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Steven Rosenberg and CAR

Jennifer N Brudno, Robert P T Somerville, Victoria Shi, Jeremy J Rose, David C Halverson, Daniel H Fowler, Juan C Gea-Banacloche, Steven Z Pavletic, Dennis D Hickstein, Tangying L Lu, Steven A Feldman, Alexander T Iwamoto, Roger Kurlander, Irina Maric, Andre Goy, Brenna G Hansen, Jennifer S Wilder, Bazetta Blacklock-Schuver, Frances T Hakim, Steven A Rosenberg, Ronald E Gress, James N Kochenderfer
PURPOSE: Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues. METHODS: We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19...
April 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Li Liu, Bhavik Patel, Mustafa H Ghanem, Virgilio Bundoc, Zhili Zheng, Richard A Morgan, Steven A Rosenberg, Barna Dey, Edward A Berger
UNLABELLED: Adoptive transfer of CD8 T cells genetically engineered to express "chimeric antigen receptors" (CARs) represents a potential approach toward an HIV infection "functional cure" whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding...
July 2015: Journal of Virology
Daniel W Lee, James N Kochenderfer, Maryalice Stetler-Stevenson, Yongzhi K Cui, Cindy Delbrook, Steven A Feldman, Terry J Fry, Rimas Orentas, Marianna Sabatino, Nirali N Shah, Seth M Steinberg, Dave Stroncek, Nick Tschernia, Constance Yuan, Hua Zhang, Ling Zhang, Steven A Rosenberg, Alan S Wayne, Crystal L Mackall
BACKGROUND: Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells...
February 7, 2015: Lancet
Rachel E Beard, Zhili Zheng, Kiran H Lagisetty, William R Burns, Eric Tran, Stephen M Hewitt, Daniel Abate-Daga, Shannon F Rosati, Howard A Fine, Soldano Ferrone, Steven A Rosenberg, Richard A Morgan
BACKGROUND: The development of immunotherapy has led to significant progress in the treatment of metastatic cancer, including the development of genetic engineering technologies that redirect lymphocytes to recognize and target a wide variety of tumor antigens. Chimeric antigen receptors (CARs) are hybrid proteins combining antibody recognition domains linked to T cell signaling elements. Clinical trials of CAR-transduced peripheral blood lymphocytes (PBL) have induced remission of both solid organ and hematologic malignancies...
2014: Journal for Immunotherapy of Cancer
James N Kochenderfer, Mark E Dudley, Sadik H Kassim, Robert P T Somerville, Robert O Carpenter, Maryalice Stetler-Stevenson, James C Yang, Giao Q Phan, Marybeth S Hughes, Richard M Sherry, Mark Raffeld, Steven Feldman, Lily Lu, Yong F Li, Lien T Ngo, Andre Goy, Tatyana Feldman, David E Spaner, Michael L Wang, Clara C Chen, Sarah M Kranick, Avindra Nath, Debbie-Ann N Nathan, Kathleen E Morton, Mary Ann Toomey, Steven A Rosenberg
PURPOSE: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells...
February 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Daniel Abate-Daga, Steven A Rosenberg, Richard A Morgan
Pancreatic cancer remains largely an incurable disease necessitating the development of novel therapeutic approaches. Adoptive immunotherapy using chimeric antigen receptor (CAR)-transduced T cells represents an alternative treatment with curative potential. We present an overview of the engineering of novel CARs targeting prostate stem cell antigen (PSCA), implications for the development of immunotherapies, and potential strategies to circumvent on-target/off-tumor toxicities.
2014: Oncoimmunology
Daniel Abate-Daga, Kiran H Lagisetty, Eric Tran, Zhili Zheng, Luca Gattinoni, Zhiya Yu, William R Burns, Anne M Miermont, Yaroslav Teper, Udo Rudloff, Nicholas P Restifo, Steven A Feldman, Steven A Rosenberg, Richard A Morgan
Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta...
December 2014: Human Gene Therapy
John H Sampson, Bryan D Choi, Luis Sanchez-Perez, Carter M Suryadevara, David J Snyder, Catherine T Flores, Robert J Schmittling, Smita K Nair, Elizabeth A Reap, Pamela K Norberg, James E Herndon, Chien-Tsun Kuan, Richard A Morgan, Steven A Rosenberg, Laura A Johnson
PURPOSE: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues...
February 15, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Giao Q Phan, Steven A Rosenberg
BACKGROUND: Current FDA-approved therapeutic options for patients with metastatic melanoma include dacarbazine, interleukin 2, ipilimumab, vemurafenib, dabrafenib, and trametinib, but long-term tumor regression using available agents remains out of reach for most patients. Adoptive cell transfer (ACT) with autologous tumor-infiltrating lymphocytes (TILs) has shown encouraging results in clinical trials, with evidence of durable ongoing complete responses in patients with advanced melanoma...
October 2013: Cancer Control: Journal of the Moffitt Cancer Center
James N Kochenderfer, Mark E Dudley, Robert O Carpenter, Sadik H Kassim, Jeremy J Rose, William G Telford, Frances T Hakim, David C Halverson, Daniel H Fowler, Nancy M Hardy, Anthony R Mato, Dennis D Hickstein, Juan C Gea-Banacloche, Steven Z Pavletic, Claude Sportes, Irina Maric, Steven A Feldman, Brenna G Hansen, Jennifer S Wilder, Bazetta Blacklock-Schuver, Bipulendu Jena, Michael R Bishop, Ronald E Gress, Steven A Rosenberg
New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions...
