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  • American Association for Cancer Research (AACR)  (9)
  • 1
    Online Resource
    Online Resource
    Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 20 ( 2018-10-15), p. 5058-5071
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 20 ( 2018-10-15), p. 5058-5071
    Abstract: Purpose: In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB). Experimental Design: We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN. Results: Tumor RT was associated with upregulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T cells as well as FoxP3+ regulatory T cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration, and adversely affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T cells. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1. Conclusions: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. Clin Cancer Res; 24(20); 5058–71. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-3427
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
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    Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 5 ( 2016-03-01), p. 1161-1172
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 5 ( 2016-03-01), p. 1161-1172
    Abstract: Purpose: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental Design: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor–bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model. Results: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen–specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia. Conclusions: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials. Clin Cancer Res; 22(5); 1161–72. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-1516
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Abstract PR03: Prophylactic nodal irradiation abrogates the synergy of tumor radiotherapy and immune checkpoint blockade
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Immunology Research Vol. 5, No. 3_Supplement ( 2017-03-01), p. PR03-PR03
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 5, No. 3_Supplement ( 2017-03-01), p. PR03-PR03
    Abstract: Background: Prophylactic nodal irradiation (PNI) is a strategy used to treat early stage cancers with the potential to enhance local control and prevent metastatic spread. It remains unclear whether irradiation of tumor-associated draining lymph nodes (LN) influences anti-tumor T cell responses. Our aim was to investigate the in vivo effects of nodal irradiation on the phenotype and function of tumor infiltrating lymphocytes (TIL) and the impact of PNI on the anti-tumor effects of immunotherapy. Methods: The Small Animal Radiation Research Platform (SARRP) delivered imaged-guided stereotactic radiation (RT) to tumor (T-only) or tumor and LN (T+LN). Syngeneic tumors (MC38 colon, B16 melanoma) were implanted in C57BL/6 mice and irradiated (12Gy x1) and/or treated with immune checkpoint blockade with αCTLA-4 IgG2a (depleting) or αPD-1 IgG1. The composition of the tumor microenvironment (TME) was assayed by flow cytometry. To query tumor-antigen specific T cell responses, adoptive transfer experiments were performed using OVA-specific CD8+ T-cells from Rag-/- OT-1 mice and OVA-MHC class I tetramer (SIINFEKL). Tumor lysate was also collected for chemokine analysis, and tumor outgrowth was quantified over time. Results: T-only RT resulted in a significant increase (P & lt;0.01) in the proportion and absolute number of tumor infiltrating CD8+ effector T cells in comparison with T+LN RT. Immunosuppressive subsets (CD11b+ Gr-1hi MDSCs and FoxP3+ CD4+ Tregs) were also significantly increased in the T-only group. Ultimately, T-only RT significantly enhanced the CD8 effector:Treg ratio relative to untreated and T+LN treated tumors. Using the OVA-MHC class I tetramer to identify tumor-antigen specific CD8 T-cells, we observed that T-only RT significantly increased (P & lt;0.05) the number of tumor-specific CD8-T cells in the TME compared with T+LN RT. Interestingly, T-only RT resulted in a a significant expansion of non-OVA specific CD8 T cells which was not observed with T+LN RT, suggesting a polyclonal anti-tumor immune response. Functionally, a significant increase (P & lt;0.01) in the absolute number of IFNγ+ and TNFα+ antigen-specific TIL were noted with T-only RT. Mechanistically, a distinct chemokine signature correlated with robust TME immune infiltration and significantly elevated levels of CCL3/4/5 and CXCL10 (P & lt;0.05) were observed in tumor lysate collected from T-only RT tumors relative to T+LN RT samples. In an effort to understand the implications of the RT target on potential synergy with immune checkpoint blockade we performed survival experiments with T-only and T+LN RT in combination with αPD-1 or αCTLA-4. T-only RT in combination with αCTLA-4 yielded the best outcome with a 86% long-term survival (day 90 post-RT) compared with 30-36% long-term survival in mice treated with other combinations of RT + immune checkpoint blockade. Intriguingly, favorable CD8 effector:Treg ratio was able to predict treatment response and was dramatically higher (P & lt;0.001) among mice treated with T-only RT in combination with αCTLA-4. Conclusions: We have successfully developed a SARRP-based early stage cancer model with the ability to target or spare the tumor-associated LN. Results to date demonstrate significant immunological differences that are contingent upon inclusion/exclusion of the LN. Long-term survival experiments suggest response and survival advantages with T-only RT, particularly in combination with αCTLA-4 blockade. Taken together, these data suggest that PNI may dampen anti-tumor immune responses and that Tumor-only RT might be a better strategy in combination immunotherapy regimens, although these results should be explored in carefully designed clinical trials. This abstract is also being presented as Poster B41. Citation Format: Ariel E. Marciscano, Ali Ghasemzadeh, Thomas R. Nirschl, Brian J. Francica, Debebe Theodros, Esteban Velarde, J Wong, Daniel LJ Thorek, Theodore L. DeWeese, Charles G. Drake. Prophylactic nodal irradiation abrogates the synergy of tumor radiotherapy and immune checkpoint blockade. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR03.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM16-PR03
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2732517-9
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  • 4
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    Stereotactic Radiation Therapy Augments Antigen-Specific PD-1–Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Immunology Research Vol. 3, No. 4 ( 2015-04-01), p. 345-355
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 3, No. 4 ( 2015-04-01), p. 345-355
    Abstract: The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti–PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell– and B cell–mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti–PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen–MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. Cancer Immunol Res; 3(4); 345–55. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-14-0196
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2732517-9
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  • 5
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    Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Communications Vol. 3, No. 8 ( 2023-08-08), p. 1486-1500
    Details
    In: Cancer Research Communications, American Association for Cancer Research (AACR), Vol. 3, No. 8 ( 2023-08-08), p. 1486-1500
    Abstract: While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1–4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/− spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist. Significance: Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.
