Oral Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2024

Patient Age is a Distinct Variable that Impacts CAR T Cell Generation, and Age-Related Biomarkers Can Predict Manufacturing Outcomes (#8)

Palak H Mehta 1 , Shivali S Chinni 1 , Patrick Leung 1 , Aaron J Harrison 2 , Hannah Hughes-Parry 3 4 , Misty R Jenkins 3 4 5 , Michael H Kershaw 2 , Anthony Jaworowski 1 6 7 , Clare Y Slaney 2 , Rachel M Koldej 8 9 , David S Ritchie 8 9 , Kylie M Quinn 1 6
  1. School of Health and Biomedical Sciences , Royal Melbourne University Of Technology, Melbourne, VIC, Australia
  2. Immune Innovation Laboratory , Peter MacCallum Cancer Foundation, Melbourne, VIC, Australia
  3. Immunology Division, Walter and Eliza Hall Institute , Melbourne, VIC, Australia
  4. Department of Medical Biology , University of Melbourne, Melbourne, VIC, Australia
  5. Institute of Molecular Science, La Trobe University, Melbourne, VIC, Australia
  6. Department of Biochemistry, Biomedicine Discovery Institute, Monash University , Melbourne, VIC, Australia
  7. Burnet Institute , Melbourne, VIC, Australia
  8. Department of Medicine, University of Melbourne , Melbourne, VIC, Australia
  9. Australian Cancer Research Foundation Translational Laboratory , Royal Melbourne Hospital , Melbourne, VIC, Australia

Chimeric antigen receptor (CAR) T cell therapy (CTT) is a ground-breaking, T cell-based treatment for haematological cancers. It is well known that advanced age undermines T cell activation and function, which could compromise CAR T cell generation and function, but age has not been extensively examined as an independent variable for CTT. Our study therefore aims to dissect the impact of age vs malignancy on CAR T cell generation and test whether age-related markers can predict CAR T cell product characteristics. To examine this, PBMCs from younger (20-30 years old (yo)) and older (60+ yo) healthy donors, and multiple myeloma (MM) patients (60+ yo) were used to generate CAR T cells, with the evaluation of yield, phenotype, and function. Matching PBMCs were also assessed for age-related markers relating to T cell differentiation, senescence, exhaustion and metabolic dysfunction. Correlative analyses were performed with markers to predict specific CAR T cell product features. Both older and MM donors had more differentiated T cells, and both yielded fewer but more differentiated, more cytotoxic CAR T cells expressing more IFNg, CD107a and granzyme B than young donors. Older and MM donors did not differ in expression of differentiation or senescence markers or in PD-1 expression, but LAG3 expression and metabolic deficits were specifically increased in MM donors. Markers of T cell differentiation were the most predictive for CAR T cell yield, phenotype and cytotoxicity, although a marker of senescence (CD57) was most predictive for cytokine production. Our findings underscore that patient age is a major variable that shapes CAR T cell yield, phenotype and cytotoxicity, and we hypothesise that it is likely to impact CTT efficacy. Age-related markers, particularly markers of T cell differentiation, are predictive of CAR T cell generation outcomes and could support the design of age-optimised CTT treatment plans.