A centerpiece of the Clinical Trials Team efforts has been to translate the basic insights from the Laboratory of Thomas A. Waldmann into innovative clinical trials evaluating receptor directed monoclonal antibody (MoAb) mediated treatment of T-cell leukemia/lymphomas and Hodgkin's lymphoma. The Clinical Trials Team has undertaken clinical trials of monoclonal antibody mediated therapy of T-cell leukemia/lymphomas with antibodies directed toward CD2, CD25, CD30, CD52 and CD122 and most recently a clinical trial with the anti-CCR4 monoclonal antibody. A major program was the evaluation of yttrium-90 labeled daclizumab (anti-CD25), anti-IL-2R alpha in the treatment of Hodgkin's lymphoma. The scientific basis for this choice was that with the exception of T regs CD25 is not expressed by normal resting lymphoid cells but it is expressed on both a percentage of Reed-Sternberg (RS) cells and all regulatory CD4+ CD25+ T cells (T regs) rosetting around the RS cells. In the initial trial 30 consecutive patients with HL were entered and treated with an initial dose of 10 or 15 mCi of 90Y-daclizumab depending on the transplant status. If patients tolerated the initial cycle without significant hematologic toxicity they could receive 90Y-daclizumab, IL-15 mCi per cycle every 6 to 10 weeks to a maximum of 7 doses in the absence of unacceptable toxicity. There were 7 PRs (partial remissions) and 12 CRs (complete remissions). Toxicities primarily were myelodysplastic syndrome. Responses were observed in patients whose Reed-Sternberg cells were negative provided the adjacent polyclonal T-cells were positive for CD25 due to the crossfire effects of the beta emissions from yttrium-90. To increase the period of time of emissions a trial evaluating 90Y-daclizumab directed monoclonal antibody therapy in combination with autologous stem cell therapy for high risk relapsed Hodgkin's disease patients has been initiated. A major impediment to the Clinical Trials Team monoclonal antibody mediated therapeutic program for patients with T cell leukemia/lymphomas has been the lack of interest in the orphan disease ATL by biopharmaceutical companies developing mAbs who have concluded that ATL is not a worthwhile clinical indication for business reasons. Fortunately we have been able to join a Phase II trial for antibodies directed against chemokine receptor 4 (CCR4) in the treatment of ATL. The defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 the target CCR4 which is highly expressed in ATL patients (88%) has been shown to be safe and well tolerated for patients. The Clinical Trials Team has initiated a trial with this agent. In addition to receptor directed monoclonal antibody mediated trials the Clinical Trials Team has initiated an initial clinical evaluation of JAK inhibitors for patients with smoldering or chronic ATL in a Phase II trial with the JAK1 inhibitor ruxolitinib. Previously it was demonstrated in collaboration with the Waldmann Laboratory that patients with early phases of adult T-cell leukemia (smoldering or chronic ATL) the retrovirus HTLV-1 encoded Tax protein constitutively activates two autocrine (IL-2/IL-2R) and IL-15/IL-15R and one paracrine loop (IL-9/IL-9R). These cytokine pathways transmit activating signals that phosphorylate JAK1/JAK3/STAT5 intermediate proteins. These studies supported the therapeutic potential for JAK1 and JAK3 inhibitors in the treatment of ATL. Furthermore, the application of molecular interference loss-of-function shRNA JAK1 and JAK3 screens to target ATL cell lines showed that JAK1 and JAK3 are critical for the proliferation and survival of cytokine dependent ATL cell lines. High-throughput matrix screens were performed for cellular signaling analysis directed at known targets and pathways to define synergistic agents. It was shown the focus was on the JAK1 inhibitor ruxolitinib. It was demonstrated that there was considerable additivity and synergy between ruxolitinib and the Bcl-xLinhibitor navitoclax. To translate these studies on the gamma cytokine JAK/STAT pathway the Clinical Trials Team has initiated a Phase II trial evaluating the safety and efficacy of ruxolitinib in patients with smoldering or chronic adult T-cell leukemia (ATL).
