AML-specific cytotoxic antibodies in patients with durable graft-versus-leukemia responses

Gillissen, Marijn A.; Kedde, Martijn; Jong, Greta de; Moiset, Gemma; Yasuda, Etsuko; Levie, Sophie E.; Bakker, Arjen Q.; Claassen, Yvonne; Wagner, Kay Uwe; Böhne, Martino; Hensbergen, Paul J.; Speijer, Dave; Helden, Pauline M. van; Beaumont, Tim; Spits, Hergen; Hazenberg, Mette D.

doi:10.1182/blood-2017-02-768762

Cited by 22 publications

(19 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27 Immunologic consolidation can be effective when newly infused donor immune cells that are naive with regard to the patient's AML elicit a GvL response independent of HLA-related antigen presentation, for example, to targets that are expressed on the membrane of AML blasts. 28,29 Thus, as also suggested by other studies, immunological consolidation is of importance for survival in this setting. GvHD occurred in some but not all surviving patients suggesting that immunologic consolidation can also be effective when it does not lead to GvHD.…”

Section: Discussionsupporting

confidence: 61%

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Jong

Janssen

Biemond

et al. 2019

European J of Haematology

Self Cite

View full text Add to dashboard Cite

Objective: Relapse of AML after allogeneic hematopoietic stem cell transplantation (HSCT) has a poor prognosis, and standard of care therapy is lacking. Early (<6 months) relapse is associated with dismal outcome, while the majority of relapses occur early after transplantation. A more precise indication which patients could benefit from reinduction therapy is warranted. Methods:We retrospectively analyzed outcomes of 83 patients with postallogeneic HSCT relapse. Patients were divided based on intention to treat (curative vs supportive care). Results:Of the 50 patients treated with curative intent, 44% reached complete remission (CR) upon reinduction chemotherapy, and of these patients, 50% survived.Two survivors reached CR after immunotherapy (donor lymphocyte infusion (DLI), without reinduction chemotherapy). Sixty-nine percent of the survivors had received high-intensity cytarabine treatment, followed by immunologic consolidation. Relapse <3 months after transplantation was predictive for adverse survival (P = .004), but relapse <6 months was not. In fact, >50% of the survivors had a relapse <6 months. Conclusion:We confirmed the dismal prognosis of postallogeneic HSCT relapse.Importantly, our data demonstrate that patients fit enough to receive high-dose chemotherapy, even when relapse occurred <6 months, had the best chance to obtain durable remissions, in particular when immunologic consolidation was performed after reaching CR. K E Y W O R D S acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, graft-versusleukemia, outcome Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred treatment for patients with (MRD positive) intermediate-risk or poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). While transplant related mortality has decreased, the risk for relapse has not. Disease relapse is a common and important cause of the poor long-term survival of allogeneic HSCT recipients with AML. Relapse accounts for 30%-40% of deaths after allogeneic HSCT, depending on the type of the donor and disease status at transplant. 1,2 Prognosis of postallogeneic HSCT AML relapse is poor 3,4 and has hardly improved in the past decades. There is no standard of care for patients who relapse after allogeneic HSCT. Age (<37 year) and a longer time (>5 months) between allogeneic HSCT and relapse have been identified as favorable prognostic factors. 3,5,6 Other factors such as clinical condition and personal considerations of the patient may be weighed in the decision to either give supportive care, offer low-dose chemotherapy, or attempt high-dose reinduction chemotherapy. In reality, curative treatment options are often limited, and in many cases, it can be more appropriate to refrain from intensive treatment regimens and opt for best supportive care. Most AML relapses occur in the first 6 months after allogeneic HSCT, a period during which many patients still receive immunosuppressive therapy. Rapid tapering of immunosuppression can potentially lead ...

show abstract

Section: Discussionsupporting

confidence: 61%

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Jong

Janssen

Biemond

et al. 2019

European J of Haematology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Earlier, we have examined whether patients with AML successfully treated with allogeneic HSCT generate AML-specific antibodies (7)(8)(9). Allogeneic HSCT can evoke an immunotherapeutic graft-versus-leukemia reaction, which includes a B-cell response and the generation of tumor-specific antibodies (10).…”

