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Hodi, Frank

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Hodi

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Frank

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Hodi, Frank
Author's Publications: search.filters.isAuthorOfPublication.6fa97a8e-5e2f-4e39-9598-db8d77437ce1

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    Alpha-CTLA-4 mAb-associated Panenteritis: A Histologic and Immunohistochemical Analysis
    (Ovid Technologies (Wolters Kluwer Health), 2008) Oble, Darryl A.; Mino-Kenudson, Mari; Goldsmith, Jeffrey; Hodi, Frank; Seliem, Rania M.; Dranoff, Glenn; Mihm, Martin; Hasserjian, Robert; Lauwers, Gregory Y.
    Monoclonal antibodies (mAbs) against the cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule are used as an adjuvant to experimental tumor immunization protocols in the treatment of malignant melanomas and ovarian cancers. Aside from noted early therapeutic successes, a spectrum of adverse effects, including severe gastroenteritis, has been reported. We report herein our observations of 5 patients who developed severe gastrointestinal toxicity affecting the gastric, small intestinal, and colonic mucosa. The endoscopic findings were variable, ranging from normal to diffusely erythematous and ulcerated mucosa. The constant histologic findings included a lymphoplasmacytic expansion of the lamina propria with increase in intraepithelial lymphocytes. Increased epithelial apoptosis was also a distinctive feature. Cryptitis and glandular inflammation were observed in the colon, ileum, and stomach, whereas villous blunting was present in the ileal and duodenal mucosa. Immunohistochemical analysis revealed a marked increase of all T-cell subsets (CD3+, CD4+, and CD8+) and of CD4CD25 regulatory T cells. We conclude that the panenteritis associated with injection of alpha-CTLA-4 mAbs demonstrates histology resembling autoimmune enteropathy. Furthermore, although the pathogenesis of immune dysregulation after the infusion of alpha-CTLA-4 mAbs remains unclear, we suspect that the increased number of regulatory T cells in the gastrointestinal mucosa may play a role in the pathogenicity.
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    Anti–PD-1–Related Pneumonitis during Cancer Immunotherapy
    (New England Journal of Medicine (NEJM/MMS), 2015) Nishino, Mizuki; Sholl, Lynette; Hatabu, Hiroto; Ramaiya, Nikhil H.; Hodi, Frank
    The use of antibodies against programmed cell death 1 (PD-1), which block inhibitory T-cell checkpoints, is a promising new therapy for advanced cancers.1 Recent trials have shown substantial clinical activity of anti–PD-1 antibodies in advanced cancers and led to the approvals of these agents, including pembrolizumab for melanoma and nivolumab for melanoma and squamous-cell lung cancer.2-4 Pneumonitis related to the use of antibodies against PD-1 is an immune-mediated toxic effect that resulted in three drug-related deaths in a phase 1 trial.1 Clinical identification and management of pneumonitis are contingent on radiographic assessment. We report three cases of pneumonitis associated with the use of anti–PD-1 antibodies in patients with melanoma.
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    Application of Protein Microarrays for Multiplexed Detection of Antibodies to Tumor Antigens in Breast Cancer
    (American Chemical Society (ACS), 2008) Anderson, Karen S.; Ramachandran, Niroshan; Wong, Jessica; Raphael, Jacob V.; Hainsworth, Eugenie; Demirkan, Gokhan; Cramer, Daniel; Aronzon, Dina; Hodi, Frank; Harris, Lyndsay; Logvinenko, Tanya; LaBaer, Joshua
    There is strong preclinical evidence that cancer, including breast cancer, undergoes immune surveillance. This continual monitoring, by both the innate and the adaptive immune systems, recognizes changes in protein expression, mutation, folding, glycosylation, and degradation. Local immune responses to tumor antigens are amplified in draining lymph nodes, and then enter the systemic circulation. The antibody response to tumor antigens, such as p53 protein, are robust, stable, and easily detected in serum; may exist in greater concentrations than their cognate antigens; and are potential highly specific biomarkers for cancer. However, antibodies have limited sensitivities as single analytes, and differences in protein purification and assay characteristics have limited their clinical application. For example, p53 autoantibodies in the sera are highly specific for cancer patients, but are only detected in the sera of 10-20% of patients with breast cancer. Detection of p53 autoantibodies is dependent on tumor burden, p53 mutation, rapidly decreases with effective therapy, but is relatively independent of breast cancer subtype. Although antibodies to hundreds of other tumor antigens have been identified in the sera of breast cancer patients, very little is known about the specificity and clinical impact of the antibody immune repertoire to breast cancer. Recent advances in proteomic technologies have the potential for rapid identification of immune response signatures for breast cancer diagnosis and monitoring. We have adapted programmable protein microarrays for the specific detection of autoantibodies in breast cancer. Here, we present the first demonstration of the application of programmable protein microarray ELISAs for the rapid identification of breast cancer autoantibodies.
