Joseph D. Rosenblatt, M.D.
Professor of Medicine; Division Chief Hematology Oncology
Description of Research
Dr. Rosenblatt’s research is focused on the development of novel immune and gene therapy approaches to cancer. Dr. Rosenblatt has studied novel strategies for recruitment of immune effector cells to tumors using localized elaboration or delivery of chemokines and/or delivery of co-stimulatory molecules in order to effect an improved antitumor immune response. Chemokine delivery has been investigated alone or in combination with, expression of co-stimulatory ligands such as CD80, and/or CD40L using a variety of vector strategies, including the use of herpes simplex amplicon vectors in murine tumor models. In parallel efforts, Dr. Rosenblatt’s laboratory in collaboration with Dr. Khaled Tolba, in the Division of Hematology-Oncology, has investigated the use of HSV derived helper virus-free amplicons to augment the immunogenicity and antigen presenting capability of human chronic lymphocytic leukemia cells. CD40L, CD80 and the TNF family member LIGHT have been used to target CLL cells and augment immunogenicity using HSV amplicons as a delivery system.
In addition to these efforts, Dr. Rosenblatt’s laboratory working in tandem with Seun-Uon Shin, Ph. D., a research associate professor in the Division of Hematology and Oncology, has pioneered the delivery of immune effector molecules as well as anti-angiogenic molecules to the site of human tumors, using genetically engineered antibody fusion proteins. These proteins combine the antigen binding and localizing capabilities of antibodies with the ability to deliver a biological payload in the form of an anti-angiogenic peptide, or immune effector molecule. Antibody fusion proteins targeting the human breast and ovarian cancer antigen HER2/neu, and the highly prevalent EGFR antigen found in lung, head and neck, triple negative breast cancer and other solid tumors, have been linked to extracellular domains of T-cell co-stimulatory molecules such as CD80, or co-stimulatory ligands for NK and T-cells such as NKG2D-L, and the antibody fusion proteins synthesized and purified. These fusion proteins have been tested in animal models and are capable of augmenting antitumor immunity in a manner which invokes both the innate as well as the adaptive immune response.
A second class of antibody fusion protein involves the delivery of a biological anti-angiogenic payload to the site of tumors in the form of a modified endostatin peptide. Antibody endostatin fusion proteins have been synthesized against both the HER2 and EGFR targets, and have demonstrated the ability to inhibit angiogenesis in vivo efficacy in a variety of animal models, leading to tumor regression in breast cancer xenograft models. As a corollary of this research, the effects of these antibody endostatin fusion proteins have also recently been explored in relation to the phenomenon known as vasculogenic mimicry. Antibody-endostatin fusion proteins have been demonstrated to inhibit the ability of tumors to form vascular-like channels in vitro, and are currently being tested against in vivo tumor models. Vasculogenic mimicry has not been effectively targeted in the clinic, and the Rosenblatt lab is exploring whether combined inhibition of endothelial angiogenesis, as well as vasculogenic mimicry by human tumors, may be a more effective means of preventing tumor growth and metastasis.
In addition to these studies, Dr. Rosenblatt’s laboratory has been studying the role of B cells in modulating antitumor immunity. In the context of studying antibody fusion proteins, it was noted that B cell deficient mice mounted more aggressive T cell responses to tumor. The laboratory has investigated the reasons for altered immune responses in the absence of B cells, and the role of B cells in modulating the adaptive anti-tumor immune response in murine models.
- The laboratory has developed novel antibody chemokine, and co-stimulatory ligand fusion proteins with immune effector functions, and preserved targeting capabilities.
- The laboratory has pioneered the use of HSV amplicon vectors as a means of augmenting immunogenicity in malignancy, particularly CLL.
- The laboratory has developed antibody endostatin fusion proteins with profound effects on angiogenesis and vasculogenic mimicry in human tumor xenografts.
- The laboratory is currently investigating a novel approach involving inhibition of both vasculogenic mimicry by tumors, and angiogenesis as a means of inhibiting tumor growth, using anti-HER2 and anti-EGFR endostatin fusion proteins.
- The laboratory is collaborating with an industrial partner in moving an anti-EGFR-IgG1 endostatin fusion protein into the clinic.
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):