The Multiple Myeloma Hub previously summarised activities on chimeric antigen receptor (CAR) T cells in China. Jianxiang Wang presented this topic at the 2nd European CAR T-cell Meeting, which has been summarised here. The article provided a summary of some of the investigational new drugs (IND) developed in China at the time.
At the 3rd European CAR T-cell Meeting, held virtually in February 2021, Jianxiang Wang presented information on the progression of CAR-T trials in China, specifically on reducing manufacturing times (FasTCAR) and incorporating a second target (dual CAR). He reported results from the trials evaluating the efficacy of GC022F and GC012F in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM), respectively.1
Overview of clinical research with CAR T-cells in China
- China is leading in CAR T-cell research with 265 ongoing clinical trials, mostly investigator-initiated studies, followed by 217 trials in the US
- Thirteen industries are involved in a total of 21 IND trials, including five phase II trials
- Of these five trials, three are in non-Hodgkin lymphoma (NHL), one in MM, and one in ALL
- The indications for these trials included B-cell NHL (57%), myeloma (19%), leukemia (19%), and solid tumor (5%). Almost 74% of the trials were performed with cell therapy targeting CD19
Key advantages of FasT CAR T-cells2
- FasTCARTM is a registered manufacturing platform that enables a concurrent activation and transduction of T cells with an optimized infection process that also avoids the need for ex vivo cell expansion. Altogether, it significantly shortens this part of the manufacturing process from 9−14 days to 22−36 hours
- Preclinical studies with the FasTCAR technology have demonstrated that these CAR T-cells are superior in expansion and memory cell formation and reduce T-cell exhaustion, which ultimately could lead to more effective and durable treatments than the conventional CAR T-cell therapy
- Reducing the timelines and processes could also help make these cutting-edge cell therapies a more affordable treatment option
- FasTCAR products are being evaluated as therapeutic candidates for patients with MM, B-ALL, B-NHL, and solid tumors such as ovarian or breast cancer
GC022F – CD19/CD22 FasT dual CAR-T cell in R/R B-ALL
Study design
- This is a single-center phase I clinical trial (NCT04129099) evaluating the safety and tolerance of GC022F FasT CAR T-cell product targeting CD19 and CD22 in R/R B-ALL
- Enrolled patients (n = 11) were given a single dose of GC022F as follows:
- Low dose with median of 6.25 × 104/kg (6.03−6.46 × 104/kg) (n = 2)
- Medium dose with median of 1.49 × 105/kg (1.00−1.53 × 105/kg) (n = 7)
- High dose with median of 2.28 × 105/kg (2.28−2.28 × 105/kg) (n = 2)
- Primary endpoint was the incidence and severity of adverse events, cytokine release syndrome (CRS), and neurotoxicity
Results
The data cutoff date was November 4, 2020. The median follow-up was 126 days (range, 14−279 days). There was a transduction efficiency of 29.8% (17.0−60.1%) with the optimized manufacturing process and a 100% manufacture success rate.
Patient baseline characteristics
The median bone marrow (BM) blasts was 42% (range, 0−73%). See further details on baseline characteristics in Table 1.
Table 1. Baseline characteristics*
Characteristic |
n = 11 |
---|---|
Gender (M/F) |
6/5 |
Median age, years (range) |
11 (3−48) |
BM Blasts at enrollment |
|
≥ 60%, n (%) |
2 (18.2) |
30−59%, n (%) |
4 (36.4) |
5−29%, n (%) |
1 (9.1) |
< 5%, n (%) |
4 (36.4) |
Relapsed after allo-HSCT, n |
1 |
Previous CD19 CAR-T, n |
3 |
Both CD19 CAR-T and allo-HSCT, n |
1 |
allo-HSCT, allogeneic hematopoietic stem cell transplant; BM, bone marrow; CAR-T, chimeric antigen receptor T-cell therapy. *Data from Wang J. 20211 |
Efficacy
- In four patients with BM blasts < 5%, three patients achieved minimal residual disease (MRD) negativity on Day 28, except one, who showed a persistent MRD positivity on day 14
- Of the seven patients with BM blasts > 5%, six achieved MRD negativity
- Six MRD-negative patients followed allogeneic hematopoietic stem cell transplant (allo-HSCT), and all maintained a MRD-negative complete response (CR) except one, who died of graft-versus-host disease (GvHD), and infection
- Of the other three MRD-negative CR patients without allo-HSCT, one is still MRD negative at 4 months, another relapsed at 2.6 months, and the last one had MRD-positive recurrence at 4 months
- All relapsed patients were CD19 and CD22 positive
Safety
- The most common adverse events included leukopenia, lymphopenia, thrombocytopenia, anemia, neutropenia, and fever. See Table 2 for further details.
