P1, N=37, Recruiting, AvenCell Europe GmbH | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Dec 2025

P1, N=12, Recruiting, University of Pennsylvania | Active, not recruiting --> Recruiting

P1, N=24, Not yet recruiting, Guangzhou Bio-gene Technology Co., Ltd

P1/2, N=24, Recruiting, Guangzhou Bio-gene Technology Co., Ltd | Not yet recruiting --> Recruiting | Initiation date: Nov 2023 --> Mar 2024

Despite these challenges, as a new targeting method for AML treatment, CAR-T cell therapy still has great prospects. Ongoing research aims to further optimize this treatment mode.

P1, N=65, Recruiting, Cellectis S.A. | Trial completion date: Mar 2023 --> Dec 2024 | Trial primary completion date: Mar 2023 --> Dec 2024

P1, N=31, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Protein structure prediction suggests that linker length and compactness influence the functionality of the generated bispecific CARs. Thus, we present a bispecific CAR design strategy to prevent immune escape in AML that can be extended to other peptide-scFv combinations.

P1, N=37, Recruiting, AvenCell Europe GmbH | Not yet recruiting --> Recruiting

Moreover, we demonstrate induction of a CD28CD27CD57KLRG1 senescent T-cell phenotype by MSCs. In summary, we show that MSCs are potent modulators of anti-leukemic T cells, and targeting their modes of action would likely be beneficial in a combinatorial approach with AML-directed immunotherapy.

The CD33/CD123 bispecific CAR T cells were able to control acute myeloid leukemia (AML) in a xenograft AML mouse model similar to monospecific CD33 and CD123 CAR T cells while showing no on-target off-tumor effects. Based on our findings, human CD33/CD123 bispecific CAR T cells are a promising cell-based approach to prevent AML and support clinical investigation.

For the first time, we demonstrate in a PDX model that rational combinatorial targeting by AdCAR-T can cure heterogenic disease. In conclusion, we elucidate the clinical relevance of heterogeneity in antigen expression in pediatric AML and present a novel concept for precision immunotherapy by combinatorial targeting, utilizing the AdCAR platform.

Our findings indicate a growing interest in the clinical development of CAR T-cell therapies applied to pediatric oncology. Most of these studies are in early phase I and II and focus primarily on hematological cancers using second-generation constructs targeting CD19. The is a steady increase in the number of studies registered each year that predicts future FDA approvals using CAR T-cell products.

Ex vivo activated nsCAR cells efficiently recognize and kill leukemia cell lines while sparing peripheral blood cells bearing the same target antigen. The nsCAR cells also show increased cytotoxicity against leukemias over unmodified activated γδ T cells suggesting improvement in tropism and/or binding efficiency. In summary, our findings showed that the combination of nsCAR on γδ T cells may increase the therapeutic index to allow expansion of CAR-T therapy to cancers with unacceptable target expression on critical healthy cell populations.

Finally, we present an overview of the results obtained from clinical trials evaluating the efficacy of CAR-T cell therapies in cHL, highlighting their potential as a promising therapeutic option. Collectively, this article provides a comprehensive review of the current understanding of cHL pathogenesis and the rationale for CAR-T cell therapy development, offering insights into the future directions of this rapidly evolving field.

P1, N=60, Recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Dec 2023 --> Jul 2024

No abstract available

P1/2, N=20, Recruiting, Xuzhou Medical University

P1/2, N=24, Not yet recruiting, Guangzhou Bio-gene Technology Co., Ltd

The modular platform has the potential to overcome recent limitations of CAR T cell therapy in AML. These results support the rational for clinical translation of this novel and modular CAR T cell platform.

IGM-2537 bound with high affinity and avidity to CD123. In vitro, IGM-2537 engaged both CD123 and CD3 to induce potent T-cell activation and T-cell mediated cytotoxicity of CD123+ AML cells, and autologous CD123+ basophils and plasmacytoid dendritic cells (pDCs). Though IGM-2537 demonstrated comparable maximal killing activity to a comparator IgG TCE, IGM-2537 demonstrated minimal cytokine release.

Rational pharmacological targeting of either of these pathways, blocking by Simvastatin and activation by BIO-acetoxime, respectively, rescued TP53-deficient AML cell sensitivity to CAR T-cell-mediated killing in vitro...Furthermore, we identified the cholesterol pathway as a potential therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising avenue to enhance the efficacy of CAR T-cell therapy in TP53-deficient AML/MDS. Our data suggest that the combination of CAR T-cell therapies with pharmacological co-interventions – as exemplified in this study – may be a preferable strategy towards more efficacious and tolerable cellular therapies for patients with TP53-mutant myeloid neoplasms.