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    Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation
    (American Association for Cancer Research (AACR), 2015) Van Allen, Eliezer; Golay, H. G.; Liu, Yan; Koyama, S.; Wong, Kwok-Kin; Taylor-Weiner, Amaro; Giannakis, Marios; Harden, M.; Rojas-Rudilla, V.; Chevalier, A.; Thai, T.; Lydon, C.; Mach, S.; Wong, J. A.; Rabin, A. R.; Helmkamp, J.; Sholl, Lynette; Carter, Scott; Oxnard, Geoffrey; Janne, Pasi; Getz, Gad; Lindeman, Neal; Hammerman, Peter S.; Garraway, Levi; Hodi, Frank; Rodig, Scott; Dranoff, Glenn; Barbie, David
    PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer.
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    Activity of the Heat Shock Protein 90 Inhibitor Ganetespib in Melanoma
    (Public Library of Science, 2013) Wu, Xin-Qi; Marmarelis, Melina Elpi; Hodi, Frank
    Heat shock protein 90 (HSP90) is involved in the regulation of diverse biological processes such as cell signaling, proliferation and survival, and has been recently recognized as a potential target for cancer therapy. Ganetespib is a potent ATP competitive inhibitor of HSP90. Ganetespib downregulated the expression of multiple signal transducing molecules including EGFR, IGF-1R, c-Met, Akt, B-RAF and C-RAF, resulting in pronounced decrease in phosphorylation of Akt and Erk1/2 in a panel of five cutaneous melanoma cell lines including those harboring B-RAF and N-RAS mutations. Ganetespib exhibited potent antiproliferative activity on all five of these cell lines, with IC50 values between 37.5 and 84 nM. Importantly, Ganetespib is active on B-RAF mutated melanoma cells that have acquired resistance to B-RAF inhibition. Ganetespib induced apoptosis and cell cycle arrest at G1 and/or G2/M phase. Ganetespib induced cell cycle arrest was accompanied by altered expression of cyclin-dependent kinase inhibitor (CDKI) p21Cip1 and p27Kip1, cyclins B1, D1 and E, and/or cyclin-dependent kinases 1, 2 and 4. HSP90 is functionally important for melanoma cells and HSP90 inhibitors such as ganetespib could potentially be effective therapeutics for melanoma with various genetic mutations and acquired resistance to B-RAF inhibition.
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    Immunity to the Melanoma Inhibitor of Apoptosis Protein (ML-IAP; livin) in Patients with Malignant Melanoma
    (Springer-Verlag, 2011) Zhou, Jun; Yuen, Noah K.; Zhan, Qian; Velazquez, Elsa F.; Murphy, George; Giobbie-Hurder, Anita; Hodi, Frank
    Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I–IV patients and healthy controls by ELISPOT. A broad array of \(CD4^+\) and \(CD8^+\) cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific \(CD4^+\) and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target.
