Impact of CD19 CAR T-Cell Therapy on Measles, Mumps, Rubella and Varicella-Zoster Virus Antibody Titres in Lymphoma Patients
Authors: Foy-Stones Hayley , Gardiner Nicola , Walsh Ellen , Doherty Derek G , Mc Elligott Anthony M , Armstrong Chris , Hervig Tor , Crowley Brendan , Vandenberghe Elisabeth , Henderson Robert , Higgins Elizabeth , Bacon Larry 
Published: December 2024

Introduction
CD19-directed chimeric antigen receptor (CAR) T-cell therapy has proven efficacy in treating relapsed/refractory high-grade B-cell malignancies. However, the impact of CAR T-cell therapy on humoral immunity remains unclear. CD19 CAR T-cell therapies induce B-cell aplasia and hypogammaglobulinemia, attributed to the on-target, off-tumour targeting of the CD19 antigen on both malignant and normal B-cells. Nevertheless, studies have demonstrated the presence of B-cell-independent, long-lived plasma cells lacking CD19 after CAR T-cell therapy, contributing to sustained humoral immunity. Few studies have systematically evaluated the impact of CAR T-cell therapy on prior protection against vaccine-preventable pathogens. It is unclear from current evidence whether patients should undergo a full series of childhood vaccinations, or receive re-vaccination against a limited number of specific pathogens.
Methods
We conducted a retrospective study on 12 patients who underwent fludarabine and cyclophosphamide lymphodepletion for tisagenlecleucel (n=7) or axicabtagene ciloleucel (n=5), for treating r/r DLBCL (n=11) and tFL (n=1). The median age of the cohort was 62 years (Interquartile range [IQR]: 54-67), comprising predominately males (75%). Serum samples were collected before and at day 100±9 post-therapy for quantitative measurement of measles, mumps, rubella (MMR) and Varicella-Zoster Virus (VZV) IgG levels. We conducted a retrospective chart review of the CD4 T-cell and CD19 B-cell counts at day 100±32. Paired t-tests were performed using GraphPad (V10.1.1).
Results
At pre- and day 100 post-CAR T-cell infusion, the seroprevalence rate for measles IgG antibodies was 100%. The measles IgG positivity cut-off was &gt;16.5 IU/mL and values &gt;300 IU/mL were reported as 300 IU/mL. No statistical significance was observed between the pre and post-titres (IQR: 141.8 - 300 IU/mL vs 108.2 - 300 IU/mL).
Pre-CAR T-cell therapy, 58.3% of participants (n=7) had positive anti-mumps IgG titres, 16.7% (n=2) had equivocal titres and 25% (n=3) had negative titres. At day 100, the 9 patients who had positive anti-mumps IgG titres before therapy continued to test positive, with two participants shifting from equivocal to positive titres. The 3 patients who were negative pre-CAR-T cell therapy remained negative post-therapy. The mumps IgG positivity cut-off was &gt;11 IU/mL and values &lt;5 IU/mL were reported as 5 IU/mL. We did not observe significance between the pre- and post-titres (IQR: 8.52 - 162.0 IU/mL vs 8.01 - 141.1 IU/mL).
The seroprevalence rate of rubella IgG before CAR T-cell therapy was 100% at pre- and day 100. The rubella IgG positivity cut-off was &gt;10 IU/mL. No significant differences were observed between the pre and post-titres (IQR: 23.9 - 49.5 IU/mL vs 18.7 - 43.5 IU/mL).
VZV seroprevalence was 100% before and day 100 after CAR T-cell therapy. VZV IgG had a positivity cut-off of &gt;100 mIU/mL. The difference between pre- and post-titres (IQR: 583.8 - 1328 mIU/mL vs 543.0 - 1465 mIU/mL) did not reach statistical significance (p=0.06).
An immune reconstitution limit for CD4 T-cells of &gt;0.2 x 109/L was set, as per EBMT/JACIE/EHA guidelines. At day 100 post-CAR T-cell therapy, 42% of participants (n=5) achieved successful immune reconstitution of CD4 T-cells (IQR: 0.11 - 0.56 x 109/L) and we found no detectable levels of CD19 B-cells.
Conclusion
Our preliminary study contributes evidence supporting the persistence of prior immunity against MMR and VZV following CD19 CAR T-cell therapy. Our findings highlight that our patient cohort does not require MMR or VZV re-vaccination after CAR T-cell therapy. Based on this limited study, our findings emphasise the importance of tailoring immunisation schedules to individuals, in conformity with the EBMT/JACIE/EHA guidelines. Our institutional policy recommends assessing MMR and VZV antibody titres at pre-CAR T-cell therapy, with no re-vaccination needed for patients who exhibit positive antibody titres. Our preliminary results also showed that most patients did not have successful immune reconstitution of CD4 T-cells by day 100. Patients who exhibit negative pre-CAR T-cell antibody titres should be considered for re-vaccination post-therapy when the CD4 T-cells are &gt;0.2 x 109/L. Further research is warranted to elucidate the long-term effects of CAR T-cell therapy on immune function.