Section: Introductionmentioning

confidence: 99%

A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia

et al. 2019

Self Cite

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a high-risk disease with a poor prognosis, particularly in elderly patients. Because current AML treatment relies primarily on untargeted therapies with severe side effects that limit patient eligibility, identification of novel therapeutic AML targets is highly desired. We recently described AT1413, an antibody produced by donor B cells of a patient with AML cured after allogeneic hematopoietic stem cell transplantation. AT1413 binds CD43s, a unique sialylated epitope on CD43, which is weakly expressed on normal myeloid cells and overexpressed on AML cells. Because of its selectivity for AML cells, we considered CD43s as a target for a bispecific T-cell-engaging antibody (bTCE) and generated a bTCE by coupling AT1413 to two T-cell-targeting fragments using chemo-enzymatic linkage. In vitro, AT1413 bTCE efficiently induced T-cell-mediated cytotoxicity toward different AML cell lines and patient-derived AML blasts, whereas endothelial cells with low binding capacity for AT1413 remained unaffected. In the presence of AML cells, AT1413 bTCE induced upregulation of T-cell activation markers, cytokine release, and T-cell proliferation. AT1413 bTCE was also effective in vivo. Mice either coinjected with human peripheral blood mononuclear cells or engrafted with human hematopoietic stem cells [human immune system (HIS) mice] were inoculated with an AML cell line or patient-derived primary AML blasts. AT1413 bTCE treatment strongly inhibited tumor growth and, in HIS mice, had minimal effects on normal human hematopoietic cells. Taken together, our results indicate that CD43s is a promising target for T-cell-engaging antibodies and that AT1413 holds therapeutic potential in a bTCE-format. Significance: These findings offer preclinical evidence for the therapeutic potential of a bTCE antibody that targets a sialylated epitope on CD43 in AML.

show abstract

“…Only recently, Gillissen et al found donor-derived antibodies against SNRNP200 in patients with AML after hematopoietic stem cell transplantation. Those antibodies provide anti-leukemic activity after binding to SNRNP200, which is expressed on the cell surface of AML blasts, but which is an intracellular component of the splicosome in normal cells [ 31 ]. We also identified cell surface proteins which are accessible to antibodies such as CD44 and CD99, but sample size was too small to detect significant alterations in protein expression.…”

Section: Discussionmentioning

confidence: 99%

Pilot Study on Mass Spectrometry–Based Analysis of the Proteome of CD34+CD123+ Progenitor Cells for the Identification of Potential Targets for Immunotherapy in Acute Myeloid Leukemia

et al. 2018

View full text Add to dashboard Cite

Targeting of leukemic stem cells with specific immunotherapy would be an ideal approach for the treatment of myeloid malignancies, but suitable epitopes are unknown. The comparative proteome-level characterization of hematopoietic stem and progenitor cells from healthy stem cell donors and patients with acute myeloid leukemia has the potential to reveal differentially expressed proteins which can be used as surface-markers or as proxies for affected molecular pathways. We employed mass spectrometry methods to analyze the proteome of the cytosolic and the membrane fraction of CD34 and CD123 co-expressing FACS-sorted leukemic progenitors from five patients with acute myeloid leukemia. As a reference, CD34+CD123+ normal hematopoietic progenitor cells from five healthy, granulocyte-colony stimulating factor (G-CSF) mobilized stem cell donors were analyzed. In this Tandem Mass Tag (TMT) 10-plex labelling–based approach, 2070 proteins were identified with 171 proteins differentially abundant in one or both cellular compartments. This proof-of-principle-study demonstrates the potential of mass spectrometry to detect differentially expressed proteins in two compartment fractions of the entire proteome of leukemic stem cells, compared to their non-malignant counterparts. This may contribute to future immunotherapeutic target discoveries and individualized AML patient characterization.

show abstract

AML-specific cytotoxic antibodies in patients with durable graft-versus-leukemia responses

Cited by 22 publications

References 39 publications

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia

Pilot Study on Mass Spectrometry–Based Analysis of the Proteome of CD34+CD123+ Progenitor Cells for the Identification of Potential Targets for Immunotherapy in Acute Myeloid Leukemia

Contact Info

Product

Resources

About