Abdel-Wahab O.,Leukemia Service |
Abdel-Wahab O.,New York Medical College |
Klimek V.M.,Leukemia Service |
Klimek V.M.,New York Medical College |
And 21 more authors.
Cancer Discovery | Year: 2014
Vemurafenib, a RAF inhibitor, extends survival in patients with BRAFV600-mutant melanoma but activates extracellular signal-regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAFV600K-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP-ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma. Significance: We show that in a patient with simultaneous RAS-mutant leukemia and BRAF-mutant melanoma, intermittent RAF inhibitor therapy induced a near-complete melanoma response, and addition of a MEK inhibitor prevented RAF inhibitor-induced activation of the RAS-mutant leukemia. Intermittent therapy may permit greater pathway inhibition with less toxicity, avoid chronic relief of pathway feedback, and have enhanced effectiveness compared with chronic administration. © 2014 American Association for Cancer Research.
News Article | November 30, 2016
An international group of researchers report success in mice of a method of using positron emission tomography (PET) scans to track, in real time, an antibody targeting a hormone receptor pathway specifically involved in prostate cancer. This androgen receptor pathway drives development and progression of the vast majority of prostate cancers. The technique shows promise, the investigators say, as a novel way to use such an antibody to detect and monitor prostate and other hormone-sensitive cancers, as well as to guide therapy in real time. "The findings show that individually tailored imaging agents can provide a unique way of looking at disease progression in real time and in a noninvasive manner," says Daniel Thorek, Ph.D., assistant professor of radiology and radiological science at the Johns Hopkins University School of Medicine, and the paper's first author. "Perhaps someday we can put a personalized antibody such as the one we created in our study on a therapeutic agent and conduct cancer treatment using imaging with very high specificity." A summary of the findings was published in Science Translational Medicine on Nov. 30. Thorek says the success is especially important given the challenges of working with small-animal models. "We managed to very accurately and precisely monitor the mouse prostate, and that leads us to hope that a similar approach can be used to guide treatment in people," he adds. Current clinical practice detects prostate cancer by tracking the androgen receptor pathway -- a marker for the cancer -- by testing blood for prostate-specific antigen (PSA). Presence of elevated PSA indicates that the androgen receptor pathway is active and may indicate prostate cancer is present. PSA concentration in the blood, however, is affected by numerous factors, such as age and type of tumor, making it difficult to determine true androgen receptor pathway activation. Furthermore, attempts to target PSA with an antibody is complicated by the "washing out" of the antibody-PSA complex, a process in which the complex is formed but does not remain near the disease site, thus making it difficult to definitively identify and measure disease sites. In the new study, the investigators developed a new antibody called 11B6 to target human kallikrein-related peptidase 2 (hK2), another antigen that indicates androgen receptor pathway activation. Unlike PSA, hK2 is specifically active only in the prostate and an aggressive type of breast cancer. By binding free, unbound hK2 to 11B6, the research team found that the newly formed 11B6-hK2 complex is taken directly back into the cancerous cell rather than washed out. This biological process relies on a transport mechanism involving the neonatal Fc receptor, in which cells are able to recognize and take in antibodies. The Fc receptor is most well-known for how antibodies in mothers' milk are able to pass from the gut of the baby into newborns' bloodstream to provide them with immunity. As far as the research team is aware, this is the first study to exploit the biological mechanism for imaging purposes, Thorek says. In the next phase of their experiments, the team made 11B6 "light up" during PET and fluorescence imaging by binding it to zirconium-89, creating a traceable radiochemical compound called 89Zr-11B6. By imaging the 89Zr-11B6 using PET, the team showed that binding 11B6 to hK2 can measure activity of cancerous lesions robustly, in both soft tissue and bone. Prostate and breast cancer often metastasize to bone, therefore detection of lesions in all areas of the body is critical. To further demonstrate the potential value of 89Zr-11B6 imaging, the team tested the imaging agent in disease models under standard treatment regimens. In one such case, disease