AML relapse after rituximab treatment for GvHD: crucial role for B cells in GvL responses

Gillissen, Marijn A.; Jong, Greta de; Levie, Sophie E.; Yasuda, Etsuko; Bakker, Arjen Q.; Evers, Ludo M.; Pals, Steven T.; Huisman, Cynthia; Helden, Pauline M. van; Spits, Hergen; Hazenberg, Mette D.

doi:10.1038/bmt.2016.90

Cited by 8 publications

(4 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

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

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

View full text Add to dashboard Cite

show abstract

“…31 Our group investigated the B-cell repertoire of a similar patient who had an AML relapse soon after allogeneic HCT. 32 Rapid tapering of immunosuppressants resulted in strong immune responses inducing complete remission of AML, but also caused severe, steroid-refractory GvHD. Treatment with rituximab resolved GvHD, but AML relapsed soon after.…”

Section: Functional Involvement Of Tumour-specific Antibodies In Gvl mentioning

confidence: 99%

“…One of these antibodies induced complement-mediated lysis of AML cells, suggesting a functional role for this antibody in this patient's GvL response. 32 To further investigate whether B cells could be involved in GvL responses, we investigated the B-cell repertoire of three patients with AML who mounted potent tumourclearing GvL responses after allogeneic HCT. 33 All patients had B cells that were of HCT donor origin and which produced antibodies that recognized antigens expressed by AML cells.…”

Section: Functional Involvement Of Tumour-specific Antibodies In Gvl mentioning

confidence: 99%

Tumour-reactive B cells and antibody responses after allogeneic haematopoietic cell transplantation

Jong

Gillissen

Spits

et al. 2020

Immuno-Oncology Technology

View full text Add to dashboard Cite

For many high-risk haematologic malignancies, such as acute myeloid leukaemia, the success of therapy relies mainly on invoking a curative antitumour immune response. This can be achieved by inducing a graft-versus-leukaemia response following allogeneic haematopoietic cell transplantation. While the contribution of T cells and natural killer cells to graft-versus-leukaemia responses is established, the contribution of B cells and antibodies is relatively unexplored. This article reviews what is known about the contribution of B cells and tumour-specific antibody responses to a successful graft-versus-leukaemia response leading to eradication of the tumour.

show abstract

“…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 to the initiation of a graft‐versus‐leukemia (GvL) effect and remission of leukemia . When patients relapse after cessation of immunosuppressive therapy or when tapering of immunosuppression does not result in remission, hypomethylating therapy such as azacitidine or decitabine may be used to induce remission.…”

Section: Introductionmentioning

confidence: 99%

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Jong

Janssen

Biemond

et al. 2019

European J of Haematology

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

AML relapse after rituximab treatment for GvHD: crucial role for B cells in GvL responses

Cited by 8 publications

References 19 publications

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

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

Tumour-reactive B cells and antibody responses after allogeneic haematopoietic cell transplantation

Survival of early posthematopoietic stem cell transplantation relapse of myeloid malignancies

Contact Info

Product

Resources

About