Advances of cell therapies in China: Reducing manufacturing time with FasT dual CAR T-cells

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

• FasTCAR^TM 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*

allo-HSCT, allogeneic hematopoietic stem cell transplant; BM, bone marrow; CAR-T, chimeric antigen receptor T-cell therapy. *Data from Wang J. 20211
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

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*

ALT, alanine aminotransferase; AST, aspartate aminotransferase. *Data from Wang J. 20211
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)

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

C, cyclophosphamide; D, day; F, fludarabine; h, hours; QC, quality control.
*Adapted from Wang J. 2021^1
†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*

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.
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)

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*

AST, aspartate aminotransferase; LDH, lactate dehydrogenase; TEAE, treatment-emergent adverse event. *Data from Wang J. 20211
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)

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.