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  • American Association for Cancer Research (AACR)  (14)
  • 1
    Online Resource
    Online Resource
    Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti–PD-1 Refractory Melanoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 8 ( 2021-08-01), p. 1996-2013
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 8 ( 2021-08-01), p. 1996-2013
    Abstract: Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti–PD-1– resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. Significance: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-1546
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2607892-2
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  • 2
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    Online Resource
    Abstract 5224: The PRecision Oncology For Young peopLE (PROFYLE) Program: A national precision oncology program for children, adolescents and young adults with hard-to-cure cancer in Canada
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5224-5224
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5224-5224
    Abstract: Background: Over 4,300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom have refractory/metastatic disease or will relapse. A national collaborative program, PRecision Oncology For Young peopLE (PROFYLE), was created with the goal to develop and implement a pipeline providing access to tumor molecular profiling to identify novel targeted treatment options in a clinically relevant timeframe for CAYA with hard-to-cure cancers. Design: PROFYLE includes more than 20 institutions, building upon 3 pre-existing regional precision oncology programs (Personalized Oncogenomics (POG), SickKids Cancer Sequencing (KiCS), and Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood (TRICEPS)). PROFYLE has united an interdisciplinary team of experts, leaders, research team, end-users and advocates from across Canada to form 14 domain specific nodes unified by a shared governance structure. PROFYLE includes genomic and transcriptomic sequencing of paired germline/cancer fresh/frozen samples. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. Profiling results are reviewed by multidisciplinary Molecular Tumor Boards. A report including a results/recommendations summary of actionable findings (therapeutic, diagnostic, prognostic, cancer predisposition), potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations is provided to the treating oncologist. Results: To date, & gt;900 CAYA are enrolled. Cancer diagnoses: 36% sarcoma, 16% leukemia/lymphoma, 16% CNS tumor, 13% neuroblastoma, 19% other. At study entry, 44% of participants had not relapsed, 40% had 1 relapse, 9% 2 relapses, 4% 3+ relapses. 17% had a cancer-predisposing pathogenic/likely pathogenic germline variant, 40% had ≥1 potentially actionable somatic alteration, 9.7% had a therapeutically targetable somatic alteration. The most frequent classes of therapeutic alterations were cell cycle (15%), RAS/MAPK (14%), epigenetic (13%), RTK (12%), PI3K/AKT/mTOR (10%), DNA repair (9%), immune checkpoint (8%). Of clinicians who reported the utility of results, 56% indicated the findings were useful for clinical management. Future Directions: With a comprehensive molecular view of cancer, PROFYLE will transform our understanding of underlying disease mechanisms, facilitate and improve diagnostic and prognostic indicators, and identify new therapeutic strategies and targets. Data from this interdisciplinary, multi-institutional research program will inform the development of a framework to innovatively link research, clinical and system considerations with Canadian values relevant to genomic profiling and drug access for CAYA in Canada. Citation Format: Stephanie A. Grover, Lesleigh Abbott, Jason N. Berman, Jennifer A. Chan, Avram E. Denburg, Rebecca J. Deyell, Conrad V. Fernandez, Cynthia Hawkins, Jan-Willem Henning, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Philipp F. Lange, Michael F. Moran, Daniel A. Morgenstern, Antonia Palmer, Shahrad R. Rassekh, Donna L. Senger, Adam Shlien, Daniel Sinnett, Caron Strahlendorf, Patrick J. Sullivan, Michael D. Taylor, Suzanne Vercauteren, Anita Villani, James A. Whitlock, David Malkin, on behalf of the Terry Fox PROFYLE Consortium. The PRecision Oncology For Young peopLE (PROFYLE) Program: A national precision oncology program for children, adolescents and young adults with hard-to-cure cancer in Canada [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5224.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5224
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
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    Abstract DDT02-01: First-time disclosure of M3258: A selective inhibitor of the immunoproteasome subunit LMP7 with potential for improved therapeutic utility in multiple myeloma compared to pan-proteasome inhibitors
