Lymphoma afflicts over 70,000 individuals each year in the United States with a 1 in 47 lifetime risk, yet despite improved therapeutic options, most will die of their disease. Radiation remains the single most effective therapy for the treatment of localized lymphoma, but the ability to escalate the absorbed dose to curative levels in patients with multifocal sites of disease is limited by non-target organ toxicity. Dr. Gopal has spent the last 15 years evaluating, translating, and optimizing the use of molecularly targeted radioimmunotherapy (RIT) for the treatment of lymphoma and has been well funded and recognized for his work. He was the first to propose and confirm and problem of competitive targeting of tumor antigens and leads a P01 project on RIT based transplantation for lymphoma. This K24 Midcareer Investigator Award in Patient-Oriented Research (POR) will capitalize on Dr. Gopal's expertise in lymphoma and RIT, his leadership as the Director of Clinical Research in Hematologic Malignancies, his role as principal investigator on the hematologic malignancy database and tissue acquisition protocol, and his successful track record of mentoring along with the extensive infrastructure at his center to foster the development of the next generation of investigators in patient oriented research in lymphoma, hematologic malignancies, and stem cell transplantation. He will devote 50% of his time to mentoring in POR.
Aim 1 will specifically evaluate the potential for circulating rituximab blocking of CD20 and investigate 2 methods to circumvent this challenge with the readout via detailed dosimetry analysis.
The second Aim will determine the clinical impact of delivering myeloablative doses of anti-CD45 RIT prior to autologous stem cell transplantation as a method to treat refractory lymphoma and correlate outcomes with absorbed doses to tumor sites.
Aim 3 will evaluate ability of pre-transplant disease control by means of 'mega-dose'anti-CD20 RIT to afford improved disease-free survival after reduced intensity allogeneic transplantation.
In Aim 4 Dr. Gopal hypothesizes that the nodal irradiation delivered with RIT could provide a beneficial immunomodulatory effect and tests this premise by comparing CD20 and CD45 targeting on lymphocyte subsets, and evaluating inflammatory cytokines, and graft-versus host disease. These projects will provide an ample opportunity for POR mentoring of oncology trainees as well as co-mentoring of related nuclear medicine and hematopatholgy fellows to help ensure the success of the next generation of clinical scientists.
This proposal supports the training of the next generation of patient oriented investigators in molecular targeted therapies for lymphoma, a disease which is fatal in the majority of the 70,000 individuals afflicted each year in the United States. Dr. Gopal has a successful track record in research and mentorship for clinician-scientists and in this application will apply his expertise in combination with the outstanding research environment to further our understanding of the use of molecularly targeted radiation prior to hematopoietic stem cell transplantation.
|Green, Damian J; O'Steen, Shyril; Lin, Yukang et al. (2018) CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. Blood 131:611-620|
|Budde, Lihua E; Wu, David; Martin, Daniel B et al. (2018) Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Br J Haematol 183:601-607|
|Poston, Jacqueline N; Fromm, Jonathan R; Rasmussen, Heather A et al. (2018) A pilot study of weekly brentuximab vedotin in patients with CD30+ malignancies resistant to brentuximab vedotin every 3 weeks. Br J Haematol :|
|Chow, Victor A; Shadman, Mazyar; Gopal, Ajay K (2018) Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood 132:777-781|
|Puronen, Camille E; Cassaday, Ryan D; Stevenson, Philip A et al. (2018) Long-Term Follow-Up of 90Y-Ibritumomab Tiuxetan, Fludarabine, and Total Body Irradiation-Based Nonmyeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B Cell Lymphoma. Biol Blood Marrow Transplant 24:2211-2215|
|Greenbaum, Adam M; Green, Damian J; Holmberg, Leona A et al. (2018) Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Blood Res 53:223-226|
|Mostaghel, Elahe A; Martin, Paul S; Mongovin, Stephen et al. (2017) Androgen receptor expression in mantle cell lymphoma: Potential novel therapeutic implications. Exp Hematol 49:34-38.e2|
|Li, Ang; Davis, Chris; Wu, Qian et al. (2017) Management of venous thromboembolism during thrombocytopenia after autologous hematopoietic cell transplantation. Blood Adv 1:707-714|
|O'Steen, Shyril; Green, Damian J; Gopal, Ajay K et al. (2017) Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas. Cancer Res 77:3885-3893|
|Cowan, Andrew J; Stevenson, Phillip A; Gooley, Ted A et al. (2017) Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma. Br J Haematol 176:583-590|
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