- The median time of onset for CRS was 6 days (range, 3−19 days), and the median duration was 8 days (range, 3−11). Only one patient (9%) developed Grade ≥ 3 CRS
- Grade 1 immune effector cell-associated neurotoxicity (ICANS) was observed in only two (18%) patients
Table 2. Safety*
Adverse event (≥ 25% All Grade), n (%) |
All patients (n = 11) |
|
---|---|---|
All Grades |
Grade ≥ 3 |
|
Leukopenia |
11 (100) |
11 (100) |
Lymphopenia |
10 (91) |
10 (91) |
Thrombocytopenia |
9 (82) |
3 (27) |
Anemia |
9 (82) |
4 (36) |
Neutropenia |
8 (73) |
8 (73) |
Fever |
7 (64) |
1 (9) |
Hypocalcemia |
4 (36) |
0 (0) |
Hypokalemia |
4 (36) |
0 (0) |
Elevated ALT/AST |
3 (27)/3 (27) |
0 (0) |
ALT, alanine aminotransferase; AST, aspartate aminotransferase. *Data from Wang J. 20211 |
GC012F – BCMA/CD19 FasT dual CAR T-cell for R/R MM
Study design
- Multicentre prospective, open-label study (NCT04236011) to determine the safety and efficacy of GC012F CAR T-cells in patients diagnosed with R/R MM and with B-cell maturation antigen (BCMA) expression
- Patients received the following dose levels of GC012F in a single infusion. See Figure 1 for details
-
- Dose level 1: 1 × 105 cells/kg
- Dose level 2: 2 × 105 cells/kg
- Dose level 3: 3 × 105 cells/kg
- The primary endpoint is the incidence and severity of adverse events following GC012F infusion
Figure 1. Dose levels of GC012F*
C, cyclophosphamide; D, day; F, fludarabine; h, hours; QC, quality control.
*Adapted from Wang J. 20211
†Lymphodepletion regime was 30 mg/m2/day fludarabine and 300 mg/m2/day cyclophosphamide for 3 days.
Results
Patient baseline characteristics
- Fifteen (15/16) patients had a high-risk profile, and five (5/16) had ≥1 extramedullary plasmacytoma. See Table 3.
- Enrolled patients were heavily pretreated, with a median of 5 (2−9) prior regimens, and the vast majority (94%) were exposed to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 therapy.
Table 3. Patient baseline characteristics*
Characteristic |
n = 16 |
---|---|
Median age, years (range) |
56 (27−71) |
Male, n (%) |
10 (63) |
Type, n (%) |
|
IgG |
7 (44) |
IgA |
4 (25) |
IgD |
3 (19) |
Light chain |
2 (13) |
Median years since diagnosis (range) |
3 (1−10) |
High-risk profile†, n (%) |
15 (94) |
Double-hit‡, n (%) |
3 (19) |
Extramedullary plasmacytomas ≥ 1, n (%) |
5 (31) |
Median prior regimens of therapy, n (range) |
5 (2−9) |
Median prior lines of therapy, n (range) |
5 (2−7) |
Prior auto-SCT, n (%) |
4 (25) |
Triple exposed§,ǁ, n (%) |
15 (94) |
PI refractory |
15 (94) |
IMiD refractory |
14 (88) |
Anti-CD38 refractory |
4 (25) |
Penta exposedǁ, n (%) |
10 (63) |
Primary refractory, n (%) |
3 (19) |
Refractory to last therapy, n (%) |
12 (75) |
Auto-SCT, autologous hematopoietic stem-cell; IMiD, immunomodulatory drugs; PI, proteasome inhibitor. *Data from Wang J. 20211 †By mSMART 3.0. ‡By presence of two del(17p), t(14;16), t(14,20), gain 1q, or p53 mutation. §PI, IMiD, and any other therapies including anti-CD38 antibody. ǁ≥1 PI (two PIs, ixazomib and bortezomib, were approved in China), ≥1 IMiDs (only lenalidomide is approved for MM in China), and ≥3 other antimyeloma drugs of any other class. |
Efficacy
- The median follow-up was 7.3 months (range, 1−10 months). Only one of the 16 patients enrolled did not achieve a response to treatment
- ORR was achieved in 15 out of 16 patients (94%) with a very good partial response (VGPR) or better
- CR or stringent CR (sCR) was achieved in nine out of 16 patients (56%)
- Six patients out of six (100%) in Dose Level 3 achieved sCR
- Median duration of response (DoR) has not been achieved yet
- All evaluable patients were MRD negative at a minimum of 10-4 sensitivity by next-generation flow at 3 months (n = 11) and 6 months (n = 10)
Safety
- The most common adverse events (AEs) included lymphopenia, neutropenia, leukopenia, and thrombocytopenia. See Table 4
- Two patients (12%) experienced Grade 3 CRS. The remaining 14 patients (88%) showed Grade 1-2 CRS
- None of the patients developed ICANS
Table 4. Safety*
Adverse event |
All Grades, n (%) |
Grade ≥3, n (%) |
---|---|---|
Hematologic TEAE (≥25% All grades) |
||
Lymphopenia |
13 (81) |
13 (81) |
Neutropenia |
13 (81) |
13 (81) |
Leukopenia |
11 (69) |
11 (69) |
Thrombocytopenia |
11 (69) |
11 (69) |
Anemia |
8 (50) |
7 (44) |
Hypoalbuminemia |
8 (50) |
0 (0) |
Nonhematologic TEAE (≥25% All grades) |
||
LDH increase |
11 (69) |
0 (0) |
AST increase |
7 (44) |
5 (31) |
Diarrhea |
4 (25) |
0 (0) |
Lower respiratory tract infection |
3 (19) |
3 (19) |
AST, aspartate aminotransferase; LDH, lactate dehydrogenase; TEAE, treatment-emergent adverse event. *Data from Wang J. 20211 |
Conclusion
The preclinical findings suggest that the FasTCAR platform can successfully manufacture the necessary product in 1 day with younger, less exhausted T cells and improved efficacy than conventional dual CAR-T cells.
Early clinical data for the CD19/CD22 FasT dual CAR T-cell GC022F, shows a favorable safety profile and good efficacy in treating R/R B-ALL patients.
Preliminary clinical data with the BCMA/CD19 FasT dual CAR T-cell GC012F, also showed a favorable safety profile, and promising efficacy in treating relapsed MM refractory compared with the currently available therapies.
Further studies with a larger sample size and longer-term follow-up are needed with both FasT dual CAR T-cell products.