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. DDT02-01-DDT02-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. DDT02-01-DDT02-01
    Abstract: Large multifunctional peptidase 7 (LMP7, β5i, PSMB8) is a chymotrypsin-like proteolytic subunit of the immunoproteasome, which degrades ubiquitinated proteins and generates peptides for presentation on MHC class I. In contrast to the constitutive proteasome, which is broadly expressed, the immunoproteasome is specifically present in normal and malignant hematopoietic cells and can be induced in non-hematopoietic cells by inflammatory stimuli such as IFNγ. Pan-proteasome inhibitors like Bortezomib, which is approved in multiple myeloma and mantle cell lymphoma, indiscriminately inhibit the proteolytic activities of multiple subunits of the constitutive proteasome and immunoproteasome, including LMP7. Widespread proteasome inhibition is believed to underpin the adverse safety profiles of these agents and limit their therapeutic potential. Selective LMP7 targeting could achieve improved antitumor activity as a result of enhanced target inhibition, meanwhile circumventing the dose-limiting severe toxicities associated with pan-proteasome inhibitors. Based on the aforementioned hypothesis, a drug discovery program was initiated to identify selective inhibitors of LMP7. This led to the discovery of M3258, a covalent-reversible, potent, selective and orally-bioavailable inhibitor of LMP7. M3258 demonstrated strong in vivo antitumor activity, up to complete regression, in multiple myeloma xenograft models at daily oral doses as low as 1 mg/kg. This was associated with significant and prolonged suppression of tumor LMP7 activity. Furthermore, M3258 was efficacious in several multiple myeloma models that were refractory to Bortezomib. Subacute GLP toxicology studies with M3258, applied orally on a once-daily schedule, identified the lymphatic and hematopoietic systems in rat and dog and intestinal system in dog alone as main target organs. Importantly, M3258 was without effect on the peripheral and central nervous systems and cardiac and respiratory organs. Overall, M3258 demonstrated a superior preclinical therapeutic window and more restricted spectrum of toxicities compared to pan-proteasome inhibitors. Supported by robust preclinical data, clinical phase I assessment of M3258 in multiple myeloma patients is planned to begin in 2019. Citation Format: Michael Sanderson, Michael Busch, Christina Esdar, Manja Friese-Hamim, Mireille Krier, Jianguo Ma, Djordje Musil, Felix Rohdich, Willem Sloot, Gina Walter, Ugo Zanelli, Oliver Schadt, Markus Klein. First-time disclosure of M3258: A selective inhibitor of the immunoproteasome subunit LMP7 with potential for improved therapeutic utility in multiple myeloma compared to pan-proteasome inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr DDT02-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-DDT02-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
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    Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 22 ( 2017-11-15), p. 7034-7046
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 22 ( 2017-11-15), p. 7034-7046
    Abstract: Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034–46. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-0647
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
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    Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Discovery Vol. 6, No. 2 ( 2016-02-01), p. 202-216
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 2 ( 2016-02-01), p. 202-216
    Abstract: T cell–mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell–mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell–mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti–PD-1 and anti–CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K–AKT pathway inhibitors. Significance: This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K–AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K–AKT pathway to increase the efficacy of immunotherapy. Cancer Discov; 6(2); 202–16. ©2015 AACR. See related commentary by Rizvi and Chan, p. 128. This article is highlighted in the In This Issue feature, p. 109
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-0283
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2607892-2
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  • 6
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    Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Discovery Vol. 6, No. 8 ( 2016-08-01), p. 827-837
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 8 ( 2016-08-01), p. 827-837
    Abstract: Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte–associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified. Significance: These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827–37. ©2016 AACR. See related commentary by Teng et al., p. 818. This article is highlighted in the In This Issue feature, p. 803
