Immunotherapy of acute myeloid leukemia based on γδ T cells

Patients with relapsed or refractory acute myeloid leukemia (AML) are at increased risk of mortality. Higher γδ T cell count in a bone marrow or peripheral blood of patients with leukemia is associated with better survival. However, γδ T cells are rare in the blood and functionally impaired or exhausted in patients with malignancies. Promising results are reported on the treatment of various malignancies with in vivo expansion of autologous γδ T cells using zoledronic acid (zol) and IL-2. Here we demonstrated that zol and IL-2, in combination with a novel genetically engineered K562 CD3/CD137L/CD28/IL15RA quadruplet artificial antigen presenting cell (aAPC), efficiently expand allogeneic donor-derived γδ T cells using a GMP-compliant protocol sufficient to achieve cell doses for future clinical use. We achieved a 633-fold expansion of γδ T cells after day 10 of co-culture with aAPC, the majority of which exhibited central (47%) and effector (43%) memory phenotypes. Additionally, >90% of the expanded γδ T cells expressed NKG2D, while they have low cell surface expression of PD1 and LAG2 inhibitory checkpoint receptors. In vitro real-time cytotoxicity analysis showed that expanded, previously cryopreserved, γδ T cells were effective in killing target cells. Our results demonstrate that large scale ex vivo expansion of donor-derived γδ T cells can be achieved with the use of CD3/CD137L/CD28/IL15RA quadruplet aAPC and zol/IL-2 for clinical application as promising antineoplastic immunotherapy. Figure 1 Disclosures Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia

Leukemia ◽

10.1038/s41375-021-01122-7 ◽

2021 ◽

Author(s):

Rajkumar Ganesan ◽

Vijaykumar Chennupati ◽

Balaji Ramachandran ◽

Michael Riis Hansen ◽

Sanjaya Singh ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Tumor Cells ◽

Myeloid Leukemia ◽

Bispecific Antibody ◽

Γδ T Cells ◽

Severe Toxicity ◽

Γδ T Cell ◽

Acute Myeloid

AbstractDespite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3+ T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a bispecific antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2+ γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9+ γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic bispecific antibodies (a) selectively activate Vγ9+ γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9+ γδ T cells into cell–cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9+ γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.

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Higher TIGIT+CD226- γδ T cells in Patients with Acute Myeloid Leukemia

Immunological Investigations ◽

10.1080/08820139.2020.1806868 ◽

2020 ◽

pp. 1-11

Author(s):

Zhenyi Jin ◽

Tianbi Lan ◽

Yun Zhao ◽

Jinxia Du ◽

Jie Chen ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Γδ T Cells ◽

Acute Myeloid

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Prospects for immunotherapy of acute myeloid leukemia using γδ T cells

Immunotherapy ◽

10.2217/imt-2016-0139 ◽

2017 ◽

Vol 9 (2) ◽

pp. 111-114 ◽

Cited By ~ 5

Author(s):

Leena Halim ◽

Ana Catarina Parente-Pereira ◽

John Maher

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Γδ T Cells ◽

Acute Myeloid

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CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody switch

Leukemia ◽

10.1038/s41375-021-01208-2 ◽

2021 ◽

Author(s):

Xin He ◽

Zijie Feng ◽

Jian Ma ◽

Xuyao Zhang ◽

Sunbin Ling ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Domain ◽

Single Domain Antibody ◽

Car T Cells ◽

Domain Antibody ◽

Car T ◽

Acute Myeloid

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Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

Cancers ◽

10.3390/cancers13020186 ◽

2021 ◽

Vol 13 (2) ◽

pp. 186

Author(s):

Marcus Bauer ◽

Christoforos Vaxevanis ◽

Haifa Kathrin Al-Ali ◽

Nadja Jaekel ◽

Christin Le Hoa Naumann ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Multispectral Imaging ◽

Immune Cell ◽

Genetic Alterations ◽

Spatial Proximity ◽

Secondary Acute Myeloid Leukemia ◽

Acute Myeloid

Background: Myelodysplastic syndromes (MDS) are caused by a stem cell failure and often include a dysfunction of the immune system. However, the relationship between spatial immune cell distribution within the bone marrow (BM), in relation to genetic features and the course of disease has not been analyzed in detail. Methods: Histotopography of immune cell subpopulations and their spatial distribution to CD34+ hematopoietic cells was determined by multispectral imaging (MSI) in 147 BM biopsies (BMB) from patients with MDS, secondary acute myeloid leukemia (sAML), and controls. Results: In MDS and sAML samples, a high inter-tumoral immune cell heterogeneity in spatial proximity to CD34+ blasts was found that was independent of genetic alterations, but correlated to blast counts. In controls, no CD8+ and FOXP3+ T cells and only single MUM1p+ B/plasma cells were detected in an area of ≤10 μm to CD34+ HSPC. Conclusions: CD8+ and FOXP3+ T cells are regularly seen in the 10 μm area around CD34+ blasts in MDS/sAML regardless of the course of the disease but lack in the surrounding of CD34+ HSPC in control samples. In addition, the frequencies of immune cell subsets in MDS and sAML BMB differ when compared to control BMB providing novel insights in immune deregulation.

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A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽

10.1038/s41375-020-01109-w ◽

2021 ◽

Author(s):

Mohamed-Reda Benmebarek ◽

Bruno L. Cadilha ◽

Monika Herrmann ◽

Stefanie Lesch ◽

Saskia Schmitt ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Tumor Antigens ◽

Adoptive T Cell Therapy ◽

Single Chain ◽

T Cell Therapy ◽

Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

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CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia

Journal of Hematology & Oncology ◽

10.1186/s13045-017-0553-5 ◽

2018 ◽

Vol 11 (1) ◽

Cited By ~ 48

Author(s):

Jinghua Wang ◽

Siyu Chen ◽

Wei Xiao ◽

Wende Li ◽

Liang Wang ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Car T Cells ◽

Car T ◽

Acute Myeloid

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Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽

10.1182/blood.v97.9.2764 ◽

2001 ◽

Vol 97 (9) ◽

pp. 2764-2771 ◽

Cited By ~ 77

Author(s):

Beth D. Harrison ◽

Julie A. Adams ◽

Mark Briggs ◽

Michelle L. Brereton ◽

John A. Liu Yin

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Dendritic Cells ◽

T Cell ◽

Myeloid Leukemia ◽

T Cell Responses ◽

Cell Responses ◽

Antigen Presenting ◽

Acute Myeloid ◽

Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

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