Joseph D. Rosenblatt, M.D.
Professor of Medicine; Division Chief Hematology Oncology
Description of Research
Development of novel immune therapy and gene therapy strategies for cancer. Dr. Rosenblatt’s research involves the development of novel immune therapy and gene therapy strategies for cancer. Novel means of immune effector molecule delivery, which combines the antigen binding capabilities and localization characteristics of antibodies with the local delivery of a co-stimulatory molecule and/or anti-angiogenic peptide, are under investigation. Antibody fusion proteins targeting the human breast and ovarian cancer her2/neu antigen, linked to the extracellular domains of the B7.1 and/or the NKG2D-L costimulatory ligand, have been synthesized and the in vitro ability to bind to cognate antigenic targets and to deliver a local costimulatory signal documented. Antibody NKG2D-L fusions show impressive activity in preclinical models and act by linking the innate and adaptive immune systems. Additional fusions currently being tested in the laboratory include fusion of the anti-angiogenic peptide endostatin to anti-her2/neu antibody sequences. A novel anti-body fusion, which targets delivery of a mutant endostatin to the site of her2/neu expressing tumors, has been synthesized in collaboration with Seung-Uon Shin, Ph.D., in the Department of Medicine, and shows excellent efficacy in preclinical models. This fusion appears to substantially improve the results obtained with either antibody or endostatin alone, and is being readied for Phase I testing. Newer fusion proteins are being synthesized that target EGFR for solid tumors, and CD2D in lymphomas are also being tested for efficacy. Antibody-endostatin fusions are being readied for Phase I testing in man.
Dr. Rosenblatt's laboratory has also studied the effect of B cells on T-cell antitumor response. The B-cell deficient model also has demonstrated that T-cell responses to tumor may be better than those seen in the immunocompetent mouse. The laboratory is aggressively investigating the reasons for altered responses in the absence of B cells and the possibility of applying this approach to the human setting using antibody depletion of B cells. The effects of B cells on expression and differentiation of Treg cells and/or cytolytic CD8+ T-cells is being studied in murine models, and human correlates are being investigated.
- Developed novel antibody-chemokine and antibody co-stimulatory ligand fusion proteins with dual function and preserved targeting capabilities
- Demonstrated the potential role for HSV amplicon vectors in gene therapy of malignancy particularly CLL
- Demonstrated the utility of combining chemokine delivery with co-stimulating ligands in augmenting mouse response to tumors
- Demonstrated the effect of B cells on T cell response to tumor in several animal models
- Development of antibody-endostatin fusion proteins targeting her2 and EGFR expressing cancers
Selected Cancer-Related Publications
- Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA, Han TH, Sievers EL, Bartlett NL. A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies. Clin Cancer Res 18:248-255, 2012. Read more »
- Cho HM, Rosenblatt JD, Tolba K, Shin SJ, Shin DS, Calfa C, Zhang Y, Shin SU. Delivery of NKG2D Ligand Using an Anti-HER2 Antibody-NKG2D Ligand Fusion Protein Results in an Enhanced Innate and Adaptive Antitumor Response. Cancer Res 70:10121-30, 2010. Read more »
- Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide,vincristine, ifosfamide, etoposide, cytarabin, and thalidomide (R-MACLO-IVAM-T),a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma 51:406-14, 2010. Read more »
- Schreiber TH, Deyev VV, Rosenblatt JD, Podack ER. Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination. Cancer Res 69:2026-33, 2009. Read more »
- Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Ren H, Harrop K, Whiting N, Drachman JG. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin's lymphoma. J Clin Oncol 27:4371-7,2009. Read more »
- Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett NL, Bosly A, Pinter-Brown L, Kennedy D, Sievers EL, Gopal AK. A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol 146:171-9, 2009. Read more »
Collaborating in the Multidisciplinary Research Program(s):