Research progress of dual-target CAR-T therapy targeting CD19 and CD22 from an international perspective in patients with ALL

Targeting CD19 chimeric antigen receptor T cells (CAR-T) has changed the treatment landscape
for children and adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL).
Many clinical trials targeting CD19 CAR-T products have had good efficacy results, with a response rate of 62%-97%.

However, relapse remains an obstacle
to long-term cure for most patients.
The two main mechanisms of recurrence after CAR-T therapy are targeted antigen modulation and CAR-T cell depletion
.
In order to overcome antigen modulation and delay CAR-T cell depletion, researchers proposed CAR-T therapy strategies
targeting multiple antigens.
In view of the significant anti-leukemia effect of targeting CD22 CAR-T cells, targeting CD19 and CD22 dual-target CAR-T therapy has become a key area
of clinical exploration.

• Progress of the AUTO3 trial in the UK

The UK AUTO3 trial (NCT03289455) explored the efficacy
of dual-target CAR-T therapy targeting CD19 and CD22 in children and young adults with B-ALL.
In this trial, 13/15 (86%) patients achieved a complete response (CR), of which 9 relapsed; The 12-month event-free survival (EFS) and overall survival (OS) rates were 32% and 60%,
respectively.
The investigators of the trial considered the poor long-term persistence of CAR-T cells as the main reason for treatment failure, but antigen modulation also played a role
.

• Trial progress at Stanford University and the National Cancer Institute

Stanford University and the National Cancer Institute conducted two phase 1 dose-escalation clinical trials
targeting CD19 and CD22 dual-target CAR-T products in adults (NCT03233854) and pediatric patients (NCT03448393) of B-ALL or non-Hodgkin lymphoma (NHL).
In trials in adult patients, 15/17 (88%) patients with B-ALL achieved CR; Of these, 10 cases relapsed; The median follow-up was 9.
3 months and median progression-free survival (PFS) was 5.
8 months
.
In the pediatric trial, 12/20 (60%) children and young adults with B-ALL achieved CR, of which 10 were CAR-T naïve patients; The median follow-up was 23.
5 months, and 4 patients experienced disease recurrence; median recurrence-free survival (RFS) was not achieved
.
Relapse in both trials was associated with
the absence or reduction of CD19 antigen.

• Trial progress at the Seattle Children's Institute (SCRI).
  

SCRI conducted the PLAT-05 trial (NCT03330691), which also explored the efficacy
of dual-target CAR-T therapy targeting CD19 and CD22 in children and young adults with B-ALL.
Preliminary results from the trial suggested that the drug had limited activity targeting CD22, and the researchers subsequently redesigned the chimeric antigen receptor (CAR)
targeting CD22.
In early data, the CR rate in the first 18 patients was 89%.

Although the CAR targeting CD19 and CD22 is relatively separated, the implantation of this CAR-T product is more conducive to the role
of CAR targeting CD22.
The product was subsequently further optimized to enhance the CAR activity targeting CD19, but the CAR activity targeting CD22 was still stronger
.
The effect of lower targeted CD19 CAR activity on remission durability requires studies and longer-term follow-up
.

• Experimental progress at the University of Pennsylvania, USA

Researchers at the University of Pennsylvania developed two separate CAR-T products: a CAR-T product targeting CD22 (CART22-65s) and a humanized CAR-T product targeting CD19 (huCART19), and conducted a Phase 1 clinical trial
of a combined protocol.
The two CAR-T products were prepared by one leukapheresis and returned to the patient
within 3 days.
Of the 13 patients with B-ALL, 11 had an assessable response at day 28 and 11 achieved CR.

With a median follow-up of 11.
8 months, 10 patients maintained CR without further treatment, and one patient received replacement therapy
due to detection of minimal residual disease (MRD) by next-generation sequencing.
Quantitative PCR data indicate that CART22-65s and huCART19 have different expansion peaks, which are also associated
with cytokine release syndromes caused by each.
The longer durability of the two CAR-T products is also associated
with long-term remission in a subset of patients.