    Type of Medium: Online Resource
    ISSN: 2767-9764
    URL: Article
    DOI: 10.1158/2767-9764.CRC-23-0249
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 3098144-X
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  • 6
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    TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Immunology Research Vol. 6, No. 4 ( 2018-04-01), p. 422-433
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 6, No. 4 ( 2018-04-01), p. 422-433
    Abstract: The cGAS–STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow–derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422–33. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-17-0263
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2732517-9
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  • 7
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    Abstract 267: Combining androgen deprivation with immune checkpoint blockade delays the development of castration resistance in a murine model of prostate cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 267-267
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 267-267
    Abstract: Androgen deprivation therapy induces immune cell infiltration in human prostate cancer. These findings suggest that immunotherapy may be most efficacious when administered concurrently with androgen deprivation, early in disease progression. We used a subcutaneous allograft model of murine prostate cancer (Myc-Cap), which mimics the development of human castration-resistant prostate cancer (CRPC) progression to study the anti-tumor effects of concurrent hormonal/immunotherapy. Implanted Myc-Cap tumors initially respond to androgen deprivation (degarelix acetate or bilateral orchiectomy), but mice eventually progress with CRPC. To test the hypothesis that the combination of androgen deprivation and immune checkpoint blockade could mediate pre-clinical benefit, we treated mice with either anti-PD-1, a depleting anti-CTLA-4 antibody (IgG2A), a non-depleting anti-CTLA-4 antibody (IgG1 D265A) or antibody combinations in the peri-castration period, then followed mice for the development of castration-resistant disease. Interestingly, the depleting anti-CTLA-4 antibody with/without anti-PD-1 antibody was strikingly effective in preventing the emergence of castration-resistant disease. The median castration-resistance free survival was 22 days in mice treated with androgen deprivation alone versus 32 days in mice treated with androgen deprivation and depleting anti-CTLA-4 antibody (P & lt;0.05, compared to androgen deprivation alone) versus 30 days in mice treated with androgen deprivation, depleting anti-CTLA-4 and anti-PD-1 (P & lt;0.05, compared to androgen deprivation alone; non-significant, compared to androgen deprivation and depleting anti-CTLA-4 antibody). Immunologically, we found that castration increases intratumoral infiltration of helper, cytotoxic and regulatory T cells (Tregs), natural killer cells, and macrophages, as well as effector cytokine production of T cells. We also found up-regulated expression of CTLA-4 and PD-1 as well as their respective ligands. Mechanistic studies showed that androgen deprivation combined with depleting anti-CTLA-4 /anti-PD-1 significantly reduces intratumoral Tregs and increases interferon-γ- or tumor necrosis factor-α- producing T cells in the tumor and its draining lymph node. In conclusion, while androgen deprivation renders the tumor microenvironment more immunogenic; the combination of androgen deprivation and depleting anti-CTLA-4 antibody with/without anti-PD-1 can significantly delay the development of CRPC. Citation Format: Ying-Chun Shen, Christina Kochel, Brian J. Francica, Angela Alme, Christopher Nirschl, Thomas Nirschl, Zoila Areli Lopez Bujanda, Maria A. Carrera H, Mark Selby, Alan Korman, Charles G. Drake. Combining androgen deprivation with immune checkpoint blockade delays the development of castration resistance in a murine model of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 267. doi:10.1158/1538-7445.AM2015-267
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-267
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract PR09: ADU-S100 (MIW815) synergizes with checkpoint blockade to elicit an antitumor CD8+ T-cell response to control distal tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 4_Supplement ( 2020-04-01), p. PR09-PR09
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 4_Supplement ( 2020-04-01), p. PR09-PR09