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    Defining the Critical Hurdles in Cancer Immunotherapy
    (BioMed Central, 2011) Fox, Bernard A; Schendel, Dolores J; Butterfield, Lisa H; Aamdal, Steinar; Allison, James P; Ascierto, Paolo Antonio; Atkins, Michael B; Bartunkova, Jirina; Bergmann, Lothar; Berinstein, Neil; Bonorino, Cristina C; Borden, Ernest; Bramson, Jonathan L; Britten, Cedrik M; Cao, Xuetao; Carson, William E; Chang, Alfred E; Characiejus, Dainius; Coukos, George; de Gruijl, Tanja; Dillman, Robert O; Dolstra, Harry; Durrant, Lindy G; Finke, James H; Galon, Jerome; Gollob, Jared A; Gouttefangeas, Cécile; Grizzi, Fabio; Guida, Michele; Håkansson, Leif; Hege, Kristen; Herberman, Ronald B; Hoos, Axel; Huber, Christoph; Hwu, Patrick; Imai, Kohzoh; Jaffee, Elizabeth M; Janetzki, Sylvia; June, Carl H; Kalinski, Pawel; Kaufman, Howard L; Kawakami, Koji; Kawakami, Yutaka; Keilholtz, Ulrich; Khleif, Samir N; Kiessling, Rolf; Kotlan, Beatrix; Kroemer, Guido; Lapointe, Rejean; Levitsky, Hyam I; Lotze, Michael T; Maccalli, Cristina; Maio, Michele; Marschner, Jens-Peter; Mastrangelo, Michael J; Masucci, Giuseppe; Melero, Ignacio; Melief, Cornelius; Nelson, Brad; Nicolini, Andrea; Nishimura, Michael I; Odunsi, Kunle; Ohashi, Pamela S; O'Donnell-Tormey, Jill; Old, Lloyd J; Ottensmeier, Christian; Papamichail, Michael; Parmiani, Giorgio; Pawelec, Graham; Proietti, Enrico; Qin, Shukui; Rees, Robert; Ribas, Antoni; Ridolfi, Ruggero; Ritter, Gerd; Rivoltini, Licia; Romero, Pedro J; Salem, Mohamed L; Scheper, Rik J; Seliger, Barbara; Sharma, Padmanee; Shiku, Hiroshi; Singh-Jasuja, Harpreet; Song, Wenru; Straten, Per Thor; Tahara, Hideaki; Tian, Zhigang; van Der Burg, Sjoerd H; von Hoegen, Paul; Wang, Ena; Welters, Marij JP; Winter, Hauke; Withington, Tara; Wolchok, Jedd D; Xiao, Weihua; Zitvogel, Laurence; Zwierzina, Heinz; Marincola, Francesco M; Gajewski, Thomas F; Wigginton, Jon M; Disis, Mary L; Choudhury, A. Raja; Dranoff, Glenn; Hodi, Frank; Murphy, William J.
    Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
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    The Protein Kinase C Inhibitor Enzastaurin Exhibits Antitumor Activity against Uveal Melanoma
    (Public Library of Science, 2012) Wu, Xinqiang; Zhu, Meijun; Fletcher, Jonathan; Giobbie-Hurder, Anita; Hodi, Frank
    GNAQ mutations at codon 209 have been recently identified in approximately 50% of uveal melanomas (UM) and are reported to be oncogenic through activating the MAPK/Erk1/2 pathway. Protein kinase C (PKC) is a component of signaling from GNAQ to Erk1/2. Inhibition of PKC might regulate GNAQ mutation-induced Erk1/2 activation, resulting in growth inhibition of UM cells carrying GNAQ mutations. UM cells carrying wild type or mutant GNAQ were treated with the PKC inhibitor enzastaurin. Effects on proliferation, apoptosis, and signaling events were evaluated. Enzastaurin downregulated the expression of several PKC isoforms including PKCβII PKCθ, PKCε and/or their phosphorylation in GNAQ mutated cells. Downregulation of these PKC isoforms in GNAQ mutated cells by shRNA resulted in reduced viability. Enzastaurin exhibited greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis. Enzastaurin-induced G1 arrest was associated with inhibition of Erk1/2 phosphorylation, downregulation of cyclin D1, and accumulation of cyclin dependent kinase inhibitor p27\(^{Kip1}\). Furthermore, enzastaurin reduced the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells. Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27\(^{Kip1}\) accumulation and/or inhibition of enzastaurin-induced survivin and Bcl-2 upregulation. PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis. Inhibition of the PKC pathway provides a basis for clinical investigation in patients with UM.