Our long-term goal Is to develop Immune therapies that target aberrantly expressed proteases In blasts and leukemia stem cells. PR1 peptide (VLQELNVTV) is a peptide derived from the leukemia- associated antigens proteinase 3 (P3) and neutrophil elastase (NE), which is presented on HLA-A2 to PR1- speclfic cytotoxic T lymphocytes (PR1-CTL). During the last grant period, we showed that PR1 is cross- presented by dendritic cells (DCs) and B cells, and we showed the mechanism required proteasome cleavage exogenous P3 and NE taken up by antigen-presenting cells. We completed a phase 2 PRI peptide vaccine trial that showed immune responses in 58% and clinical responses in 16%, but responses were limited to patients with low leukemia burden. We developed a strategy to adoptively transfer donor- derived PR1-CTL to stem cell transplant recipients to treat high leukemia burden. As an alternate strategy, we identified a T cell receptor (TCR)-like monoclonal antibody (8F4) with specificity for a conformational epitope of PR1 bound to the HLA-A2 molecule. 8F4 induces complement-dependent cytotoxicity (CDC) of AML and LSC and inhibits AML progenitor cell growth but not normal bone marrow progenitors, which supports further study of 8F4 as a potential therapeutic monoclonal antibody (mAb) for AML. Our preliminary data show that 8F4 prevents AML engraftment and reduced or eliminated established primary human AML xenografts in vivo. 8F4 also significantly reduced or eliminated leukemia stem cells (LSCs) in mouse models. We produced a humanized 8F4 (Hu8F4) and showed it significantly reduced (>95%) established human AML xenografts. Thus, 8F4 is the first TCR-like mAb that inhibits growth of AML and LSC and eliminates AML in vivo. In prior years of this grant, we have used a PRI peptide vaccine to induce immunity in patients with AML, CML, and MDS and more recently we initiated two adoptive cell therapy trials with PRI-specific CTL in AML and CML, respectively. In this proposal, we will characterize the 8F4 mAb as a novel therapeutic modality for leukemia. Our central hypothesis is that immune therapy targeting surface PR1/HLA-A2 molecules can selectively eliminate leulfemia and leuliemia stem cells, but not normal hematopoietic cells. To investigate the therapeutic potential of this novel antibody to improve the outcome of patients with myeloid malignancies, we will pursue the following Specific Aims 1) characterize the activity of HU-8F4 against human AML, 2) perform pre-clinical treatment validation and safety studies of Hu-8F4, and 3) conduct a first-in-human phase 1 clinical trial with Hu8F4 in patients with relapsed AML.
Successful completion of these studies will provide the biological, pre-clinical and clinical bases for exploring the therapeutic potential of a highly novel TCR-like antibody (8F4) to treat leukemia. 8F4 eliminates leukemia and leukemia stem cells in mouse models of primary human leukemia without eliminating normal blood cells or normal hematopoietic stem cells. Therefore, 8F4 shows promise as a highly AML-specific agent with low potential for toxicity. We will conduct a first-in-human clinical trial with this antibody in AML.
|Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564|
|Johanning, Gary L; Malouf, Gabriel G; Zheng, Xiaofeng et al. (2017) Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype. Sci Rep 7:41960|
|Katerndahl, Casey D S; Heltemes-Harris, Lynn M; Willette, Mark J L et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol 18:694-704|
|Kanagal-Shamanna, Rashmi; Loghavi, Sanam; DiNardo, Courtney D et al. (2017) Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica 102:1661-1670|
|Mu, Yunxiang; Zelazowska, Monika A; McBride, Kevin M (2017) Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene. J Exp Med 214:3543-3552|
|Kelly, A D; Kroeger, H; Yamazaki, J et al. (2017) A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. Leukemia 31:2011-2019|
|Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406|
|Pratz, Keith W; Levis, Mark (2017) How I treat FLT3-mutated AML. Blood 129:565-571|
|Kerros, Celine; Tripathi, Satyendra C; Zha, Dongxing et al. (2017) Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells. J Biol Chem 292:10295-10305|
|Kayser, Sabine; Levis, Mark J (2017) Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol :|
Showing the most recent 10 out of 450 publications