activity was imaged and quantified in mice treated with saline and a second group with enzalutamide, a drug used to treat prostate cancer by inhibiting the androgen receptor hormone activity. All of the mice had prostate cancer. Following initial castration, imaging of 89Zr-11B6 allowed the research team to see lower androgen receptor pathway activity, as one might expect. This effect was augmented in the animals with adjuvant enzalutamide treatment. This may inform current clinical practice as the use of adjuvant enzalutamide after castration may show benefit to patients with prostate cancer. By tracking the antibody localization to disease sites in real time, the team hopes this may be a way to determine optimal dosages that don't compromise efficacy while avoiding negative side effects. Imaging of the antibody uptake before and after treatment could, in theory, aid in the decision of whether to keep a patient on chosen drug. If a response is seen, the imaging agent could be used to choose the right dose, balancing the therapeutic effect and minimizing adverse effects. And if there is not an imaging change with a particular drug, this tool would provide a caregiver with rapid information to discontinue ineffective treatments, saving time and cost. The team is currently conducting preliminary nonhuman primate toxicity tests, the final step before applying for human clinical trials, and has thus far found no adverse effects. Other authors on this paper include Diane S. Abou and Marise R.H. van Voss of the Johns Hopkins University School of Medicine; Philip A. Watson, Sang-Gyu Lee, Anson T. Ku, Kwanghee Kim, Michael G. Doran, Elmer Santos, Darren Veach, Mesruh Turkekul, Emily Casey, Jason S. Lewis, Howard I. Scher, Hans Lilja, Steven M. Larson and David Ulmert of Memorial Sloan Kettering Cancer Center; Stylianos Bournazos of Rockefeller University; Katharina Braun of the University of Bochum; Kjell Sjöström of Innovagen AB; Urpo Lamminmäki of the University of Turku; Sven-Erik Strand of Lund University; and Mary L. Alpaugh of Rowan University. Funding for this study was provided by the National Cancer Institute of the National Institutes of Health (P30 CA008748, P30 CA006973, P30 CA008748-48, S10 RR020892-01, S10 RR028889-01, R33 CA127768-02, P50-CA86438), the National Institutes of Health Molecular Imaging Fellowship Program (5R25CA096945-07), the Geoffrey Beene Cancer Research Center, the W.H. Goodwin and A. Goodwin and their Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, the Radiochemistry and Molecular Imaging Probe Core (P50-CA086438), the Steve Wynn Prostate Cancer Foundation Young Investigator Award, the Knut and Alice Wallenberg Foundation, the Bertha Kamprad Foundation and the David H. Koch Fund of the Prostate Cancer Foundation, the Ludwig Center for Cancer Immunotherapy, the Swedish Cancer Society, the Swedish National Health Foundation, the Swedish Research Council (Medicine- 20095), the Memorial Sloan Kettering Cancer Center Specialized Programs of Research Excellence in Prostate Cancer (P50 CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers and the Hascoe Charitable Foundation. D.L.J.T., D.U., U.L., S.-E.S., and H.L. are shareholders of Diaprost Inc. D.L.J.T., S.-E.S., and D.U. currently serve as board members of Diaprost Inc. D.L.J.T., A.K., S.-E.S., S.M.L., and D.U. are inventors on a patent (62257179) submitted by the MSKCC that covers systems, methods and compositions for imaging AR axis activity in carcinoma. D.U. is also the inventor on a patent (20060182682) held by Diaprost Inc. that covers diagnostic imaging of PCa using 11B6. S.-E.S. and U.L. are inventors on a patent application (WO2015075445) submitted by Diaprost Inc. that covers the humanized anti-hK2 antibody.
Lesokhin A.M.,Sloan Kettering Cancer Center |
Lesokhin A.M.,New York Medical College |
Hohl T.M.,Fred Hutchinson Cancer Research Center |
Kitano S.,Sloan Kettering Cancer Center |
And 17 more authors.
Cancer Research | Year: 2012
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of cytotoxic antitumor T effector cells. Heterogeneity in these cells poses a significant barrier to studying the in vivo contributions of individual MDSC subtypes. Herein, we show that granulocyte-macrophage colony stimulating factor, a cytokine critical for the numeric and functional development of MDSC populations, promotes expansion of a monocyte-derived MDSC population characterized by expression of CD11b and the chemokine receptor CCR2. Using a toxin-mediated ablation strategy to target CCR2-expressing cells, we show that these monocytic MDSCs regulate entry of activated CD8 T cells into the tumor site, thereby limiting the efficacy of immunotherapy. Our results argue that therapeutic targeting of monocytic MDSCs would enhance outcomes in immunotherapy. ©2011 AACR.
