Grant Number:	3R01CA244328-01A1S1 Interpret this number
Primary Investigator:	Jim, Heather
Organization:	H. Lee Moffitt Cancer Ctr & Res Inst
Project Title:	Accelerated Aging After Chimeric Antigen Receptor T-Cell Therapy (CART): Leveraging a Novel Population of Cancer Survivors to Elucidate Mechanisms of Dementia
Fiscal Year:	2023

PROJECT SUMMARY/ABSTRACT Aggregations of misfolded proteins (e.g., tau, amyloid-b) are known to play a causal role in Alzheimer’s disease (AD) and related dementias (i.e., frontotemporal, Lewy body, vascular dementias) (ADRD), but can also be found in the postmortem brains of older adults without ADRD. Thus, a central question in AD is why cognitive pathology manifests in some individuals but not others. Animal models can provide insight into molecular mechanisms of pathogenic protein aggregation and clearance, but generalizability to humans is less clear. This supplement will build on the team’s previous collaborative research demonstrating that observational studies of cancer patients can be used to gain insights into ADRD pathobiology. Specifically, the supplement will focus on the association of accelerated cellular aging (i.e., DNA damage response, telomere shortening, cellular senescence, epigenetic aging, inflammatory senescence-associated secretory phenotype, oxidative stress, cellular metabolism) and plasma markers of neurodegeneration (e.g., amyloid-b, tau, ) with cognitive variability (i.e., an early indicator of ADRD). We will leverage data from a newly-funded study (R01CA244328) of longitudinal change in PROs and neurocognition in a novel cancer patient population, recipients of chimeric antigen receptor T-cell therapy (CAR- T) for relapsed/refractory hematologic malignancies. Over 90% of CAR-T recipients experience excessive release of pro-inflammatory cytokines (i.e., cytokine release syndrome or CRS) and/or neuroinflammation (i.e., immune effector cell neurotoxicity syndrome or ICANS) as side effects of treatment. We know of no other disease paradigm by which such extreme phenotypes of accelerated cellular aging, inflammation, and neuroinflammation can be observed in humans. As such, this supplement will provide a window into how these phenotypes are associated with human cognitive processes in vivo. Parent grant data to be leveraged by supplement includes smartphone-based real-time ecological momentary assessment (EMA) to asses cognitive variability; validated PRO questionnaires; actigraphy data regarding sleep, physical activity, and sedentary behavior; clinical information; and banked blood. New work in the supplement includes analysis of banked blood at the same time points (i.e., pre-CAR-T baseline, 3 and 12 months later), the addition of a blood sample at 7 days post-CAR-T (i.e., when systemic inflammation and neuroinflammation are expected to be greatest), and isolation and storage of T-cells at each time point to use as a resource for future scientific investigation. Goals of the supplement are as follows: 1) to examine accelerated cellular aging, neurodegeneration, and cognitive variability (i.e., an early indicator of ADRD) in the year after CAR-T therapy, 2) to determine psychosocial and behavioral ADRD risk factors associated with accelerated cellular aging, neurodegeneration, and cognitive variability in the year after CAR-T therapy, and 3) to explore the association of accelerated cellular aging with recovery and response to CAR-T. Results will provide new insights into putative mechanisms of ADRD, which will be evaluated further in ADRD patients in future studies.





None. See parent grant details.