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-1545
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Abstract 4509: A pan-Canadian precision oncology program for children, adolescents and young adults with hard-to-cure cancer: The PRecision Oncology For Young peopLE (PROFYLE) Program
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4509-4509
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4509-4509
    Abstract: Background: Over 4,300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom have refractory/metastatic disease or will relapse. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options in a clinically relevant timeframe for all CAYA with hard-to-cure cancers in Canada. Design: Building upon 3 pre-existing regional precision oncology programs, PROFYLE now includes & gt;20 institutions and has united an interdisciplinary team of experts, leaders, research teams, end-users and advocates from across Canada. The program has 14 domain specific nodes that are unified by a shared governance structure, and has harmonized biobanking, genomics, bioinformatics and reporting procedures. PROFYLE includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples, proteomic analysis, and cancer modelling. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. Profiling results are reviewed by multidisciplinary Molecular Tumor Boards. A report including a results/recommendations summary of actionable findings (therapeutic, diagnostic, prognostic, cancer predisposition), potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations is provided to the treating oncologist. Results: & gt;1,000 CAYA are included from all of the provinces. Cancer diagnoses: 34% sarcoma, 16% leukemia/lymphoma, 16% CNS tumor, 11% neuroblastoma, 23% other. 17% of participants had a cancer-predisposing pathogenic/likely pathogenic germline variant, 45% had ≥1 potentially actionable somatic alteration, 22.6% had a therapeutically targetable somatic alteration. The most frequent classes of therapeutic alterations were RAS/MAPK (15%), cell cycle (14%), epigenetic (13%), RTK (12%), PI3K/AKT/mTOR (11%), DNA repair (9%), immune checkpoint (8%). Of clinicians who reported the utility of results, 55% indicated the findings were useful for clinical management. Future Directions: Collaborations with other national and international initiatives and data from this interdisciplinary, multi-institutional research program will inform the development of a framework to innovatively link research, clinical and system considerations with Canadian values relevant to multi-omic profiling and drug access for CAYA. In addition, we believe that with a comprehensive molecular view of cancer, PROFYLE will transform our understanding of underlying disease mechanisms, facilitate and improve diagnostic and prognostic indicators, and identify new therapeutic strategies and targets for CAYA patients with cancer. Citation Format: Stephanie A. Grover, Lesleigh Abbott, Jason N. Berman, Guillaume Bourque, Jennifer A. Chan, Avram E. Denburg, Rebecca J. Deyell, Conrad V. Fernandez, Cynthia Hawkins, Jan-Willem Henning, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Philipp F. Lange, Paul Moorehead, Michael F. Moran, Daniel A. Morgenstern, Sapna Oberoi, Antonia Palmer, Shahrad R. Rassekh, Donna L. Senger, Adam Shlien, Daniel Sinnett, Caron Strahlendorf, Patrick J. Sullivan, Michael D. Taylor, Suzanne Vercauteren, Anita Villani, Stephanie Villeneuve, James A. Whitlock, David Malkin, on behalf of the PROFYLE Consortium. A pan-Canadian precision oncology program for children, adolescents and young adults with hard-to-cure cancer: The PRecision Oncology For Young peopLE (PROFYLE) Program. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4509.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4509
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Abstract 4363: Loss of PTEN promotes resistance to T cell-mediated immunotherapy
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4363-4363
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4363-4363