December 12, 2013: Blood
Eric Tran, Dhanalakshmi Chinnasamy, Zhiya Yu, Richard A Morgan, Chyi-Chia Richard Lee, Nicholas P Restifo, Steven A Rosenberg
Fibroblast activation protein (FAP) is a candidate universal target antigen because it has been reported to be selectively expressed in nearly all solid tumors by a subset of immunosuppressive tumor stromal fibroblasts. We verified that 18/18 human tumors of various histologies contained pronounced stromal elements staining strongly for FAP, and hypothesized that targeting tumor stroma with FAP-reactive T cells would inhibit tumor growth in cancer-bearing hosts. T cells genetically engineered with FAP-reactive chimeric antigen receptors (CARs) specifically degranulated and produced effector cytokines upon stimulation with FAP or FAP-expressing cell lines...
June 3, 2013: Journal of Experimental Medicine
James N Kochenderfer, Steven A Rosenberg
Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells...
May 2013: Nature Reviews. Clinical Oncology
Richard A Morgan, Laura A Johnson, Jeremy L Davis, Zhili Zheng, Kevin D Woolard, Elizabeth A Reap, Steven A Feldman, Nachimuthu Chinnasamy, Chien-Tsun Kuan, Hua Song, Wei Zhang, Howard A Fine, Steven A Rosenberg
No curative treatment exists for glioblastoma, with median survival times of less than 2 years from diagnosis. As an approach to develop immune-based therapies for glioblastoma, we sought to target antigens expressed in glioma stem cells (GSCs). GSCs have multiple properties that make them significantly more representative of glioma tumors than established glioma cell lines. Epidermal growth factor receptor variant III (EGFRvIII) is the result of a novel tumor-specific gene rearrangement that produces a unique protein expressed in approximately 30% of gliomas, and is an ideal target for immunotherapy...
October 2012: Human Gene Therapy
David F Stroncek, Carolina Berger, Martin A Cheever, Richard W Childs, Mark E Dudley, Peter Flynn, Luca Gattinoni, James R Heath, Michael Kalos, Francesco M Marincola, Jeffrey S Miller, Gustavo Mostoslavsky, Daniel J Powell, Mahendra Rao, Nicholas P Restifo, Steven A Rosenberg, John O'Shea, Cornelis J M Melief
A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines...
2012: Journal of Translational Medicine
Dhanalakshmi Chinnasamy, Zhiya Yu, Sid P Kerkar, Ling Zhang, Richard A Morgan, Nicholas P Restifo, Steven A Rosenberg
PURPOSE: We investigated the feasibility of delivering the proinflammatory cytokine interleukin (IL)-12 into tumor using T cells genetically engineered to express a chimeric antigen receptor (CAR) against the VEGF receptor-2 (VEGFR-2). EXPERIMENTAL DESIGN: Two different strains of mice bearing five different established subcutaneous tumors were treated with syngeneic T cells cotransduced with an anti-VEGFR-2 CAR and a constitutively expressed single-chain murine IL-12 or an inducible IL-12 gene after host lymphodepletion...
March 15, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
James N Kochenderfer, Mark E Dudley, Steven A Feldman, Wyndham H Wilson, David E Spaner, Irina Maric, Maryalice Stetler-Stevenson, Giao Q Phan, Marybeth S Hughes, Richard M Sherry, James C Yang, Udai S Kammula, Laura Devillier, Robert Carpenter, Debbie-Ann N Nathan, Richard A Morgan, Carolyn Laurencot, Steven A Rosenberg
We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients...
March 22, 2012: Blood
Tristen S Park, Steven A Rosenberg, Richard A Morgan
Administration of ex vivo cultured, naturally occurring tumor-infiltrating lymphocytes (TILs) has been shown to mediate durable regression of melanoma tumors. However, the generation of TILs is not possible in all patients and there has been limited success in generating TIL in other cancers. Advances in genetic engineering have overcome these limitations by introducing tumor-antigen-targeting receptors into human T lymphocytes. Physicians can now genetically engineer lymphocytes to express highly active T-cell receptors (TCRs) or chimeric antigen receptors (CARs) targeting a variety of tumor antigens expressed in cancer patients...
November 2011: Trends in Biotechnology
Hildegund C J Ertl, John Zaia, Steven A Rosenberg, Carl H June, Gianpietro Dotti, Jeffrey Kahn, Laurence J N Cooper, Jacqueline Corrigan-Curay, Scott E Strome
T cells that are genetically modified to express single-chain chimeric antigen receptors (CAR) have shown promise in early cancer immunotherapy clinical trials. Unfortunately, 2 recent deaths in cancer patients treated with CAR T cells have created some uncertainty on how to best mitigate patient risk, while continuing to advance this very promising therapeutic avenue. In order to address these concerns, the Recombinant DNA Advisory Committee (RAC) held a symposium, the objectives of which were to first review the reported treatment-associated toxicities and, second, to discuss methods for improving safety and efficacy...
May 1, 2011: Cancer Research
Dhanalakshmi Chinnasamy, Zhiya Yu, Marc R Theoret, Yangbing Zhao, Rajeev K Shrimali, Richard A Morgan, Steven A Feldman, Nicholas P Restifo, Steven A Rosenberg
Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis...
November 2010: Journal of Clinical Investigation
James N Kochenderfer, Wyndham H Wilson, John E Janik, Mark E Dudley, Maryalice Stetler-Stevenson, Steven A Feldman, Irina Maric, Mark Raffeld, Debbie-Ann N Nathan, Brock J Lanier, Richard A Morgan, Steven A Rosenberg
Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses. We treated a patient with advanced follicular lymphoma by administering a preparative chemotherapy regimen followed by autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognized the B-cell antigen CD19. The patient's lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient's bone marrow after infusion of anti-CD19-CAR-transduced T cells...
November 18, 2010: Blood
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