Dr. John E. Janik and colleagues from the National Institutes of Health and from the Roger Williams Medical Center report in the Proceedings of the National Academy of Sciences on a novel radioimmunotherapy that generated responses in 50% of relapsed Hodgkin’s lymphoma (HL) patients. Even with drastic improvement of treatment strategies for HL over the past 50 years, many patients remain unresponsive to therapy or undergo relapse. Although radionuclide-labeled monoclonal antibodies have been previously tested, the current strategy of using 90Y-daclizumab (i.e. radiolabeled IL-2 receptor alpha subunit, 90Y-labeled CD25) was designed to provide two distinct advantages. First, CD25 is expressed on some Reed-Sternberg cells (large, malignant cells indicative of HL), is overexpressed on T cells surrounding Reed-Sternberg cells – and, except for Treg cells, CD25 is not expressed on resting lymphoid cells. Second, since 90Y acts through “crossfire”, it can kill at a distance of several tumor cell diameters – including Reed-Sternberg cells that do not express CD25, as long as a surrounding T cell does.
The report discusses the use of this strategy (10-15 mCi 90Y-daclizumab every 6-10 weeks, up to seven doses) in treating 46 HL patients in a phase II trial. Thrombocytopenia and granulocytopenia affected 40 of the 46 patients. Although 13% of the 46 patients developed myelodysplastic syndrome (median time to diagnosis was 37 months), the study is too small to determine the roles played by pre-90Y-daclizumab chemotherapy and by systemic radioimmunotherapy; therefore, the authors recommend that subsequent trials incorporate pretreatment cytogenic studies prior to 90Y-daclizumab exposure. Despite these potential complications, 90Y-daclizumab single agent treatment resulted in 14 complete and 9 partial remissions, which were achieved following two to five infusions. Since a separate study using saturating doses of daclizumab alone failed to generate any complete or partial responses, the authors of the current trial recognize a critical role for 90Y. They also suggest a positive role for their trial’s use of repeated dosing, which increases the tumor’s total radiation. Correlative studies using phosphorylated H2AX expression as a marker of radiation-induced DNA damage indicated that nonmalignant cells in the tumor microenvironment were predominantly affected; the authors suggest that in this way, the ability of the microenvironment to nurture the tumor is compromised. Aiming for further optimization, the authors have begun a subsequent trial incorporating autologous bone-marrow transplant and escalating doses of 90Y-daclizumab.[Janik JE, Morris JC, O’Mahony D, Pittaluga S, Jaffe ES, Redon CE, Bonner WM, Brechbiel MW, Paik CH, Whatley M, Chen C, Lee JH, Fleisher TA, Brown M, White JD, Stewart DM, Fioravanti S, Lee CC, Goldman CK, Bryant BR, Junghans RP, Carrasquillo JA, Worthy T, Corcoran E, Conlon KC, Waldmann TA. 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma. Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13045-50.]