    Abstract: T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. Here, we interrogated the role of loss of expression of the tumor suppressor, PTEN, in immune resistance. In preclinical studies, we found that silencing PTEN in tumor cells inhibited T cell-mediated tumor killing and decreased T cell trafficking into tumors. In clinical studies, we observed that tumors with loss of PTEN had significantly less CD8+ T cell infiltration than PTEN-present tumors. In addition, 26% of melanomas that did not yield successful TIL growth demonstrated PTEN loss, which was more frequent than was observed in tumors that yielded successful TIL growth (11%). We further validated the association between reduced number and impaired function of TIL with PTEN loss using another independent cohort, TCGA dataset for SKCM. More importantly, we analyzed clinical outcomes of metastatic melanoma patients treated with the FDA-approved anti-PD-1 antibodies. Our analysis demonstrates that a greater reduction in tumor burden was achieved by PD-1 blockade in PTEN present patients, when compared with PTEN absent patients. To decipher the factors mediating the immunosuppressive effects of PTEN loss, we determined the expression profiles of tumor cells with or without PTEN expression. Our results indicated that PTEN loss increased the production of immunosuppressive factors, including CCL2 and VEGF. Anti-VEGF blocking antibody improved anti-tumor activity of transferred tumor-reactive T cells and enhanced tumor infiltration of transferred T cells in PTEN-silenced tumors. These results suggest that loss of PTEN can facilitate the resistance of T cell-mediated immune responses by increasing the expression of immunosuppressive factors. Given that PTEN loss results in activation of the PI3K pathway, we evaluated the efficacy of immunotherapy in combination with a selective PI3Kβinhibitor to treat spontaneously developed BRAF mutant, PTEN null melanomas in genetically engineered mouse models. Our result showed that the combination of PI3Kβ inhibitor and anti-PD-1 significantly delayed tumor growth in tumor-bearing mice. Mice treated with this combination had a median survival time of 28 days, which is longer than the survival time of mice treated with either therapy. Increased numbers of T cells at tumor sites were found in mice receiving the combination therapy compared with mice receiving either agent alone. Taken together, our results demonstrate that PTEN loss contributes to the generation of immunosuppressive tumor microenvironment. Notably, this study provides the first direct clinical evidence to support the association between PTEN loss and poor clinical outcome in immunotherapy treated patients. In addition, our study indicates that inhibition of the PI3K-AKT pathway can improve the efficacy of immunotherapy in cancer. Citation Format: Weiyi Peng, Jie Qing Chen, Chengwen Liu, Shruti Malu, Caitlin Creasy, Michael Tetzlaff, Chunyu Xu, Jodi McKenzie, Chunlei Zhang, Xiaoxuan Liang, Leila Williams, Wanleng Deng, Guo Chen, Rina Mbofung, Alexander Lazar, Carlos Torres-Cabala, Zachary Cooper, Pei-Ling Chen, Trang Tieu, Stefani Spranger, Xiaoxing Yu, Chantale Bernatchez, Marie-Andree Forget, Cara Haymaker, Rodabe Amaria, Jennifer McQuade, Isabella Glitza, Tina Cascone, Haiyan Li, Lawrence Kwong, Timothy Heffernan, Jianhua Hu, Roland Bassett, Marcus Bosenberg, Scott Woodman, Willem Overwijk, Gregory Lizée, Jason Roszik, Thomas Gajewski, Jennifer Wargo, Jeffrey Gershenwald, Laszlo Radvanyi, Michael Davies, Patrick Hwu. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4363.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4363
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
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    Abstract 5567A: JNJ-‘6196: A next generation STING agonist with potent preclinical activity by the IV route
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5567A-5567A
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5567A-5567A
    Abstract: The Stimulator of Interferon Genes (STING) protein is a key mediator of innate immunity that plays a central role in the immune response to invading pathogens (bacterial, viral) and transformed cells. A next generation human STING agonist, JNJ-‘6196 was developed that cures mice of their tumors in preclinical models when administered by the IV route. JNJ-‘6196 was rationally selected to have a weaker binding affinity and fast off rate but functionally is a strong cytokine inducer and an efficient activator of human dendritic cells. JNJ-‘6196 exhibits a unique cytokine induction profile in human PBMCs compared to other cyclic dinucleotides (CDNs) that are not curative by the IV route in mice with higher levels of pro-inflammatory cytokines that mediate antitumor activity and lower levels of those that promote suppressive M2 macrophages. In preclinical models of cancer in mice, JNJ-‘6196 eliminates bilateral tumors when administered IV, and demonstrates activity over a wide therapeutic range. Cured mice are immune to further re-challenge due to the expansion and persistence of tumor specific CD8+ T-cells following JNJ-‘6196 administration. Moreover, JNJ-‘6196 increased the effectiveness of checkpoint inhibitors, turning a PD-1 resistant model into a responsive model. Although it is a very potent inducer of antitumor cytokines in mouse and cyno, it is tolerated at similar dose levels as other CDNs that are not systemically active. The functional properties that confer systemic activity were investigated by comparing gene