    Abstract: Stimulator of interferon genes (STING) is a critical component of an innate immune pathway that activates robust antiviral and antitumor responses in mouse models. Activation of the STING pathway by intratumoral (IT) injection of synthetic cyclic dinucleotides (CDNs) is being explored as a cancer therapy and has shown potent antitumor activity in preclinical models. Here we assessed the benefit of combining immune checkpoint blockade with ADU-S100 (MIW815), a CDN under clinical evaluation, in different syngeneic mouse tumor models. In mice bearing dual flank 4T1 mammary carcinoma tumors resistant to anti-PD-1 treatment, adding a single dose of ADU-S100 with anti-PD-1 induced eradication of both injected and noninjected tumors, leading to near-complete responses, demonstrating that ADU-S100 potentiates the activity of checkpoint blockade. Tumor control was CD8+ T cell-dependent and correlated with an enhanced CD8+ T-cell effector profile in both the periphery and in noninjected tumors. Combining a single injection of ADU-S100 with anti-PD-1 also elicited enhanced tumor control in the dual flank MC-38 colon carcinoma model compared to ADU-S100 or anti-PD-1 treatment alone. Those mice cured by combination treatment were also protected from tumor rechallenge. Moreover, in the poorly immunogenic B16.F10 model, adding ADU-S100 to the ineffective combination therapy of anti-PD-1 and anti-CTLA-4 induced tumor-specific CD8+ T-cell responses and tumor control, leading to multiple complete responses and durable immunity in surviving animals. Together, these results highlight the immune correlates of STING-mediated antitumor efficacy and illustrate the potential of combining ADU-S100 with checkpoint inhibitors for the treatment of human cancer. Clinical trials of ADU-S100 in combination with anti-PD-1 or with anti-CTLA-4 are ongoing and could further elucidate the immunologic mechanism of action and therapeutic effect in humans. This abstract is also being presented as Poster B47. Citation Format: Weiwen Deng, Anthony L. Desbien, Kelsey Sivick Gauthier, Gabrielle Reiner, Leticia Corrales, Tamara Schroeder, Laura Hix Glickman, Natalie H. Surh, Brian Francica, Justin J. Leong, Ken Metchette, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, Steven L. Bender, Chudi Ndubaku, Meredith L. Leong, Andrea van Elsas, Sarah M. McWhirter. ADU-S100 (MIW815) synergizes with checkpoint blockade to elicit an antitumor CD8+ T-cell response to control distal tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR09.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM18-PR09
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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  • 9
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    Abstract 631: Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8 T-cell immunity that effectively combines with checkpoint inhibitors
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 631-631
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 631-631
    Abstract: Activation of the STING pathway by intratumoral (IT) injection of synthetic cyclic dinucleotides (CDNs) induces stable tumor regression in preclinical models, yet the underlying immune correlates are not fully understood. ADU-S100, a CDN under clinical evaluation, was administered IT with an optimized dosing regimen to explore the immune requirements for antitumor efficacy in mouse syngeneic tumor models. We show that CD8+ T cells are necessary and sufficient for durable antitumor immunity elicited by ADU-S100 and that activation of STING in hematopoietic cells mediates CD8+ T cell induction. Both type I IFN and TNFα, which are induced by STING pathway activation, influence the antitumor immune response. The combination of ADU-S100 and anti-PD1 treatment enhances CD8+ T cell-dependent, noninjected tumor control that correlates with an enhanced effector profile of CD8+ T cells in the tumor. Combination of ADU-S100 with checkpoint inhibition also enhances durable immunity in a poorly immunogenic tumor model. Together, these results elucidate the immune correlates to STING-mediated antitumor efficacy and highlight the potential of combining STING agonists with checkpoint inhibition in the clinic. Citation Format: Anthony L. Desbien, Kelsey Sivick Gauthier, Leticia Corrales, Gabrielle Reiner, Laura Hix Glickman, George Katibah, Thomas E. Hudson, Uyen Vu, Natalie H. Surh, Brian Francica, Weiwen Deng, David B. Kanne, Justin J. Leong, Chudi Ndubaku, Ken Metchette, Jeffery M. McKenna, Steven L. Bender, Meredith L. Leong, Thomas W. Dubensky Jr., Andrea van Elsas, Sarah M. McWhirter. Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8 T-cell immunity that effectively combines with checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 631.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-631
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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