Peptide-loaded langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo
Romano E.,Sloan Kettering Institute for Cancer Research |
Romano E.,Sloan Kettering Cancer Center |
Rossi M.,Sloan Kettering Institute for Cancer Research |
Rossi M.,Sloan Kettering Cancer Center |
And 33 more authors.
Clinical Cancer Research | Year: 2011
Purpose: We compared the efficacy of human Langerhans cells (LC) as tumor immunogens in vivo with monocyte-derived dendritic cells (moDC) and investigated how interleukin 15 (IL15) supports optimal DC-stimulated antitumor immunity. Experimental Design: American Joint Committee on Cancer stage III/IV melanoma patients participated in this first clinical trial comparing melanoma peptide-pulsed LC with moDC vaccines (NCT00700167, www.ClinicalTrials.gov). Correlative studies evaluated mechanisms mediating IL15 support of DC-stimulated antitumor immunity. Results: Both DC vaccines were safe and immunogenic for melanoma antigens. LC-based vaccines stimulated significantly greater tyrosinase-HLA-A*0201 tetramer reactivity than the moDC-based vaccines. The two DC subtypes were otherwise statistically comparable, in contrast to extensive prior data in vitro showing LC superiority. LCs synthesize much more IL15 than moDCs and stimulate significantly more antigen-specific lymphocytes with a cytolytic IFN-γ profile even without exogenous IL15. When supplemented by low-dose IL15, instead of IL2, moDCs stimulate 5 to 6 logs more tumor antigen-specific effector memory T cells (TEMRA) over 3 to 4 weeks in vitro. IL2 and IL15 can be synergistic in moDC stimulation of cytolytic T cells. IL15 promotes T-cell expression of the antiapoptotic bcl-2 and inhibits candidate regulatory T-cell (Treg) expansion after DC stimulation, countering two effects of IL2 that do not foster tumor immunity. Conclusions: MoDC-based vaccines will require exogenous IL15 to achieve clinical efficacy. Alternatively, LCs can couple the endogenous production of IL15 with potent T-cell stimulatory activity. Optimization of full-length tumor antigen expression for processing into multiple immunogenic peptides for presentation by both class I and II MHC therefore merits emphasis to support more effective antitumor immunity stimulated by LCs. ©2011 AACR.
Kitano S.,Exploratory Oncology Research and Clinical Trial Center |
Postow M.A.,Sloan Kettering Cancer Center |
Ziegler C.G.,Sloan Kettering Cancer Center |
Kuk D.,Sloan Kettering Cancer Center |
And 9 more authors.
Cancer immunology research | Year: 2014
Evaluation of myeloid-derived suppressor cells (MDSC), a cell type implicated in T-cell suppression, may inform immune status. However, a uniform methodology is necessary for prospective testing as a biomarker. We report the use of a computational algorithm-driven analysis of whole blood and cryopreserved samples for monocytic MDSC (m-MDSC) quantity that removes variables related to blood processing and user definitions. Applying these methods to samples from patients with melanoma identifies differing frequency distribution of m-MDSC relative to that in healthy donors. Patients with a pretreatment m-MDSC frequency outside a preliminary definition of healthy donor range (<14.9%) were significantly more likely to achieve prolonged overall survival following treatment with ipilimumab, an antibody that promotes T-cell activation and proliferation. m-MDSC frequencies were inversely correlated with peripheral CD8(+) T-cell expansion following ipilimumab. Algorithm-driven analysis may enable not only development of a novel pretreatment biomarker for ipilimumab therapy, but also prospective validation of peripheral blood m-MDSCs as a biomarker in multiple disease settings. ©2014 American Association for Cancer Research.
Balachandran V.P.,Memorial Hospital |
Cavnar M.J.,Memorial Hospital |
Zeng S.,Memorial Hospital |
Bamboat Z.M.,Memorial Hospital |
And 16 more authors.
Nature Medicine | Year: 2011
Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8 + T cells and induced regulatory T cell (T reg cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents. © 2011 Nature America, Inc. All rights reserved.