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Yair Herishanu,
Patricia Pérez-Galán,
Delong Liu,
Angélique Biancotto,
Stefania Pittaluga,
Berengere Vire,
Federica Gibellini,
Ndegwa Njuguna,
Elinor Lee,
Lawrence Stennett, [......],
Maryalice Stetler-Stevenson,
Constance Yuan, Richard Sherry,
Diane C Arthur,
Irina Maric,
Therese White,
Gerald E Marti,
Peter Munson,
Wyndham H Wilson,
Adrian Wiestner
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ABSTRACT: Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-κB activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-κB activation, we detected phosphorylation of SYK and IκBα, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370.
Blood 10/2010; 117(2):563-74. · 9.90 Impact Factor
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ABSTRACT: Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable tumor from which (2) TIL can be generated that (3) exhibit tumor-specific reactivity. From July 2002 to July 2007, 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from tumors that were larger in diameter and digests that had a higher percentage of lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation.
Journal of immunotherapy (Hagerstown, Md.: 1997) 10/2010; 33(8):840-7. · 3.20 Impact Factor
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Mark E Dudley,
James C Yang, Richard Sherry,
Marybeth S Hughes,
Richard Royal,
Udai Kammula,
Paul F Robbins,
JianPing Huang,
Deborah E Citrin,
Susan F Leitman,
John Wunderlich,
Nicholas P Restifo,
Armen Thomasian,
Stephanie G Downey,
Franz O Smith,
Jacob Klapper,
Kathleen Morton,
Carolyn Laurencot,
Donald E White,
Steven A Rosenberg
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ABSTRACT: The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.
We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.
Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.
Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
Journal of Clinical Oncology 10/2008; 26(32):5233-9. · 18.37 Impact Factor
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ABSTRACT: Recurrent chronic pelvic pain should prompt physicians to reassess the patient. The threshold to perform laparoscopy, and to consider and surgically treat all potential disease associated with pain, even non-gynecologic etiologies, should be low, especially in those whose pain is focal or unresponsive to hormone therapy.
Fertility and sterility 05/2008; 89(4):962-3. · 3.97 Impact Factor
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ABSTRACT: Local destruction of individual metastases by any of a number of effective modalities fails as a treatment for most patients with disseminated cancer because of the presence of either undetected micrometastases or simply too many lesions. The availability of a systemic therapy that could reduce the number of metastases to a manageable few would dramatically increase the utility of surgical metastasectomy or other locally ablative measures. Interleukin-2-based immunotherapy can serve exactly this function in some patients with renal cancer or melanoma. We review the effectiveness of surgery in treating limited relapses or residual disease in patients who have responded to systemic immunotherapy. These data indicate that a surprising percentage of such patients can enjoy durable disease-free survival after surgical removal of their oligometastases, and, for a significant minority, it appears to be curative.
Seminars in Radiation Onchology 05/2006; 16(2):131-5. · 4.03 Impact Factor
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Kimberly R Lindsey,
Linda Gritz, Richard Sherry,
Andrea Abati,
Patricia A Fetsch,
Lisa C Goldfeder,
Monica I Gonzales,
Kimberly A Zinnack,
Linda Rogers-Freezer,
Leah Haworth,
Sharon A Mavroukakis,
Donald E White,
Seth M Steinberg,
Nicholas P Restifo,
Dennis L Panicali,
Steven A Rosenberg,
Suzanne L Topalian
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ABSTRACT: Two clinical trials were conducted to evaluate the clinical efficacy and immunologic impact of vaccination against the tyrosinase protein plus systemic interleukin 2 (IL-2) administration in patients with advanced metastatic melanoma.
Full-length tyrosinase was employed as an immunogen to induce diverse immunologic responses against a commonly expressed melanoma antigen. Heterologous prime/boost vaccination with recombinant vaccinia and fowlpox vectors encoding tyrosinase was first explored in a randomized three-arm phase II trial, in which vaccines were administered alone or concurrently with low-dose or high-dose IL-2. In a subsequent single cohort phase II trial, all patients received the same vaccines and high-dose IL-2 sequentially rather than concurrently.
Among a total of 64 patients treated on these trials, 8 objective partial responses (12.5%) were observed, all in patients receiving high-dose IL-2. Additional patients showed evidence of lesional regression (mixed tumor response) or overall regression that did not achieve partial response status (minor response). In vitro evidence of enhanced immunity against tyrosinase following protocol treatments was documented in 3 of 49 (6%) patients tested serologically, 3 of 23 (13%) patients tested for T-cell recognition of individual tyrosinase peptides, and 4 of 16 (25%) patients tested for T-cell recognition of full-length tyrosinase protein with real-time reverse transcription-PCR techniques.
Whereas prime/boost immunization with recombinant vaccinia and fowlpox viruses enhanced antityrosinase immunity in some patients with metastatic melanoma, it was ineffective alone in mediating clinical benefit, and in combination with IL-2 did not mediate clinical benefit significantly different from that expected from treatment with IL-2 alone.
Clinical Cancer Research 05/2006; 12(8):2526-37. · 7.74 Impact Factor
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Sattva S Neelapu,
Barry L Gause,
Daniel A Nikcevich,
Stephen J Schuster,
Jane Winter,
Jon P Gockerman,
Thomas Loughran,
Ken Takeshita,
Giorgio Inghirami,
Dean McGaughey, [......],
Miriam Ferraro,
Elizabeth Jones,
Elaine S Jaffe,
Douglas J Schwartzentruber,
David Danforth, Richard Sherry,
Erik Kass,
Carter Van Waes,
Craig W Reynolds,
Larry J Kwak
Clinical lymphoma 07/2005; 6(1):61-4. · 3.11 Impact Factor
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Mark E Dudley,
John R Wunderlich,
Paul F Robbins,
James C Yang,
Patrick Hwu,
Douglas J Schwartzentruber,
Suzanne L Topalian, Richard Sherry,
Nicholas P Restifo,
Amy M Hubicki,
Michael R Robinson,
Mark Raffeld,
Paul Duray,
Claudia A Seipp,
Linda Rogers-Freezer,
Kathleen E Morton,
Sharon A Mavroukakis,
Donald E White,
Steven A Rosenberg
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ABSTRACT: We report here the adoptive transfer, to patients with metastatic melanoma, of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen. This approach resulted in the persistent clonal repopulation of T cells in those cancer patients, with the transferred cells proliferating in vivo, displaying functional activity, and trafficking to tumor sites. This led to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction. This approach presents new possibilities for the treatment of patients with cancer as well as patients with human immunodeficiency virus-related acquired immunodeficiency syndrome and other infectious diseases.
Science 11/2002; 298(5594):850-4. · 31.20 Impact Factor
