We summarize here the findings, challenges and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.
19 days ago
Journal • CAR T-Cell Therapy
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CD123 (Interleukin 3 Receptor Subunit Alpha) • CD33 (CD33 Molecule) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • CLEC12A (C-Type Lectin Domain Family 12 Member A)
These gated CAR-T cells exhibited lower expression of exhaustion markers (PD1, Tim3, LAG3, and CD39), higher frequency of memory T cells (CD62L+CD45RA+), and enhanced expansion. While targeting AML, the moderated circuit CAR signal also helped to mitigate cytokine release syndrome, potentially addressing one of the ongoing challenges in CAR-T immunotherapy.
Loop33 × 123 CAR-T targeting CD33 and CD123 could efficiently eliminate AML cells and prolong survival of tumor-bearing mice, while addressing the issue of immune escape.
P1, N=18, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025
2 months ago
Trial completion date • Trial primary completion date • CAR T-Cell Therapy • Metastases • Immune cell
Our study reveals that a BRD4 inhibitor can reduce CAR-T cell exhaustion and block exhausted T cell terminal differentiation by downregulating BATF activity and expression together with upregulating EGR1 activity and expression, presenting an approach for improving the effectiveness of CAR-T cell therapy.
P1, N=60, Recruiting, City of Hope Medical Center | Trial completion date: Jul 2025 --> Mar 2025 | Trial primary completion date: Jul 2024 --> Mar 2025
2 months ago
Trial completion date • Trial primary completion date • CAR T-Cell Therapy • Checkpoint inhibition
In this review, the latest significant breakthroughs in AML CAR T cell therapy are presented. Furthermore, the limitations of CAR T-cell technology and future directions to overcome these challenges are discussed.
Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.
Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ).
Innovative approaches to combat the immunosuppressive milieu of the tumor microenvironment in hematologic malignancies are of high clinical significance and may lead to increased survival, improved quality of life, and decreased toxicity of cancer therapies. Standard procedures will likely involve a combination of CAR T/NK-cell therapies with other treatments, leading to more comprehensive cancer care.
The described approach enables GMP-compatible production of sufficient numbers of CAR19 and CAR123 T cells for clinical application and provides the basis for non-viral manufacturing of novel experimental CAR-T cells that can be tested in early-phase clinical trials. This manufacturing approach can complement and advance novel experimental immunotherapeutic strategies against human hematologic malignancies.
P1, N=22, Active, not recruiting, University of Pennsylvania | Recruiting --> Active, not recruiting | N=12 --> 22 | Trial primary completion date: Aug 2024 --> Dec 2033
5 months ago
Enrollment closed • Enrollment change • Trial primary completion date
This review discusses challenges in the development of CAR-T therapy for myeloid malignancies, especially for AML, from the perspectives of target antigen characteristics and disease-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of CAR-T cells for these diseases.
5 months ago
Review • Journal • CAR T-Cell Therapy • IO biomarker
Further, we demonstrate in PDX models that rational combinatorial targeting by AdCAR-T-cells 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.
In this review, we summarize the recent findings regarding various therapeutic targets for AML (CD33, CD123, CLL1, CD7, etc.) and the results of the latest clinical studies on these targets. Thereafter, we also discuss the challenges related to CAR-T therapy for AML and some promising strategies for overcoming these challenges, including novel approaches such as gene editing and advances in CAR design.
This review discusses the challenges in AML-targeted CAR-T cell therapy development from the perspectives of target antigen characteristics and AML-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of AML-targeting CAR-T cells.
6 months ago
Review • Journal • CAR T-Cell Therapy • IO biomarker
In an aggressive version of this model, bulk RNA sequencing analysis showed that these CD123 CAR T cells upregulated genes associated with cytotoxicity and activation/exhaustion a few days after the injection. Together, these results emphasize the importance of screening different scFvs for the development of CAR constructs to support selection of cells with the optimal risk-benefit ratio for clinical development.
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=31, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
10 months ago
Trial completion date • Trial primary completion date
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.
10 months ago
Journal • CAR T-Cell Therapy
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CD123 (Interleukin 3 Receptor Subunit Alpha) • HSPA5 (Heat Shock Protein Family A (Hsp70) Member 5) • IL3RA (Interleukin 3 Receptor Subunit Alpha)
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.
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.
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.
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
1 year ago
Trial completion date • Trial primary completion date • CAR T-Cell Therapy • Checkpoint inhibition