Update on Antigen-Specific Immunotherapy of Acute Myeloid Leukemia

Buckley, Sarah; Walter, Roland B.

doi:10.1007/s11899-015-0250-9

Cited by 13 publications

(7 citation statements)

References 127 publications

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“…At present, various CD123 therapeutic monoclonal antibodies have entered clinical trials . One of these trials is based on the CD123 antibody drug conjugate SGN‐CD123A, where the pyrrolobenzodiazepine toxin was coupled to a CD123 specific antibody , leading to targeted drug delivery. Another monoclonal antibody is Talacotuzumab, which was the first CD123 therapeutic monoclonal antibody to enter phase‐III clinical trials.…”

mentioning

confidence: 99%

CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping

Bras

Haas

Stigt

et al. 2018

Cytometry Part B Clinical

101

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Background While it is known that CD123 is normally strongly expressed on plasmacytoid dendritic cells and completely absent on nucleated red blood cells, detailed information regarding CD123 expression in acute leukemia is scarce and, if available, hard to compare due to different methodologies. Methods CD123 expression was evaluated using standardized EuroFlow immunophenotyping in 139 pediatric AML, 316 adult AML, 193 pediatric BCP‐ALL, 69 adult BCP‐ALL, 101 pediatric T‐ALL, and 28 adult T‐ALL patients. Paired diagnosis‐relapse samples were available for 57 AML and 19 BCP‐ALL patients. Leukemic stem cell (LSC) data was available for 32 pediatric AML patients. CD123 expression was evaluated based on mean fluorescence intensity, median fluorescence intensity, and percentage CD123 positive cells. Results EuroFlow panels were stable over time and between laboratories. CD123 was expressed in the majority of AML and BCP‐ALL patients, but absent in most T‐ALL patients. Within AML, CD123 expression was lower in erythroid/megakaryocytic leukemia, higher in NPM1 mutated and FLT3‐ITD mutated leukemia, and comparable between LSC and leukemic blasts. Within BCP‐ALL, CD123 expression was higher in patients with (high) hyperdiploid karyotypes and the BCR‐ABL fusion gene. Interestingly, CD123 expression was increased in BCP‐ALL relapses while highly variable in AML relapses (compared to CD123 expression at diagnosis). Conclusions Authors evaluated CD123 expression in a large cohort of acute leukemia patients, based on standardized and reproducible methodology. Our results may facilitate stratification of patients most likely to respond to CD123 targeted therapies and serve as reference for CD123 expression (in health and disease). © 2018 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.

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mentioning

confidence: 99%

CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping

Bras

Haas

Stigt

et al. 2018

Cytometry Part B Clinical

101

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“…Therapeutic strategies targeting CD33 with unconjugated antibodies, antibody-drug conjugates, immunotoxins, or radioisotopes, (either monospecific or targeting multiple antigens), have been developed or investigated in the clinical setting, and has been reviewed elsewhere [18]. Unconjugated monospecific antibodies have demonstrated modest activity in AML, with the clinical challenge of the need for continuous intravenous administration in virtue of their short half-life.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

Minagawa¹,

Jamil²,

Al‐Obaidi³

et al. 2016

PLoS ONE

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BackgroundApproximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.Methods and findingsWe developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85–90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.ConclusionsThis strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a ‘bridge” therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell inf...

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“…Antigens expressed on leukemia blasts or preferentially expressed on leukemia stem cells including CD33, CD45, CD96, CD123, CD135, CLL-1 and T cell immunoglobulin mucin-3 (TIM-3) represent potential targets for antibody-based therapy in AML [160, 161]. In ALL, CD19, CD20, CD22 and CD52 (among others) represent potential targets [162–164].…”

Section: Acute Leukemiamentioning

confidence: 99%

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia

Boyiadzis¹,

Bishop²,

Abonour³

et al. 2016

j. immunotherapy cancer

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Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0188-z) contains supplementary material, which is available to authorized users.

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Update on Antigen-Specific Immunotherapy of Acute Myeloid Leukemia

Cited by 13 publications

References 127 publications

CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping

CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping

In Vitro Pre-Clinical Validation of Suicide Gene Modified Anti-CD33 Redirected Chimeric Antigen Receptor T-Cells for Acute Myeloid Leukemia

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia

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