Repeated dosing of TM in consolidation cycles resulted in robust re-expansion of UniCAR-T with deeper remissions of extended durability. The switchable mechanism provides proven rapid reversal of safety events, enabling higher dose levels.

A summary of functional characterization data will be presented at the meeting with a focus on the lack of predictability of certain in vitro models and underlying hypotheses. Insights from these studies are now flowing into preclinical development of a novel switchable allogeneic CAR-T cell product candidate targeting CD19 and CD20 in B cell malignancies engineered to fully overcome graft-versus-host disease as well as graft rejection by host T and NK cells.

Fludarabine and cyclophosphamide were used for lymphodepletion (LD)...Finally, we found that anti-apoptotic effects of cytokines can be prevented, and CART-123 killing of AML can be restored, via ruxolitinib blockade of JAK/STAT signaling in both in vitro and in vivo settings... We conducted a pilot study of CD123-directed CAR T cells (CART-123) in adults with relapsed or refractory AML. The primary objective was safety with a secondary objective of anti-leukemia efficacy. Twenty-two subjects were screened, and 20 were eligible for the trial.

P1, N=18, Recruiting, City of Hope Medical Center | Trial completion date: Sep 2023 --> Aug 2024 | Trial primary completion date: Sep 2023 --> Aug 2024

In conclusion, hypersialylation on AML cells masks FLT3/CD123 antigens and restrains the avidity of CAR-T cells, which reduces the FLT3/CD123 CAR – T cell's response toward AML cells. Thus, sialylation removal might be a therapeutically optimal strategy to enhance CAR T cell performance.

Furthermore, FACS analysis demonstrated a significant increase in the proportion of CD8+ T cells relative to CD4+ T cells in these patients. Conclusions Ongoing experiments are currently investigating the distribution of CAF subpopulations producing COL1A1 and their correlation with the response to CAR T cell therapy.

CD123/CLL-1 CAR-T cells in tandem can simultaneously target CD123 and CLL-1 on AML cells, demonstrating a significant ability to kill single antigens and multi-target tumour cells. This suggests that CD123/CLL-1 CAR-T cells exhibit significant advantages in the expression of multiple antigens in a wide range of target cells, which may help overcome the challenges posed by tumour heterogeneity and evasion mechanisms.

PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

P1, N=31, Active, not recruiting, City of Hope Medical Center | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023

The binding of Rituximab to RQR8 leads to the elimination of 123NL CAR-T cells and cessation of their cytotoxicity. In conclusion, we successfully developed dual effects of 123NL CAR-T cells against tumor cells and immunosuppressive cells, which can avoid target escape and resist the effects of immunosuppressive microenvironment.

P1, N=32, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting

There was no significant difference in EFS between patients treated with dual-target CAR-T with those with single CD19 CAR-T. In this study, our data supported that donor-derived CAR-T therapy is a safe and potentially effective treatment for relapsed B-ALL after HSCT and may be superior to DLI.

P1, N=30, Recruiting, Shenzhen Geno-Immune Medical Institute

Several clinical trials related to CAR-T immunotherapy against CRC or BC have already been in progress. This review benefits academicians, clinicians, and clinical oncologists to explore more about the novel CAR-T targets and overcome the challenges during this therapy.

In conclusion, CD123 and CLL-1 are promising targets for AML CAR-T cell therapy. A combination of VPA pre-treatment and CAR-T against AML exhibits synergic effects.

P1, N=37, Not yet recruiting, AvenCell Europe GmbH

CAR T cells against myeloid antigens cause myeloablation as well as cytokine release syndrome, although neurotoxicity is rarely seen. Future efforts should focus on AML-specific antigen discovery or engineering, and on further enhancing the activity of CAR T cells.

P1, N=90, Recruiting, AvenCell Europe GmbH | N=45 --> 90 | Trial completion date: Jun 2023 --> Sep 2025 | Trial primary completion date: Dec 2022 --> May 2025

The 5-year relative survival rate in AML patients was estimated at 31.7%. The objective of the following review is to present the mechanism of action of CAR-T cells, and discuss the latest findings on the results of anti-CD33, -CD123, -FLT3 and -CLL-1 CAR-T cell therapy, the emerging challenges as well as the prospects for the future.