Despite impressive advances in combination chemoimmunotherapy, the majority of newly diagnosed patients with non-Hodgkin lymphomas (NHL) will relapse, and once this occurs only a minority can be cured with current treatments. The primary objective of this project is to develop and optimize an innovative strategy using high-dose radiolabeled monoclonal antibodies targeting the pan-hematopoietic antigen, CD45 in conjunction with autologous stem cell transplantation (ASCT) for patients with relapsed or refractory B or T-cell lymphomas. This approach possesses several advantages. It circumvents potential blocking of CD20 sites by rituximab, amplifies radiation exposure to sites of minimal disease, and allows treatment of CD20-negative lymphomas as well as CD20-expressing lymphomas with a safe, exportable, therapeutic radionuclide, [90]Y.
Four Aims are proposed within the context of a phase I clinical trial designed to identify the maximally tolerated dose (MTD) of [90]Y-BC8 that can be delivered prior to ASCT. First, the optimal antibody protein dose of BCS will be determined to assure that a majority of patients achieve higher radiation exposures in tumor sites than in critical normal organs (Aim 1). Second, direct comparisons of the ability of CD45 and CD20 antibodies to target tumor sites will be obtained to confirm the benefit of this strategy in patients with B-NHL (Aim 2). Third, the critical dosimetry question regarding the ability of [111]In to predict [90]Y biodistribution will be addressed by means of [86]Y PET imaging (Aim 3). Following these dosimetry studies, all patients will be treated with [90]Y-BC8 in order to estimate the MTD of this therapy prior to ASCT (Aim 4). This comprehensive development plan should enable the successful evaluation of this innovative therapeutic strategy and achieve the long-term objectives of further establishing and augmenting the role of high dose radioimmunotherapy and ASCT in the treatment of relapsed NHL.

Public Health Relevance

Non-Hodgkin Lymphoma (NHL) afflicts over 60,000 Americans each year and in most cases is not cured. This project focuses on developing an innovative strategy to deliver potentially curative doses of intravenous targeted radiation therapy to all sites of disease in patients with relapsed NHL with the expectation that response rates, remission durations, and survival will be improved.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA044991-26
Application #
8719024
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
26
Fiscal Year
2014
Total Cost
$258,380
Indirect Cost
$120,752
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Phipps, Colin; Gopal, Ajay K; Storer, Barry E et al. (2015) Autologous transplant for relapsed follicular lymphoma: impact of pre-transplant rituximab sensitivity. Leuk Lymphoma 56:92-6
Palanca-Wessels, Maria Corinna; Press, Oliver W (2014) Advances in the treatment of hematologic malignancies using immunoconjugates. Blood 123:2293-301
Balkin, Ethan R; Kenoyer, Aimee; Orozco, Johnnie J et al. (2014) In vivo localization of ??Y and ยน??Lu radioimmunoconjugates using Cerenkov luminescence imaging in a disseminated murine leukemia model. Cancer Res 74:5846-54
Lionberger, Jack M; Pagel, John M; Sandhu, Vicky K et al. (2014) Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design. Br J Haematol 166:375-81
Mawad, Raya; Gooley, Ted A; Rajendran, Joseph G et al. (2014) Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol Blood Marrow Transplant 20:1363-8
Gopal, Ajay K; Gooley, Ted A; Rajendran, Joseph G et al. (2014) Myeloablative I-131-tositumomab with escalating doses of fludarabine and autologous hematopoietic transplantation for adults age ? 60 years with B cell lymphoma. Biol Blood Marrow Transplant 20:770-5
Matesan, Manuela; Rajendran, Joseph; Press, Oliver W et al. (2014) 90Y-ibritumomab tiuxetan therapy in allogeneic transplantation in B-cell lymphoma with extensive marrow involvement and chronic lymphocytic leukemia: utility of pretransplantation biodistribution. Nucl Med Commun 35:1132-42
Cassaday, Ryan D; Guthrie, Katherine A; Budde, Elizabeth L et al. (2013) Specific features identify patients with relapsed or refractory mantle cell lymphoma benefitting from autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 19:1403-6
Cairo, Mitchell S; Woessmann, Willi; Pagel, John (2013) Advances in hematopoietic stem cell transplantation in childhood and adolescent lymphomas. Biol Blood Marrow Transplant 19:S38-43
Mawad, Raya; Lionberger, Jack M; Pagel, John M (2013) Strategies to reduce relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Curr Hematol Malig Rep 8:132-40

Showing the most recent 10 out of 94 publications