania, have conducted clinical trials investigating these therapies in adults and children with B-cell ALL or lymphoma and demonstrated remarkable results. This now gives a lot of hope to patients who have highly treatment-resistant disease who can now potentially be cured. It is truly one of the most exciting developments in oncology and especially in childhood leukemia in the past 50 years.I am at the Children's Hospital of Philadelphia, where the first child with B-ALL was treated with CD19 CAR T cells. Given this remarkable success, our clinical immunotherapy team has subsequently treated hundreds of children and young adults on its research trials. Through multi-institutional grant mechanisms, our group also [closely] collaborates with other pediatric institutions that have been conducting these pivotal CAR T cell trials and other laboratory-based research, such as the National Cancer Institute (NCI) and Seattle Children's Hospital. It is a very small community in that respect of talented, bright investigators focused upon developing innovative therapies together for children with high risk cancers.
On a research level, my laboratory and collaborators are working to develop CAR T cell immunotherapies for children with AML. We have made a lot of progress in preclinical work, and several CD123 and CD33 CAR T cell trials are underway for adults with relapsed AML. We are planning to open a first-in-child CAR T cell trial in 2018 for children with relapsed or refractory AML. The success story of CD19 CAR T cell immunotherapy for ALL is very inspiring, and we would love to see similar success in pediatric AML, but it has been a much more difficult endeavour. Other CAR T cell immunotherapy strategies that we are investigating still in the preclinical phase are targeting TSLPR in ALL and FLT3 in ALL and AML. We are hoping to have trials against both of those antigens within the next 2 years.We hope so. It has certainly been a nice, simultaneous paradigm. The targets for CAR T cells in AML have been more challenging to identify, and the toxicities in patients with AML will likely be quite different and perhaps a bit scarier than what we typically experience with patients with ALL.Ongoing studies are actively investigating other targets in ALL beyond CD19, particularly CD22. The NCI just published very exciting first results of its CD22 CAR T cell trial, and several pediatric institutions across the country have active phase 1 CD22 trials for children with relapsed CD22+ B-ALL.
Studies are now starting to look at targeting 2 leukemia proteins simultaneously. The NCI and Stanford Cancer Institute have a brand new trial with a CAR T-cell therapy that targets CD19 and CD22 simultaneously. The question in that trial is, “Can similar rates of remission be achieved, but also possibly prevent some tumor antigen loss that is currently seen in the CD19 or CD22 alone trials?” Antigen loss is a major mechanism of failure of these and other targeted immunotherapies, so will certainly be something for which to watch closely.
In addition to CAR T-cell therapy, there are also some interesting antibody-based immunotherapies for patients with acute leukemias. The CD19 x CD3 bispecific T cell engager antibody blinatumomab (Blincyto) and the CD22-targeting antibody-drug conjugate inotuzumab ozogamicin (Besponsa) were recently FDA-approved for adults with relapsed B-ALL. Blinatumomab and inotuzumab are actively being studied in children with relapsed B-ALL via current Children’s Oncology Group (COG) trials. In AML, earlier efforts focused on targeting CD33 with the antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg), which was also recently FDA approved for adults with AML. Mylotarg has also been extensively tested in children with AML via a COG trial.
I am also particularly interested in a new CD123-targeting dual-antigen retargeting antibody, flotetuzumab, that is demonstrating interesting early activity in a phase 1 trial with adults with relapsed/refractory AML. We are actively developing a phase 1 COG trial of flotetuzumab for children with relapsed AML. It is certainly an exciting time in the leukemia field with many promising new targeted immunotherapies.Another major area of investigation is testing kinase inhibitors in specific genetic subsets of childhood B-ALL that have activated oncogenic kinase signaling. The recent identification of the Philadelphia chromosome-like (Ph-like) subset of ALL has led to two active trials through the COG, as well as similar studies at St. Jude Children’s Research Hospital, looking at the addition of kinase inhibitors to chemotherapy backbones. The COG trial AALL1131 is studying the efficacy of dasatinib (Sprycel) in children with Ph-like ALL and ABL class mutations, and the COG trial AALL1521 is investigating the addition of ruxolitinib (Jakafi) in Ph-like ALL with JAK pathway mutations.
There has also been a lot of buzz about FLT3 mutations in adult AML. The FLT3 inhibitor midostaurin (Rydapt) was FDA-approved this past year, and exciting early phase clinical trial data have been presented regarding more selective FLT3 inhibitor treatment of adults with relapsed AML. The COG is also planning to study these next-generation selective FLT3 inhibitors in children with FLT3-mutant AML, both in the relapsed and newly diagnosed settings.Globally, drug development in children has been terribly slow, because often a drug must be tested extensively in adult patients before we might have access to it in pediatrics. The approval of CD19 CAR T cells first in children with B-ALL is thus a major success in terms of efficacy, as well as getting something approved first in pediatrics.
I will also caution that children often tolerate anti-cancer agents much differently—and often better than adults—so it is critically important to assess toxicity and efficacy of new drugs specifically in a pediatric population. Children often have fewer medical comorbidities, and we are often able to drive the dose of a medication higher in children than adults safely and tolerably. It is also very important to include our adolescents and young adults, who have a foot in both the pediatric and adult worlds, in trials of new agents to determine their unique toxicity and activity profiles
While the biology of pediatric and adult leukemias certainly can differ, we have a lot to learn from each other across the age spectrum. Many of the successes in treatment of childhood ALL have now been translated to the care of adults with ALL. Conversely, there are many exciting new drugs for adults with genetic subsets AML that we also hope to be able to study in children.First and foremost, a deep molecular characteristic of a patient's leukemia is incredibly informative. Now that we have new technologies like next-generation sequencing, we can profile a child’s leukemia at a very sophisticated level to identify the mutations or alterations that might drive the leukemia and be amenable to targeted therapies.
We also know that how patients respond to the first month of chemotherapy is incredibly important and prognostic. This is what we call measurement of minimal residual disease assessments, which is usually done in North America by flow cytometry and in Europe by polymerase chain reaction (PCR)-based testing.
New and very sensitive next-generation PCR-based techniques are now available, so we will likely learn a lot more in the coming years about the prognostic impact of the depth of patients’ molecular responses with treatmetn.
Everyone is focused on precision medicine as a potential way to improve cure rates, as well as reduce therapy-induced toxicity. We all dream of being able to cure all of our patients with a minimum of side effects, which is often not the current reality with intensive multi-agent chemotherapy. If we can understand the alterations that drive specific leukemias and if we can find an effective way to target those mutations or target proteins the first time—such that we might prevent relapse or minimize time that a patient needs toxic chemotherapy—that is a "holy grail" of cancer medicine.
Supportive care is obviously critically important. Our patients are at high risk for life-threatening infections, which are major sources of morbidity or mortality. Preventing or minimizing those infections in children with acute leukemias is imperative. Knowing when to intervene with an alternative treatment when a patient isn't responding is also important, which is often guided by our knowledge of cancer biology and genetics and our ability to push the envelope safely and effectively in precision medicine.
Stay in touch with the literature. Listening to new developments will benefit the physician, and, of course, the patient.