New cell immunotherapy——STAR-T for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia

Although chimeric antigen receptor T (CAR-T) cellular immunotherapy is effective in treating malignant tumors of the hematopoietic system, there is still a need to further improve the safety of this therapy and extend its duration after remission
.

The researchers designed a T cell receptor (TCR) complex that combines the antigen recognition specificity of immunoglobulin and the recombination of the TCR signal domain, called "Synthetic Recombinant T Cell Receptor-Antigen Receptor (STAR)
.
"
STAR targeting CD19 has been shown to have the antigen specificity of immunoglobulin molecules and activate T cells in a large number of ways that do not depend on MHC when encountering antigens
.

Mononuclear cells were obtained from the peripheral blood of healthy donors and patients for pre-clinical and clinical research, and STAR was used to transduce T cells with lentiviral vectors
.

A mouse model of leukemia xenotransplantation was used to evaluate the anti-tumor function of STAR-T cells
.

In preclinical studies, STAR-T cells targeting CD19 showed strong tumor-specific cytotoxicity in vitro and in vivo
.

The addition of costimulatory molecule OX40 (STAR-OX40) to STAR further enhanced the proliferation ability of tumor-targeted T cells in xenograft mouse models and extended their duration in the model
.

In addition, the researchers demonstrated that STAR-OX40-T cells targeting CD19 have better anti-leukemia activity than CAR-T cells in leukemia mouse models
.

A human phase I clinical trial confirmed the safety and efficacy of STAR-OX40-T cells in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL)
.

From December 2019 to June 2020, the study included 10 refractory and relapsed B-ALL patients, 10 males and 8 females.
Their median age was 22.
5 years (range: 6-68)
.

All patients received a 3-day intravenous fludarabine (25 mg/m2/d) and cyclophosphamide (250 mg/m2/d) chemotherapy regimen, followed by a STAR-T cell infusion
.

When patients reach complete remission (CR), they can choose whether to undergo Allo-HSCT consolidation therapy
.

In terms of efficacy, two weeks after STAR-OX40-T cell infusion, 18/18 (100%) patients achieved CR and were negative for minimal residual disease (MRD)
.

With a median follow-up of 105 days (range: 57-216 days), 11 (61.
1%) patients in the STAR-OX40-T cell and Allo-HSCT consolidation treatment group have survived without recurrence
.

Among the 7 patients who did not receive Allo-HSCT, 1 patient had a relapse
.

In terms of safety, 10 patients (55.
6%) developed mild cytokine release syndrome (CRS), and 2 patients developed grade III neurotoxicity
.

In terms of proliferation ability, after STAR-T cell infusion, CD19 STAR-T cells in peripheral blood were tracked by qPCR and FCM and found that no matter what the dose of STAR-OX40-T cell infusion, we have observed that it is in patients.
High proliferation rate in the body, reaching a peak level on the 10th day (7-14 days) of the median.
After 6 months of treatment, it can still be detected in peripheral blood with an average of 4.
9×104 (0.
104-175×104) copies/mg Genomic DNA
.

Based on the success of targeting CD19 STAR-T cells in the treatment of B-ALL and considering the persistence of alleviation and antigen escape, the researchers further studied the efficacy of CD19/CD20 dual-target STAR-T cells
.

The researchers used dual-target STAR lentiviral vectors to transduce T cells, and also used a leukemia xenograft mouse model to evaluate the anti-tumor activity of dual-target STAR-T
.

In preclinical studies, compared with CD19/CD20 CAR-T in the 28z group or CD19/CD20 CAR-T in the CD19 CAR-T group, dual-target STAR-T can produce stronger results in leukemia xenotransplantation mouse models The anti-leukemia activity
.

In the clinical trial, the investigators included 10 relapsed/refractory B-ALL patients with CD19+ or CD19/CD20+, and the median age of the patients was 23 years (range: 11-55)
.

Except for the failure of the preparation of STAR-T cells in 1 patient, all 9 patients received a single infusion of dual target STAR-T with a median dose of 1×106/kg (6 cases were 1×106/kg, 3 For example, 2×106/kg)
.

In terms of efficacy, 8 patients (88.
9%) achieved MRD-negative CR two weeks after dual-target STAR-T treatment
.

One patient with central nervous system leukemia did not achieve remission
.

The median follow-up was 301 days (range: 14-387).
After reaching CR, 6 patients received Allo-HSCT consolidation therapy at a median of 58 (45-67) days after dual-target STAR-T infusion, and 2 patients The patients relapsed on 141 and 186 days after Allo-HSCT, 1 patient died of infection on day 122, and the remaining 3 patients were still in disease-free survival after a median follow-up of 381 (332-387) days
.

For the two patients who did not receive Allo-HSCT, one patient became MRD positive on the 30th day and died on the 45th day, and the other patient became MRD positive on the 218th day and withdrew from the clinical trial
.

In terms of safety, 7 (77.
8%) patients developed grade I CRS, and 3 patients developed neurotoxicity (2 grade I and 1 grade III)
.

In addition, in terms of proliferation ability, the proliferation of dual-target STAR-T cells in vivo is good, reaching a peak on the 10th day (7-14 days), and the number of copies in peripheral blood is 6.
35×105/mg genomic DNA
.

In summary, this new T cell, which combines the TCR construct with the variable region of scFv and contains the original signal characteristics of TCR and CAR capability, shows a good prospect in anti-leukemia activity
.

The first human clinical study showed that for the treatment of B-ALL, STAR-OX40-T cell therapy is a safe and promising treatment method
.

Long-term follow-up of these patients and even larger-scale clinical studies are necessary
.

Not only that, given that this is a CAR based on the TCR complex, STAR-OX40-T cell therapy may continue to develop in the future and contribute to the treatment of solid tumors
.

Reference source: Peihua Lu.
2021 SOHO.
EXABS-162-ALL.
Stamp "read the original text", we make progress together