According to previous data, CD19 was a hot CAR-T treatment target, and has achieved great success in relapsed and refractory B-cell malignant blood diseases, and there are already two commercial products for the treatment of relapse fefractory B-cell acute lymphocytic leukemia (B-ALL) and relapsed refractory non-Hodgkin's lymphoma (NHL).
But not all patients benefit from CD19 CAR-T therapy. For example, most clinical data reports indicate that CD19 CAR-T has an objective response rate (ORR) of 80% and a complete response rate (CR) of approximately 50% in patients with relapsed and refractory NHL, and nearly 20% of non-responses and more than half of the patients fail to achieve sustained remission.
Why can't some non-Hodgkin's lymphoma patients benefit from it? Why is it?
Because the CD19 antigen is lost on the cancer cells of these patients, for these patients, CD19 CAR-T no longer has the ability to target and attack cancer cells, which in turn can lead to the recurrence of cancer.
How to solve this problem?
CAR-T therapy targeting CD20 may be an alternative solution.
CD20 is a human B lymphocyte restriction differentiation antigen, encoded by the MS4A1 gene (located at 11q12). This antigen is a hydrophobic 4-pass transmembrane protein with a molecular weight of approximately 35 kD, Leukocyte surface antigen Leu-16, transmembrane 4 domain subfamily A member 1 and so on. This protein function may be involved in regulating B cell activation and proliferation, and may function as a calcium ion channel.
CD20 antigen is mainly present on pre-B and mature B lymphocytes, and is expressed on most B-cell non-Hodgkin lymphoma cells, but not on stem cells, pro-B cells, normal plasma cells, or other normal organizations. Plasma cells naive and stimulated plasma cells may express CD20.
According to the expression characteristics of CD20 in the development stage of B lymphocytes, it has been selected as one of the targets for the treatment of B-cell lymphoma and leukemia, and many antibody drugs have been successfully developed based on this target.
Research progress of CD20 CAR-T therapy
1. In China
As early as the end of 2012, the Molecular Immunology Department / Biotherapy Ward of the General Hospital of the Chinese People's Liberation Army launched a clinical trial of CD20 as a target for CAR-T cell therapy for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). The study, completed in 2014 and first reported the results of a phase I clinical study in 7 patients, showed that CD20 CAR-T cells combined with a tumor-reducing pretreatment regimen can prolong tumor regression (Wang Y, et al. ClinImmunol. 2014). At the same time, the team also applied to the State Intellectual Property Office for a CD20 CAR-NKT patent (engineered CD20-targeted NKT cells and its preparation method and application, patent application number: 201410062069.7).
At the beginning of 2015, Sibeman chose to cooperate with Han Weidong, director of the Molecular Immunology Laboratory of the Life Sciences Institute of the General Hospital of the PLA, to help Professor Han Weidong develop CD20 as a representative by leveraging his successful experience in translational medicine in the biomedical field and sufficient R & D funding advantages.
Based on the phase I clinical research, Han Weidong's team launched a phase IIa clinical study of CD20 CAR-T in the treatment of relapsed and refractory NHL. The results of related studies in 11 patients were included and the results were published in "Signal Transduction and Targeted Therapy" in October 2016. Six of the 11 patients were evaluated as CR after CAR-T infusion (1 of whom was transferred from Phase 1 to Phase IIa and continued CD20 CAR-T alone), 3 were PR, and 2 were stable (SD ), 2 patients (1 PR, 1 SD) also received CR after local radiotherapy in the later stage.
In early October 2017, the Han Weidong team published a research report again in the "Signal Transduction and Targeted Therapy". Based on a retrospective review of the clinical outcomes of 16 patients who can be evaluated after the test, the article highlights that 8 patients achieved CR after CAR-T infusion (or combined local radiotherapy), with the exception of 3 patients who had recurrence. As of the end of July 2017, 5 patients were still in the state of continuous CR (1 from the stage I subjects and 4 from the stage IIa subjects), of which 1 patient continued the CR stage and it has lasted 57 months, 3 cases exceeded 40 months, and 1 case exceeded 20 months. At the same time, in July 2017, the NCI in the United States reported the long-term follow-up results of CD19-CAR-T in the treatment of NHL in Molecular Therapy, showing 5 of 7 patients with CR, 4 of whom had a continuous CR period of 56, 51, 44, 38 months.
These two studies show that CAR-T treatment can not only achieve short-term efficacy in patients with relapsed and refractory NHL, but also can obtain long-term CR efficacy in most patients who obtain CR after CAR-T. It also indicates the long-term effectiveness of CAR-T therapy for CD20 in patients with relapsed and refractory NHL.
In terms of long-term safety, Han Weidong's team also observed that patients with continuous CR after CAR-T treatment are often accompanied by longer-term B cell deficiency or low, and low immunoglobulinemia. Of the 5 long-term CR patients, except for one patient who developed grade 3 shingles infection in July after CAR-T treatment, the remaining patients can effectively prevent the occurrence of grade 3 infectious diseases through regular supplementation of gamma globulin .
2. In US
In September 2017, Fred Hutch, a top cancer center, licensed a CD20 CAR-T therapy developed by Mustang Bio to the clinic as soon as possible.
Phase I / II clinical trials with partial support from Mustang Bio will be led by Dr. Mazyar Shadman, Clinical Research, Fred Hutch. The trial will recruit approximately 30 patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL). Eligible patients will first undergo a biopsy to ensure that their tumors have a CD20 marker. The researchers expressed hope that as shown in preclinical studies, CD20 CAR-T therapy could even be more effective than CD19 CAR-T.