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Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) is a difficult to treat disease with poor prognosis. Two anti-CD19 chimeric antigen receptor (CAR) T-cell products have already been approved for the treatment of R/R B-ALL. However, investigators put an effort to further improve the clinical activity and safety of CAR T-cell therapies for the treatment of these patients.
During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, three different talks were presented on novel CAR T-cell products targeting CD22 for heavily pretreated patients with B-ALL, most of who had received prior anti-CD19 therapy. In this summary article, we assess these products for their tolerability and promising clinical activity that would indicate a potential to investigate them in larger trials.
Peihua Lu presented preclinical and phase I results of an anti-CD19/CD22 dual CAR T-cell product (GC022F) which was manufactured using the FasTCARTM platform.1 Autologous CAR T-cells were generated within 24 hours and frozen after manufacturing at the site, and then subjected to quality control testing (additional ~5 days before release).
When comparing GC022F with a conventionally produced dual CAR T-cell product (manufacturing process time of 9–14 days) in preclinical settings, FasT dual CAR T-cell was associated with higher expansion and less exhaustion, higher anti-leukemia activity, and prolonged overall survival (OS) in mouse models.
A total of 11 patients with a median age of 11 years (range 3–48 years, 10 children, 1 adult) were treated in a phase I dose escalation trial (NCT04129099). Three patients had previously received CD19 CAR T-cell therapy, with one of these patients having relapsed after both anti-CD19 CAR T-cell therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nearly half of the patients (42%) had increased bone marrow (BM) blasts at enrollment. Genetic mutations included BCR-ABL1, IKZF1, E2A, PBX1, and others. No TP53 mutation was recorded.
FasT dual CAR T-cell therapy was given as a single infusion at different dose levels ranging from a median CART-cell count of 0.625 × 105 per kg to 2.28 × 105 per kg. Manufacturing success rate was 100% with a median transduction efficiency of 29.8% (range, 17.0–60.1%). Median follow-up was 126 days (range, 14–279).
All patients experienced Grade ≥ 3 leukopenia followed by Grade ≥ 3 lymphopenia (91%), neutropenia (73%), anemia (36%), and thrombocytopenia (27%) mostly due to the fludarabine-cyclophosphamide conditioning regimen. Seven patients had cytokine release syndrome (CRS) with a median time of onset of 6 days (range, 3–19) and a median duration of 8 days (range, 3–11). One Grade ≥ 3 CRS was reported. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in two patients; both were Grade 1 in severity.
All dose levels showed a good degree of expansion and persistence. FasTCAR-T therapy was associated with minimal residual disease (MRD)-negativity (MRD−) at Day 28 in nine patients. Six patients underwent consolidative allo-HSCT, maintaining their MRD− status. However, one patient died from complications of graft-versus-host disease (GvHD) and infection. Among those who did not undergo allo-HSCT, one out of four patients maintained the MRD− status at Month 4, while the other patients relapsed within 1.5–4 months after transfusion. Among three patients with prior CD19 CAR-T treatment,
Overall, this study indicated that anti-CD19/CD22 dual CAR T-cell therapy (GC022F) can be manufactured in one day and may produce CAR T-cells with a less mature and exhausted phenotype. Early clinical data suggest that this approach is associated with acceptable safety and promising efficacy in patients with R/R B-ALL.
Nitin Jain presented preliminary results of the phase I BALLI-01 trial (NCT04150497), which investigated the safety, maximum tolerated dose (MTD), and efficacy obtained in five adult patients with R/R CD22+ B-ALL treated with UCART22.2
UCART22 is an allogeneic off-the-shelf T-cell product that targets CD22 and is manufactured from non-HLA matched healthy donor cells. These CAR T-cells have been further modified using transcription activator-like effector nuclease (TALEN)-induced mutations to prevent expression of the T-cell receptor alpha constant (TRAC) and CD52 genes, to reduce the risk of GvHD and eliminate sensitivity to alemtuzumab. Preclinical experiments showed strong antitumor activity in association with a prolonged survival of immunocompromised mice engrafted with CD22+ Burkitt lymphoma cells.
The BALLI-01 study included patients with B-ALL and blast CD22 expression of ≥90% who received ≥1 standard chemotherapy and salvage therapy. Endpoints were safety, tolerability, MTD, recommended phase 2 dose (RP2D), response rates, cell expansion and persistence, and immune reconstitution.
