Infant acute lymphoblastic leukemia (ALL) represents one of the most challenging hematologic malignancies in pediatric oncology, characterized by aggressive biology, rapid relapse, and severe vulnerability to cytotoxic regimens. While chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell leukemias, sustaining durable long-term remissions remains difficult in this youngest cohort. In this interview, Lisa Niswander, MD, PhD, Physician-Scientist at Roswell Park Comprehensive Cancer Center and the Roswell Park Golisano Children’s Buffalo Cancer and Blood Disorders Program, outlines an innovative approach combining CAR T-cell immunotherapy with targeted menin inhibitors for infants harboring KMT2A gene rearrangements, explaining the distinct biological mechanisms driving infant leukemia, preclinical synergies between cellular therapy and targeted agents, and the translational infrastructure accelerating novel pediatric clinical trials.

The Distinct Biology and Clinical Challenges of Infant ALL

Leukemia diagnosed in children under 12 months of age is biologically distinct from disease presenting in older pediatric cohorts or adult populations. A key hallmark of this age group is the prevalence of a single oncogenic driver: the KMT2A gene rearrangement, seen in approximately 80% of infants with ALL. Dr. Niswander underscored this unique incidence: “There's really no other point in the age spectrum, in either pediatric or adult patients, where we can say that the vast majority of patients have a single genetic change that is the driver of their leukemia.”

This genetic fusion protein drives a particularly aggressive clinical phenotype that frequently fails to respond durably to conventional chemotherapy. While standard regimens may initially induce remission, the leukemia cells rapidly acquire treatment resistance, leading to frequent relapses. “What we know about KMT2A-rearranged disease in the infant population is that it can very quickly become resistant to our traditional chemotherapies,” Dr. Niswander noted, pointing out that “while our treatments may work initially, the vast majority of patients will unfortunately relapse eventually.” Because these infants are undergoing critical developmental milestones, the high doses of cytotoxic chemotherapies traditionally required to control the disease impose significant systemic toxicities and long-term sequelae, underscoring the urgent necessity for more targeted, less toxic alternatives.

Pairing CAR T Cells With Targeted Menin Inhibition

To overcome therapeutic resistance without introducing additional off-target systemic toxicities, Dr. Niswander’s laboratory is investigating multimodal treatment regimens that combine CAR T-cell therapy with small-molecule targeted inhibitors. While commercial CD19-directed CAR T-cell products demonstrate remarkable initial remission rates, roughly half of treated patients eventually experience disease recurrence. Rather than relying on cytotoxic combinations, combining living immunotherapies with targeted small molecules demands a nuanced understanding of cellular interactions. As Dr. Niswander highlighted, “When we're thinking about a living therapy like CAR T cells, which rely on a patient's T cells remaining alive and functional in the body, we have to be a lot more careful about what medicines we combine with them and fully understand at a mechanistic level what is happening to those T cells.”

Her investigative group is concentrating specifically on menin inhibitors, a novel class of orally bioavailable targeted agents that directly disrupt the leukemogenic oncogenic protein complex driven by the KMT2A fusion. In preclinical models of infant ALL, this rational combination has yielded striking synergistic efficacy. “We have preliminarily found in our preclinical infant ALL models that combining CAR T cells with menin inhibitors actually works better than either therapy alone,” Dr. Niswander stated. Ongoing research is deciphering whether menin inhibitors simply enhance direct leukemic cell killing or also exert positive extrinsic effects that enhance CAR T-cell persistence, metabolic fitness, and cytotoxicity.

Translational Acceleration and Pediatric Clinical Translation

Moving novel therapeutic combinations into infant patient populations requires exceptionally high preclinical safety hurdles. However, because both CAR T-cell therapies and menin inhibitors are already advancing through clinical utilization independently, the translational barrier toward prospective combination trials may be reduced. Dr. Niswander noted that “the bar is very high in pediatrics, and especially in infants, with understanding the mechanics and the safety before you move forward into bringing these therapies to patients.” However, she added that because both therapeutic modalities are already being used in clinic, establishing safety and biological synergy will help streamline clinical trial activation.

This translational progression is substantially supported by institutional resources at Roswell Park, including its on-site Good Manufacturing Practice (GMP) cell manufacturing facility, known as the GEM facility. Having institutional cell manufacturing directly adjacent to the discovery laboratory accelerates the development and refining of custom cellular therapies while fostering close multidisciplinary dialogue.

Emphasizing the value of this environment, Dr. Niswander concluded that pediatric oncology demands treatments specifically tailored to unique developmental physiology rather than adapted adult protocols, stating that “the importance of understanding how these therapies work in pediatric patients—who are not just little adults—is something that we as a field are always trying to push forward and understand.”

Conclusion

Infants diagnosed with KMT2A-rearranged ALL face high rates of therapeutic resistance and severe toxicities from standard cytotoxic chemotherapy regimens. Combining CD19-directed CAR T cells with targeted menin inhibitors offers a biologically targeted strategy designed to eliminate leukemic clones, prevent disease recurrence, and minimize developmental toxicities. By elucidating the underlying mechanisms governing how targeted therapies influence living cellular products and utilizing specialized institutional manufacturing infrastructure, researchers are working to translate rational combination regimens into curative, prospective clinical options for this vulnerable patient population.

Key Takeaways

Approximately 80% of infants under 12 months with ALL harbor a KMT2A gene rearrangement, a unique oncogenic driver associated with high rates of chemotherapy resistance and relapse.
While CD19 CAR T-cell therapy induces high initial remission rates in pediatric ALL, durable long-term control remains difficult, with roughly half of patients ultimately relapsing.
Preclinical studies demonstrate that combining CAR T-cell therapy with targeted menin inhibitors improves anti-leukemic efficacy compared to either therapeutic agent administered alone.
Co-administering small-molecule inhibitors with living cellular therapies requires precise mechanistic evaluation to ensure targeted compounds do not impair T-cell viability, function, or persistence.
On-site cellular manufacturing facilities foster seamless collaboration between laboratory discovery and translational medicine, accelerating the safe clinical development of novel pediatric protocols.

About Dr. Niswander

Lisa Niswander, MD, PhD, is a Physician-Scientist at Roswell Park Comprehensive Cancer Center and the Roswell Park Golisano Children’s Buffalo Cancer and Blood Disorders Program. She specializes in the treatment of children with acute leukemias. Dr. Niswander’s research program is focused on preclinical development of molecularly-targeted therapies and cellular immunotherapies for high-risk pediatric leukemias, particularly on improving long-term efficacy of CAR T-cell immunotherapy through combinatorial approaches that target key biologic vulnerabilities.

A New Combination Approach to KMT2A-Rearranged Infant Leukemia