Gold Nanorods Exhibit Intrinsic Therapeutic Activity via Controlling N6-Methyladenosine-Based Epitranscriptomics in Acute Myeloid Leukemia

ACS Nano ◽  
2021 ◽  
Author(s):  
Yangyang Du ◽  
Mingda Han ◽  
Kunxia Cao ◽  
Qing Li ◽  
Jiuxia Pang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gold Nanorods ◽  
Myeloid Leukemia ◽  
Therapeutic Activity ◽  
Acute Myeloid

scholarly journals Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3385
Author(s):  
Axel H. Schönthal ◽  
Steve Swenson ◽  
Radu O. Minea ◽  
Hye Na Kim ◽  
Heeyeon Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Perillyl Alcohol ◽  
Therapeutic Activity ◽  
Acute Myeloid

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.

Generation, Functional Characterization and Clinical Application of a Novel Fc-Optimized Anti-FLT3 Antibody for the Treatment of Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2187-2187
Author(s):  
Helmut R. Salih ◽  
Tina Baessler ◽  
Martin Hofmann ◽  
Ludger Grosse-Hovest ◽  
Maximilian Bamberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Target Cell ◽  
Myeloid Leukemia ◽  
10Mg Dose ◽  
Unrelated Donor ◽  
Therapeutic Activity ◽  
Flt3 Expression ◽  
Acute Myeloid

Abstract Abstract 2187 For more than a decade, chimeric/humanized second generation monoclonal antibodies (mAb) are used in cancer therapy. While their success e.g. in lymphoma therapy is undisputed, mAb are not established as treatment for acute myeloid leukemia (AML). Moreover, the therapeutic activity of available mAb leaves ample room for improvement. In the recent years, modifications of the human IgG1 Fc-part have enabled the development of third generation mAb with markedly improved capability to recruit Fc-receptor bearing immune effector cells. We here report on the development and evaluation of an Fc-optimized mAb directed to FLT3, an antigen expressed on leukemic cells of the majority of AML patients. In vitro, this antibody termed 4G8-SDIEM effectively induced antibody-dependent cellular cytotoxicity (ADCC) against FLT3-expressing AML cells at concentrations as low as 10ng/ml. Compared to the parental humanized antibody, the ADCC activity of 4G8-SDIEM was increased by a factor of 100. FLT3 expression on primary AML cells (range, 500–5000 molecules) was considerably higher as compared to healthy hematopoietic cells (several hundred molecules). 4G8-SDIEM did not induce relevant ADCC against healthy cells and did not decrease the CFU-forming capacity of bone marrow (BM) cells in vitro. The mAb was then produced in pharmaceutical quality and quantity at a university-owned production unit and used for compassionate need treatment of a 30 year old AML patient (FAB M0, complex kariotype with 45, XY, inv(3)(q21q26), -7, 9q-) with relapse after haploidentical and unrelated donor stem cell transplantation (SCT). Preclinical testing revealed that 4G8-SDIEM effectively induced ADCC of the patients peripheral blood (PB) mononuclear cells (PBMC) against NALM16 leukemia cells and autologous leukemic blasts. Directly before initiation of treatment, the percentage of leukemic blasts among the patients PBMC was 11% and 38% in PB and BM, respectively, and his AML cells displayed homogeneous FLT3 expression. The percentage of NK cells (CD56+CD3-) was 7% and 5% in PB and BM, respectively, with less than 2% displaying an activated phenotype (CD69+). 4G8-SDIEM was applied in escalating doses (d1: 10μg; d2: 100μg; d3: 1mg; d4: 2mg; d5, 7, 10: 10mg). Several hours after the first 10 mg-dose 5×108 CD3/CD19-depleted donor lymphocytes were infused. Besides elevated temperature (max. 38.2°C), no relevant side effects of treatment were observed. After the first first 10mg dose, BM blasts were nearly saturated with mAb as judged by crosscompetition assays. Serum concentration of 4G8-SDIEM reached 1.0μg/ml 1h after the first 10mg dose declining to 0.4 μg/ml 24h later. Upon treatment, serum levels of the index cytokines TNF and IL-6 (peak d4, 60 and 27pg/ml, respectively) and the percentage of activated NK cells (peak d6, 42%) in PB increased rapidly. Already at day 4, leukemic blasts were nearly completely cleared from the PB (<2%), while effects in BM were less pronounced (down to 15%) indicating that lower effector to target cell ratios in the BM limit the therapeutic activity of the mAb. In any case, the anti-leukemic effects of 4G8-SDIEM remained transient, as 10 days after initiation of therapy blast counts in PB and BM reached and later exceeded pre-treatment levels. Thus we conclude that although 4G8-SDIEM clearly exerts anti-leukemic effects in vivo, it may not be capable of inducing long-lasting responses of AML in proliferative phase. Rather, we envisage application of the mAb in settings with suitably high effector to target cell ratios such as minimal residual disease in morphological complete remission, possibly in combination with adoptive NK cell transfer. As of now, development of 4G8-SDIEM cost |CE2 million and required 2.5 years from bench to bedside. Thus, development and early clinical evaluation of novel mAb can be achieved at academic institutions at reasonable costs and time before initiation of larger clinical Phase II/III studies by the pharmaceutical industry. Such an approach may not only accelerate the developmental process for anti-tumor mAb, but rather for innovative biological drugs in general. Disclosures: Hofmann: University of Tuebingen, Germany: Patents & Royalties. Grosse-Hovest: University of Tuebingen, Germany: Patents & Royalties. Aulwurm: University of Tuebingen, Germany: Patents & Royalties. Buehring: University of Tuebingen, Germany: Patents & Royalties. Jung: University of Tuebingen, Germany: Patents & Royalties.

Novel and Emerging Drugs for Acute Myeloid Leukemia: Pharmacology and Therapeutic Activity

2011 ◽  
Vol 18 (5) ◽  
pp. 638-666 ◽  
Author(s):  
T. Robak ◽  
A. Szmigielska-Kaplon ◽  
A. Pluta ◽  
O. Grzybowska-Izydorczyk ◽  
A. Wolska ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Activity ◽  
Acute Myeloid
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