RT Journal Article
SR Electronic
T1 362 Defining T cell exhaustion and memory correlates of GD2 CAR T cell expansion in pediatric patients with solid tumor malignancies
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A381
OP A381
DO 10.1136/jitc-2022-SITC2022.0362
VO 10
IS Suppl 2
A1 Murty, Tara
A1 Ramakrishna, Sneha
A1 Kaczanowska, Sabina
A1 Contreras, Cristina
A1 Duault, Caroline
A1 Balasubrahmanyam, Priyanka
A1 Reynolds, Warren
A1 Baskar, Reema
A1 Jhaveri, Aashna
A1 Liu, Yang
A1 Altreuter, Jennifer
A1 Michor, Franziska
A1 Pichavant, Mina
A1 Sahaf, Bita
A1 Bendall, Sean
A1 Maecker, Holden
A1 Merchant, Melinda
A1 Mackall, Crystal
A1 Kaplan, Rosandra
YR 2022
UL http://jitc.bmj.com/content/10/Suppl_2/A381.abstract
AB Background Chimeric antigen receptor T cells (CAR-Ts) hold promising therapeutic potential for solid tumors but have yet to produce consistent durable responses in patients. A major limitation to response in solid tumors remains the lack of CAR-T expansion, persistence, and anti-tumor cytotoxicity. Identifying molecular markers that correlate with CAR-T activity could elucidate key biological pathways and T cell populations central to the success of CAR-Ts in patients.Methods A phase I trial (NCT02107963) was conducted to determine the feasibility of producing and safety of administering escalating doses of a third generation GD2 CAR-T (GD2-CAR.OX40.28.z.ICD9) in children and young adults with GD2+ solid tumors, including neuroblastoma and osteosarcoma. To understand biological differences correlating with CAR-T cell activity in patients, patient apheresis, CAR-T product, and post-treatment peripheral blood samples were analyzed for immune phenotype by mass cytometry (CyTOF), transcriptomic profile by RNA-sequencing (RNA-seq), and epigenetic landscape with Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq).Results Across 4 dose levels, 15 patients (8-28 years old) were enrolled, of which 13 patients were infused. At Day 28 following GD2 CAR-T infusion, 23.1% (3/13) of evaluable patients had progressive disease and 76.9% (10/13) had stable disease (SD), but all patients eventually progressed. Despite limited GD2-CAR-T persistence, half of the patients had expansion similar to that seen in clinically active CD19 and CD22 CAR-Ts. Since a major barrier to CAR-T efficacy is inadequate CAR-T expansion, we comprehensively evaluated patient immune profiles to identify determinants of CAR-T expansion. Good CAR-T expansion was found to be associated with increased abundance of naïve CD8+ T cells in apheresis by CyTOF. Similarly, RNAseq demonstrated enrichment of naïve memory T cell pathways in the apheresis samples of good expanders. ATACseq identified epigenetic differences in apheresis that may predict good CAR-T expansion in patients. CAR-T products across all patients, regardless of CAR-T expansion, expressed activation/exhaustion markers by CyTOF. RNAseq of CAR-T products revealed an enhanced exhaustion signature in poor compared to good expanders. At post-treatment timepoints, poor expanders demonstrated increased expression of T cell exhaustion markers.Conclusions Comprehensive analyses of patients’ apheresis, product, and post-treatment timepoints enable characterization of the T cell immune compartment before CAR-T treatment, after CAR-T manufacturing, and after CAR-T infusion. We identified phenotypic, transcriptomic, and epigenetic T cell signatures correlating with CAR-T expansion. These data suggest key mechanisms of underlying T cell biology that may contribute to CAR-T activity in pediatric solid tumors.Acknowledgements We are grateful to the study participants and their families, referring medical care teams, the faculty and staff of the NCI CCR Pediatric Oncology Branch, NCI CCR Center for Cellular Engineering, and the data managers involved with this work. Clinical trial supported in part by: Intramural Research Program, National Cancer Institute, NIH Clinical Center, National Institutes of Health. Scientific and financial support for the CIMAC-CIDC Network are provided through the National Cancer Institute (NCI) Cooperative Agreements: U24CA224331 (to the Dana-Farber Cancer Institute CIMAC), U24CA224309 (to the Stanford University CIMAC), and U24CA224316 (to the CIDC at Dana-Farber Cancer Institute). Scientific and financial support for the Partnership for Accelerating Cancer Therapies (PACT) public-private partnership (PPP).Trial Registration NCT02107963Ethics Approval The phase I study protocol conformed to the Declaration of Helsinki, Good Clinical Practice guidelines, and was approved by the NCI Institutional Review Board (14-C-0059) and the FDA. All patients or their legal guardians signed a document of informed consent indicating their understanding of the investigational nature and risks of this study.