Date: 12th October 2020
There are currently only three CAR T cells therapeutic agents approved by the Food and Drug Administration (FDA), and they are all for patients with B cell malignancies. Furthermore, all of them target CD19, an antigen highly restricted to the surface of B-cells, making it an ideal target against haematological malignancies. However, despite positive outcomes, relapse with CD19− disease remains a challenge. Now, scientists report the use of bispecific anti-CD20, anti-CD19 CAR T cells for relapsed, refractory B cell malignancies in a phase I, first-in-the-world, double targeted CAR T cell therapy.
Long-term progression-free survival (PFS) with anti-CD19 CAR T cell products ranges from 30–40% for aggressive B cell non-Hodgkin lymphoma (NHL). For those patients that relapse, ~30% have been revealed to be CD19-, suggesting that the single targeting of CD19 antigen may not be the most effective targeting strategy.
Simultaneous targeting of more than one B cell antigen has previously been proposed, and preclinical trials in mice have demonstrated that tandem CD19/CD20 CAR T cells proved both effective and less toxic than T cells expressing single CARs. Now scientists, from the Medical College of Wisconsin, US, and Lentigen, US, have reported promising clinical outcomes of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells in a phase 1 dose escalation and expansion trial, for relapsed B cell malignancies.
The team started by recruiting participants with failed prior treatments and whose cancer had relapsed; this accounted for 26 patients with B cell NHL or CLL (chronic lymphocytic leukemia). These patients underwent apheresis (a medical procedure to remove and separate blood) for LV20.19 CAR T cell production, although 4 patients did not meet their target doses during CAR T cell production. Of the 22 remaining patients infused with LV20.19, the overall response rate (ORR) at day 28 was 82% (18 of 22), with 14 patients (64%) achieving a complete remission. Patients who had received the highest dose of LV20.19 achieved a complete remission of 75% at day 28. Six months later, more than half of the patients’ cancer remained in remission, suggesting the dual-targeted CAR T cells were feasible as a therapeutic agent.
In terms of CAR T cell specific toxicities, 64% of patients experienced cytokine release syndrome (CRS), with grade 3–4 CRS present only 5% of patients. Neurotoxicity was present in 32% of patients, with grade 3–4 neurotoxicity in 14% of patients. All patients had full neurological recovery, overall demonstrating the therapeutic safety of the system.
Conclusions and future applications
The team here have presented the safety of treatment with dual-targeting CAR T cells in relapsed, refractory B cell malignancies and report clinical outcomes of a first-in-human bispecific, tandem anti-CD20, anti-CD19 CAR T cell product. The response rates were encouraging, especially among patients who received a non-cryopreserved infusion at the highest dose. The data suggest that this approach has the potential to improve clinical outcomes by diminishing the role of antigen escape as a mechanism of resistance.
Now a multi-institutional phase II trial is being developed to determine the true efficacy and understand how the nuances of the treatment process can result in excellent outcomes for a larger subset of patients.
From a wider perspective, the introduction of another target for CAR T cell therapy offers a great advancement in this technology. We have recently seen scientists genetically engineer an oncolytic virus to target tumour cells to force these cells to express CD19 protein on their cell surface, in order to be able to use CD19-directed CAR T cells to recognise and attack these solid tumours.. The addition of CD20 as an immunotherapy target will offer a new scope to the development of innovative alternatives to current immunotherapies, and will hopefully drive improved clinical outcomes. The data from the phase II trial for LV20.19 will be much anticipated, and will hope to show evidence of prolonged remission.
For more information please see the press release from the Medical College of Wisconsin
Shah, N. N., B. D. Johnson, D. Schneider, F. Zhu, A. Szabo, C. A. Keever-Taylor, W. Krueger, A. A. Worden, M. J. Kadan, S. Yim, A. Cunningham, M. Hamadani, T. S. Fenske, B. Dropulić, R. Orentas and P. Hari (2020). “Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial.” Nature Medicine 26(10): 1569-1575.
https://doi.org/10.1038/s41591-020-1081-3
