piperidines and Leukemia-Lymphoma--Adult-T-Cell

Novel technologies including next-generation sequencing have not only delineated the molecular pathogenesis of lymphoid malignancies but also identified novel biomarkers predicting the outcome of specific therapies. In addition, many actionable genetic alterations, which can be targeted by either specific therapeutic compounds or monoclonal antibodies, have been discovered. An appropriate selection of the patients enrolled in clinical trials using novel drugs targeting specific mutations will usher in a new era of personalized medicine in clinical practice of lymphoid malignancies.

Topics: Adenine; Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Genome, Human; Genomics; High-Throughput Nucleotide Sequencing; Humans; Indoles; Leukemia-Lymphoma, Adult T-Cell; Lymphoma; Molecular Targeted Therapy; Mutation; Piperidines; Precision Medicine; Pyrazoles; Pyrimidines; Sulfonamides; Vemurafenib

IL-15 has a pivotal role in life and death of natural killer (NK) and CD8 memory T cells. IL-15 signals through a heterotrimeric receptor involving the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ) shared with IL-2 and a private IL-15Rα subunit. IFN- or CD40 ligand-stimulated dendritic cells coordinately express IL-15 and IL-15Rα. Cell surface IL-15Rα presents IL-15 in trans to cells that express IL-2/IL-15Rβ and γc. IL-15 is being used to treat patients with metastatic malignancy. However, IL-15 is an inflammatory cytokine involved in immunological memory including that to self, thereby playing a role in autoimmune diseases. These insights provide the scientific basis for clinical strategies directed toward diminishing IL-15 action. Dysregulated IL-15 expression was demonstrated in patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, celiac disease, and alopecia areata. The monoclonal antibody Hu-Mik-β-1 targets the cytokine receptor subunit IL-2/IL-15Rβ (CD122), blocks IL-15 transpresentation, and is being used in clinical trials in patients with autoimmune diseases. In parallel, clinical trials have been initiated involving the Jak2/3 (Janus kinase-2/3) inhibitor tofacitinib and Jak1/2 inhibitor ruxolitinib to block IL-15 signaling.

Topics: Alopecia Areata; Animals; Antibodies, Monoclonal; Autoimmune Diseases; Humans; Interleukin-15; Leukemia-Lymphoma, Adult T-Cell; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Receptors, Interleukin-15; Signal Transduction

The retrovirus, human T-cell-lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I-encoded protein tax constitutively activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and activators of transcription 5) pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor CP-690,550 on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or from those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50 nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T-cell IL-15-transgenic leukemia that manifests an autocrine IL-15/IL-15Rα pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I-associated ATL and HAM/TSP.

Topics: Adult; Animals; Cell Line, Tumor; Cell Proliferation; Cytokines; Enzyme Activation; Humans; In Vitro Techniques; Interleukin-15; Janus Kinase 3; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Experimental; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Paraparesis, Tropical Spastic; Phosphorylation; Piperidines; Pyrimidines; Pyrroles; Signal Transduction; STAT5 Transcription Factor; T-Lymphocytes

The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.

Topics: Adenine Nucleotides; Antineoplastic Agents; Arabinonucleosides; Burkitt Lymphoma; Child; Clofarabine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flavonoids; Humans; Inhibitory Concentration 50; Leukemia-Lymphoma, Adult T-Cell; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured

Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1. The leukemia consists of an overabundance of activated T cells, which express CD25 on their cell surfaces. Presently, there is no accepted curative therapy for ATL. Flavopiridol, an inhibitor of cyclin-dependent kinases, has potent antiproliferative effects and antitumor activity. We investigated the therapeutic efficacy of flavopiridol alone and in combination with humanized anti-Tac antibody (HAT), which recognizes CD25, in a murine model of human ATL. The ATL model was established by intraperitoneal injection of MET-1 leukemic cells into nonobese diabetic/severe combined immunodeficient mice. Either flavopiridol, given 2.5 mg/kg body weight daily for 5 days, or HAT, given 100 microg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of human beta-2-microglobulin (beta2mu; P < .01), and prolonged survival of the leukemia-bearing mice (P < .05) as compared with the control group. Combination of the 2 agents dramatically enhanced the antitumor effect, as shown by both beta2mu levels and survival of the mice, when compared with those in the flavopiridol or HAT alone group (P < .01). The significantly improved therapeutic efficacy by combining flavopiridol with HAT provides support for a clinical trial in the treatment of ATL.

Topics: Adult; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; beta 2-Microglobulin; Cell Cycle; Cell Division; Cell Line, Tumor; Disease Models, Animal; Flavonoids; Humans; Leukemia-Lymphoma, Adult T-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Piperidines; Receptors, Interleukin-2