signatures of JNJ-‘6196 to another CDN that was not curative when administered by the IV route. Differences in the intensity of cytokine gene induction were likely responsible for systemic activity rather than genes that were selectively induced by this IV-active compound. The pharmacologic mode of action of JNJ-‘6196 was investigated and found to be Cmax driven based on efficacy and cytokine readouts. JNJ-‘6196 creates an immune inflamed microenvironment in tumors and could expand the population of patients that respond to immunotherapy. The ability to administer JNJ-'6196 systemically and the potential to synergize with other immunotherapeutics could create unique combination modalities and differentiate this compound from other STING agonists. Citation Format: Szeman Ruby Chan, Gilles Bignan, Emily Pierson, Sally Mahady, Hayley Ta, Wim Schepens, Jan Willem Thuring, Heng Keang Lim, Monicah Otieno, Thomas Wilde, Monica Singer, Nancy Bogdan, Shefali Patel, Leo Luistro, Liam Campion, Melissa Smith, Diana Wiley, Kathryn Packman, Michael Allegrezza, Caitlin Morgan, Jocelyn Sendecki, Glenn Van Aller, Daniel Krosky, Peter Connolly, James Edwards, Kim Staquet, Stuart L. Emanuel. JNJ-‘6196: A next generation STING agonist with potent preclinical activity by the IV route [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5567A.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5567A
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 10
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    Abstract 5396: Interferon-α receptor dependent and independent inhibition of type I interferon production in plasmacytoid dendritic cells from mice and melanoma patients
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5396-5396
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5396-5396
    Abstract: IFN-α is pleiotropic cytokine belonging to the type I Interferon (IFNs) family and can induce multiple biological effects, e.g. induction of apoptosis and inhibition of cell growth. These cytokines exhibit a long record of clinical use in patients with some types of cancer and viral diseases. Notably, certain autoimmune disorders have been postulated to be mediated by endogenous IFN-α and are often observed in some IFN-α-treated cancer patients. How IFN-α promotes the generation of antitumor T-cell immunity and its regulation mechanisms are still unclear. To address these questions, we focus on the main producer of IFNs, Plasmacytoid dendritic cells (pDCs), which reside in bone marrow and lymphoid organs and typically secrete type I IFNs on Toll-like receptor (TLR) triggering. We detected cytokines production by human pDCs from leukapheresis cells of melanoma patients who were treated with IFNs for 25 weeks. After stimulation with CpG-A, these pDCs after treatment (IFN-α-pDCs) produce 70% less IFN-α compare to before treatment, but compatible amount of other inflammatory cytokines e.g. IL-6. We observed the similar phenomena in murine models either after VSV infection or by systemic IFN-α delivery. We showed that these IFN-α-pDCs possess more active and mature morphology as DCs and they are particularly more effective in inducing T- and NK-cell immunity by increasing cell proliferation and differentiation. Of note, IFN-α-pDCs skewed the naïve CD4+ T cells to a Th17 antigen-presenting subset by producing more IL-17 but less IFN-γ compare to wide type pDCs. The ensemble of these results suggests that IFN-α-pDCs could be successfully used in strategies of cancer immunotherapy, especially in melanoma patients. We also demonstrate that pDCs possess two fundamental, but separate, physiologic mechanisms for negative feedback control of IFN-α production after IFNs treatment in melanoma patients. Both signaling through the canonical TLR-MyD88 pathway and feedback inhibition from IFN-α itself through the IFN-α/βR render pDCs unable to synthesize type I interferon upon TLR triggering. Mechanistically, we found that IFN-α-pDCs show increased IRF7 mRNA and protein upon TLR stimulation, but despite efficient nuclear IRF-7 translocation, type I IFN was not produced. Interestingly, Ifn-α6 promoter activity was blocked in the IFN-α-pDCs, suggesting a block of type I IFN transcription despite nuclear IRF-7 translocation. Taken together, triggering of TLR and of IFN-α/βR act independently to tightly limit systemic IFN-α production after IFNs treatment. All this reveals the complexity of the IFN-α-pDC interactions under normal and pathological conditions and stimulates further studies for identifying optimal modalities in either using these cytokines or controlling their production in melanoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5396. doi:1538-7445.AM2012-5396
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-5396
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 410466-3
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