A new study suggests that the presence of anti-murine CD19-targeted chimeric antigen receptor (anti-mCAR19) antibodies does not affect the activity of tisagenlecleucel in patients being treated for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) or diffuse large B-cell lymphoma (DLBCL). The study results were published in the journal Blood Advances.
The researchers indicated that while CAR T-cell therapies represent an important tool in treatment of R/R B-cell malignancies, the possible presence of anti-mCAR19 antibodies, and potential effects they may exert, are not well understood.
In this multinational study, patient data were pooled from 3 clinical trials. Patients with r/r B-ALL were included from the ELIANA trial (ClinicalTrials.gov Identifier: NCT02435849) and the ENSIGN trial (ClinicalTrials.gov Identifier: NCT02228096). Patients with r/r DLBCL were included from the JULIET trial (ClinicalTrials.gov Identifier: NCT02445248). The B-ALL population included pediatric and young adult patients, while the DLBCL population included only adult patients.
The researchers used flow cytometry to assess the presence of serum anti-mCAR19 antibodies both before and after tisagenlecleucel treatment, with pretreatment samples being obtained after lymphodepletion. The researchers then evaluated T-cell responses to pools of mCAR19 peptides through assays involving intracellular staining and flow cytometric analysis of interferon-gamma production. They also examined any associations with patient outcomes.
This study evaluated 143 patients with r/r B-ALL and 115 patients with r/r DLBCL. Prior to treatment, 81% of the patients with B-ALL and 94% of the patients with DLBCL demonstrated serum anti-mCAR19 antibodies. The level of anti-mCAR19 antibodies after treatment was higher than at baseline in 42% of patients with B-ALL and in 9% of patients with DLBCL.
However, the presence of anti-mCAR19 antibodies before or after treatment did not appear to influence tisagenlecleucel expansion or persistence in an analysis of the B-ALL group. The DLBCL population did not have enough posttreatment antibodies to enable all analyses.
In analyses involving mCAR19 peptides, nearly all patients showed T-cell responses of less than 1% to these peptides. This amounted to 142 of the patients with B-ALL and 107 patients with DLBCL showing this outcome.
Efficacy and safety outcomes with tisagenlecleucel also seemed unaffected by anti-mCAR19 antibodies. Day-28 responses to tisagenlecleucel were not impacted by the presence of anti-mCAR19 antibodies before or after treatment for patients with B-ALL. Patients with B-ALL showed day-28 overall response rates of 77% for the overall population and 85% for patients within the 90th percentile of median fluorescence intensity for anti-mCAR19 antibodies. Responses at 3 months in patients with DLBCL appeared to show no impacts by these antibodies. In terms of safety concerns, severity of cytokine release syndrome and neurologic adverse events did not appear to be related to levels of anti-mCAR19 antibodies in either B-ALL or DLBCL populations.
“In conclusion, data from clinical trials of tisagenlecleucel in patients with r/r B-ALL and in patients with r/r DLBCL demonstrated that the presence of preexisting anti-mCAR19 antibodies or the development of posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, efficacy, or safety,” the study investigators concluded in their report.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Mueller KT, Grupp SA, Maude SL, et al. Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Blood Adv. 2021;5(23):4980-4991. doi:10.1182/bloodadvances.2020003844