Early Data Highlight Bispecific CAR T-Cell Therapy Potential For B-Cell Lymphomas

Author: By Shreeya Nanda, Senior medwireNews Reporter 

medwireNews: A phase I study has demonstrated the tolerability and antitumour efficacy of chimeric antigen receptor (CAR) T-cell therapy targeting both CD19 and CD20 in patients with relapsed or refractory B-cell lymphomas. 

Presenting the results at the virtual AACR Annual Meeting 2021, Sanaz Ghafouri, from the University of California Los Angeles in the USA, explained that “anti-CD19 CAR T-cell therapies are highly effective in the treatment of aggressive B-cell lymphomas and provide an alternative therapeutic option for patients who have failed to respond to conventional treatments or relapsed.” 

She noted, however, that around half of treated patients “inevitably relapse by 6 months”, primarily because of the “lack of persistence of CAR T cells and/or escape or downregulation of the CD19 antigen.” 

To address these issues, the researchers designed and evaluated a bispecific anti-CD19/CD20 CAR T-cell therapy in a first-in-human trial comprising five patients with relapsed or refractory, CD19- and CD20-positive B-cell lymphomas – three with follicular lymphoma, one with blastoid-variant mantle cell lymphoma and one with primary mediastinal B-cell lymphoma (PMBCL) – at the time of reporting. Patients were aged a median of 58 years and had received 3–4 prior lines of therapy; four of them received bridging therapy. 

Naïve memory T cells were extracted from each patient, engineered via lentiviral transduction to express the bispecific CAR T-cell product, expanded and infused into the patients at a dose of 50x106 cells (n=4) or 200x106 cells (n=1) after lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 on days 3–5 prior to infusion. 

The infusions were well tolerated, said the presenter, noting that there were no dose-limiting toxicities, infections or neurologic adverse events, including immune effector cell-associated neurotoxicity. All patients experienced cytokine release syndrome, but it was of grade 1 severity in all cases. 

Four participants experienced neutropenia of grade 3 or 4, but there were no cases of febrile neutropenia, and anaemia and thrombocytopenia of this severity each occurred in one participant. 

During a median follow-up of 13 months, four of the five patients “achieved and are maintaining ongoing complete remission”, said Sanaz Ghafouri. The one unresponsive patient had stage 4 PMBCL, which became CD19- and CD20-negative (and also lost BCL6, c-MYC and CD22) at day 14 after infusion. 

This rapid emergence of multiple mutations not under selective pressure from CAR suggests the presence of a pre-existing mutation that expanded after CAR T-cells eliminated dominant clones, she speculated. 

The median durations of response, progression-free survival and overall survival were unreached, and “all responders demonstrate ongoing CAR T-cell persistence and B-cell aplasia by data cutoff”, noted the presenting author. 

And she concluded: “Further analyses with more patients and longer follow-up are needed to confirm these promising preliminary results.” 

Discussant Philip Greenberg, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, USA, agreed that the findings “appear promising”, but stressed that these are “still very early” results and “we need a lot more data as this trial continues to accrue.” 

Reference  

Abstract CT007. Ghafouri SN, Walthers C, Roshandell M, et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T-cells for the treatment of relapsed or refractory B-cell lymphomas. AACR Annual Meeting 2021; 10–15 April.