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What is the efficacy of CD20 CAR-T as a salvage therapy for relapsed/refractory B-NHL with rituximab?

 Last Update: 2022-11-01
 Source: Internet
 Author: User

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CD20 is a differentiated antigen expressed by most B cells from the pre-B cell stage (progenitor B cells do not express), which makes it a powerful target for the treatment of B cell malignancies
.
Rituximab (anti-CD20 monoclonal antibody) was approved by the US Food and Drug Administration (FDA) in 1997, which was a conceptual breakthrough
in the treatment of B-cell malignancies.
As a monotherapy or in combination with other treatment regimens, it is effective in first-line treatment of B-cell non-Hodgkin lymphoma (B-NHL) and relapsed/refractory B-NHL (R/R B-NHL), which can prolong overall survival (OS), but the treatment of high-risk R/R B-NHL patients remains a significant challenge, especially those with
resistance to CD20 monoclonal antibodies.

Recently, chimeric antigen receptor (CAR) T cell therapies targeting specific tumor-associated antigens have performed well
in clinical trials.
CD19 CAR-T cell therapy can achieve a high rate of complete remission (CR), which has the potential
to cure R/R B-NHL.
However, about 30% of patients do not respond to CD19 CAR-T cell therapy or relapse rapidly after infusion of CD19 CAR-T cells, which may be due
to downregulation or loss of CD19 antigens.
Therefore, it is urgent to study other targets of CAR-T cells in the treatment of B-NHL
.

Compared to CD19, CD20 is engulfed much more
slowly after antibody binding.
Theoretically, this stability could have a positive effect on the quality of immune synapses, making CAR's triggering and T cell activation more potent.

Therefore, Chinese scholars conducted a prospective, open-label, single-center phase I study to evaluate the efficacy and safety
of CD20 CAR-T cells in R/R B-NHL patients after short-term rituximab treatment.

Study MethodsFrom
November 21, 2017 to December 1, 2021, 15 patients
were included in the study.
The inclusion criteria were: pathologic diagnosis of CD20+B-NHL and active R/R disease after at least 4 prior rituximab-based chemotherapy, and considered to be refractory to rituximab-relapse or refractory (rituximab-R/R/R, defined as disease progression or no remission at least 1 month after the end of the most recent rituximab-containing chemotherapy).

The investigators collected the patient's autologous peripheral blood mononuclear cells (PBMCs) to make CD20 CAR-T cells
.
For 3 days before the infusion, all patients received lymphocyte-depleting doses of cyclophosphamide (400-500 mg/m for 2×3 days) and fludarabine (25 mg/m^{for 2}×3 days).

CD20 CAR-T cells are then infused intravenously in a single or divided form over the course
of a day.
Patients with persistent or recurrent toxicity are discontinued, otherwise treatment will continue until post-infusion lymphoma progresses
.

The primary endpoint of the study was safety and tolerability
in all patients.
Secondary endpoints were progression-free survival (PFS) and OS
.

Study results 01 Baseline characteristics of patients

A total of 15 patients with a median age of 48 years were included, of whom 9 (60%) had relapse and 6 (40%) were refractory to rituximab-based chemotherapy
.
The median time to last rituximab to CD20 CAR-T cell infusion was 76 days (range: 31-472), and 8 patients (53.
3%) received CD20 CAR-T cell infusion
within 3 months of the last rituximab treatment.
Thirteen patients (86.
7%) received lymphocyte scavenging chemotherapy
with cyclophosphamide and fludarabine.
The baseline features of patients and the efficacy and safety results after partial infusion are presented in Table 1
.

Table 1

02Safety of CD20 CAR-T cell transfusion

Patients tolerated the regimen well and no grade 4 toxicity
was observed.
The most common grade ≥ 3 adverse events within 1 month of infusion included: leukopenia (93.
3%), anaemia (40%), and thrombocytopenia (60%)
.
Cytokine release syndrome (CRS) developed in all patients, no grade 4 CRS, and only one patient developed immune effector cell-associated neurotoxicity syndrome
.
All patients had mild chills and intermittent fever (not higher than 40 ° C and no more than 4 hours), which were relieved
by NSAIDs.
Adverse events after CD20 CAR-T cell infusion are detailed in Table 2
.

Table 2

03Efficacy evaluation

The median follow-up was 12.
4 months
.
Patients did not achieve median PFS and OS
.

The overall response rate (ORR) was 100%, with 12 patients achieving CR and 3 patients achieving partial response (PR).

At 3 months, the patient's ORR was 86.
7% and the CR rate was 46.
7%.

The median duration of CR was 10.
3 months
.

Notably, 6 patients relapsed after CD20 CAR-T cell infusion for a median of 4.
0 months
.
All patients with relapse < 3 months<b11> from the last rituximab treatment to CAR-T cell infusion.
At the end of follow-up, six (75%) of the eight patients who received rituximab-based therapy within the previous 3 months at baseline died (median PFS: 4 months, median OS: 9.
6 months) (Figure 1).

Figure 1

Conclusion of the study

This study shows that CD20 CAR-T cells are feasible and effective
in patients with rituximab-R/R CD20+B-NHL.
The patient's best-outcome ORR was 100%, median PFS and OS were not reached, and median CR lasted more than 6 months
.
Combined with the results of other previous studies, this study provides further support for CD20 CAR-T cells in the treatment of NHL patients and offers the possibility
of CD20 CAR-T cells as salvage therapy for patients with rituximab-R/R CD20+B-NHL.
The results of the study also showed that CD20 CAR-T cells were particularly effective
in patients who were treated with rituximab for at least 3 months.

References:

Qian Cheng, Jingwen Tan, Rui Liu, et al.
CD20-specific chimeric antigen receptor-expressing T cells as salvage therapy in rituximab-refractory/relapsed B-cell non-Hodgkin lymphoma.
Cytotherapy.
2022 Oct; 24(10):1026-1034.
doi: 10.
1016/j.
jcyt.
2022.
05.
001.

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