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.
|Cowan, Andrew J; Stevenson, Philip A; Cassaday, Ryan D et al. (2016) Pretransplantation Minimal Residual Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission. Biol Blood Marrow Transplant 22:380-5|
|Cowan, Andrew J; Klippel, Zandra K; Stevenson, Philip A et al. (2016) Pre-transplantation novel agent induction predicts progression-free survival for patients with immunoglobulin light-chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation. Amyloid 23:254-259|
|Green, Damian J; Frayo, Shani L; Lin, Yukang et al. (2016) Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers. Cancer Res :|
|Graf, Solomon A; Vaughn, Jennifer E; Chauncey, Thomas R et al. (2016) Comorbidities, Alcohol Use Disorder, and Age Predict Outcomes after Autologous Hematopoietic Cell Transplantation for Lymphoma. Biol Blood Marrow Transplant 22:1582-7|
|Orozco, Johnnie J; Kenoyer, Aimee; Balkin, Ethan R et al. (2016) Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. Blood 127:352-9|
|Rufener, Gregory A; Press, Oliver W; Olsen, Philip et al. (2016) Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab. Cancer Immunol Res 4:509-19|
|Chen, Robert; Gopal, Ajay K; Smith, Scott E et al. (2016) Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128:1562-6|
|Graf, Solomon A; Gopal, Ajay K (2016) Idelalisib for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother 17:265-74|
|Green, D J; Bensinger, W I; Holmberg, L A et al. (2016) Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 51:1330-1336|
|Krem, Maxwell M; Gopal, Ajay K (2015) New targeted therapies for indolent B-cell malignancies in older patients. Am Soc Clin Oncol Educ Book :e365-74|
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