A total of five patients with a median age of 24 years (range, 22–52) received lymphodepletion with fludarabine + cyclophosphamide (FC) followed by two UCART22 dose levels: DL1, 1 × 105 cells/kg (n = 3); or DL2, 1 × 106 cells/kg (n = 2). Median number of prior therapies was 3 (range, 2–6), median percentage of BM blasts was 35%. Four patients had received prior anti-CD19 therapy, and two patients received prior anti-CD22 therapy.
Dose limiting toxicity, ICANS, or GvHD were not reported. There were three Grade 1 or 2 CRS events. Grade ≥ 3 treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) were not considered related to UCART22 infusion. Treatment discontinuation due to a UCART22-related TEAE did not occur.
Two out of five patients achieved a CR with incomplete hematologic recovery (CRi), and one of them underwent subsequent allogeneic stem cell transplantation and remains in remission while the other patient relapsed. One patient showed a significant reduction in BM blasts but eventually relapsed within 2 months. One patient remained refractory to treatment.
In summary, UCART22 did not demonstrate any unexpected toxicities, and CRS events were mild in severity and did not require tocilizumab or steroids. Two patients achieved responses and one patient showed blast reduction. FC plus alemtuzumab lymphodepletion followed by UCART22 are currently under investigation.
John H. Baird et al.,3 investigated CAR22 therapy, an autologous CAR T-cell product targeting CD22, consisting of the m971 anti-CD22 single chain variable fragments and the 41BB/CD3z endodomains, which are integrated via lentiviral transduction in T cells from patients with R/R B-ALL and CAR19-refractory large B-cell lymphoma (LBCL).
During the manufacturing process, CD4/CD8 T-cell enrichment was done on Day 0 followed by lentiviral transduction on Day 1, and washout on Day 3.
In the phase I trial (NCT04088890), manufacturing feasibility, RP2D, and safety/toxicity were investigated as primary endpoints, and key secondary endpoints included clinical efficacy and OS. Response assessment in patients who received a single infusion of 1 × 106 CAR22 T-cell following lymphodepletion therapy was carried out on Day 28, on Day 90, and then every 3 months.3
Three patients with LBCL and six patients with B-ALL, all heavily pretreated with a median six prior lines of therapies, received CAR22 T-cell therapy after it was successfully manufactured. Median peak CAR22 level reached 90 CAR+ cells/µL (range, 85–350) for the LBCL cohort, and 139 CAR+ cells/µL (range, 85–350) for the B-ALL cohort. Median follow-up was 8.9 months (range, 3.7–11.0) for the B-ALL cohort and 8.4 months (range, 6–9.3) for the LBCL cohort.
All patients with B-ALL had undergone prior allo-HSCT, and all patients with LBCL received prior CAR19 therapy.
CRS events were mild with a median time to onset of 1 day (1–11) and a median duration of 5.5 days (1–15). Grade ≥ 3 CRS was not reported. Also, neurologic events/ICANS or nonhematologic Grade ≥ 3 TEAEs did not occur.
In the LBCL cohort, all patients had a response at Day 28, with one patient achieving a CR while two patients with partial response (PR) converted to CR after 3 to 6 months. All patients remained in CR and circulating tumor DNA (ctDNA)-negativity was achieved in two patients. Median progression-free survival (PFS), OS or duration of response (DoR) were not reached.
In the B-ALL cohort, all six patients achieved a response on Day 28 with five patients being MRD-negative. However, five patients relapsed with a median PFS of 4.0 months. One patient died due to infectious complications. CD22 expression was absent in two patients at relapse.
In conclusion, the manufacturing process was found feasible. A single infusion of 1 × 106 CAR22 cells/kg was associated with a tolerable safety profile and high response rates. Initial findings suggest that CAR22 therapy induces responses in heavily pretreated, high-risk patients with LBCL and B-ALL. However, the lack of durable responses observed in the B-ALL cohort requires further investigation.
New approaches with anti-CD22 directed CAR T-cell constructs are currently under investigation. They all show good tolerability and promising efficacy signals in heavily pretreated patients with ALL; however, sustained responses may still require subsequent consolidation with allogeneic stem cell transplantation. Novel features such as faster manufacturing processes and off-the-shelf allogeneic CAR T-cell products may translate into lower costs and wider use of CAR T-cell therapies.
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