bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA28: Nanodisc platform technology for cancer vaccination
Authors: Moon James J. 
Published: February 2019

Abstract
Recent innovations in DNA/RNA sequencing have allowed for the identification of patient-specific tumor neo-antigens, ushering in the new era of personalized cancer vaccines. Peptide vaccines in general may serve as an ideal platform for neo-antigen vaccines, but the therapeutic efficacy of peptide vaccines have been limited in clinical trials. Here we present an alternative strategy where preformed nanodiscs based on synthetic high density lipoproteins, with an established clinical manufacturing procedure and excellent safety profiles in humans, are readily formulated with adjuvants and antigen peptides. We show that these nanodiscs can efficiently deliver immunostimulatory molecules and antigens, including neo-antigens to draining lymph nodes. Notably, nanodiscs elicited up to 47-fold greater frequency of tumor neoantigen-specific CD8+ T lymphocytes (CTLs) than soluble vaccines in mice and even 31-fold greater than the standard adjuvant in clinical trials (i.e. CpG in Montanide). When nanodisc vaccination was combined with anti-PD-1 immune checkpoint inhibitor, ~88% complete response was observed in MC-38 tumor-bearing mice, compared with 25% response rate in the control group that received soluble vaccine plus anti-PD-1 therapy. In more aggressive B16F10 melanoma model, nanodiscs delivering multiple MHC class I and class II neo-epitopes were combined with α-PD-1/α-CTLA-4 therapy, leading ~90% complete response in B16F10 tumor-bearing mice, compared with ~38% response rate in the control group with soluble vaccine plus α-PD-1/α-CTLA-4 therapy. Furthermore, we have demonstrated the efficacy of nanodisc technology using shared tumor antigens in murine models of HPV+ mucosal tumors. The reproductive tract tumor model was established in C57BL/6 mice by intravaginal administration of luciferase-expressing TC-1 cells, a surrogate for HPV-induced human tumors, such as cervical carcinoma. The lung metastasis model was established by intravenous injection of luciferase-expressing TC-1 tumor cells. In mice bearing intravaginal or lung TC-1 tumors, two nanodisc vaccinations with HPV16 E7 antigen generated the peak frequency of ~35% tetramer+ CTLs in peripheral blood and eliminated established TC-1 tumors in the majority of animals (without immune checkpoint blockade). Owning to the facile production process, robust therapeutic efficacy, and good safety profiles, our nano-vaccine technology offers a powerful and convenient platform for vaccination using personalized as well as shared tumor antigens.
Citation Format: James J. Moon. Nanodisc platform technology for cancer vaccination [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA28.
Abstract IA29: Peptide-TLR-7/8 agonist conjugate vaccines chemically programmed for nanoparticle self-assembly to enhance the magnitude and breadth of anticancer neoantigen CD8 T cell immunity
Authors: Lynn Geoffrey M. , Baharom Faezzah , Zhu Yaling , Coble Vincent , Ramirez-Valdez Andrei , Yamane Hide , Tobin Kennedy , Decker Brennan , Ishizuka Andrew , Seder Robert 
Published: February 2019

Abstract
T cells recognizing tumor-specific neoantigens can mediate effective anti-tumor immunity and provide the rationale for personalized cancer vaccines (PCVs). Current approaches for PCVs include synthetic long peptides given with adjuvants or RNA vaccines. Such approaches induce de novo CD8 T cell responses in ~10% or less of predicted neoantigens. Here, we focused on how peptide based neoantigen vaccines could be altered to enhance the magnitude and breadth of CD8 T cells. A key finding was that particulate peptide antigens, unlike soluble peptide antigens, are more efficiently taken up by dendritic cells in draining lymphoid tissue for increasing CD8 T cell expansion. However, due to the broad range of neoantigen physicochemical properties, ensuring consistent particle vaccine formulations with neoantigen peptides is a major challenge. Therefore, we developed a new PCV platform based on charge-modified peptide-TLR-7/8 agonist conjugates that are chemically programmed for self-assembling into nanoparticles (“SNP-7/8a”) of a defined size (20–50 nm) irrespective of the underlying neoantigen peptide composition. Bioinformatics analysis of 72 million human genome-derived neoantigens shows that SNP-7/8a ensures consistent nanoparticle formation with neoantigens at extremes of charge and hydropathy. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells in ~50% of those with high predicted MHC-I binding affinity (IEDB consensus score &lt; 0.5). Moreover, therapeutic vaccination with SNP-7/8a enhanced tumor clearance in tumor models using neoantigens, self-antigens or viral antigens. Overall, the SNP-7/8a PCV is a universal approach for co-delivering peptide antigens and immune adjuvants in nanoparticles to enhance anticancer T cell immunity.
Citation Format: Geoffrey M. Lynn, Faezzah Baharom, Yaling Zhu, Vincent Coble, Andrei Ramirez-Valdez, Hide Yamane, Kennedy Tobin, Brennan Decker, Andrew Ishizuka, Robert Seder. Peptide-TLR-7/8 agonist conjugate vaccines chemically programmed for nanoparticle self-assembly to enhance the magnitude and breadth of anticancer neoantigen CD8 T cell immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA29.
Abstract IA34: Mapping immune recognition of non-self neoantigens in human pancreatic cancer
Authors: Luksza Marta , Leung Joanne P. , Solovyov Alexander , Redmond David , Merad Miriam , Gnjatic Sacha , Iacubuzio-Donohue Christine , DeMatteo Ronald P. , Chan Timothy A. , Wolchock Jedd , Leach Steven D. , Greenbaum Benjamin D. , Merghoub Taha , Balachandran Vinod P. 
Published: February 2019

Abstract
Endogenous T-cell responses to cancer-specific mutations (neoantigens) are a common denominator of successful immunotherapies. However, endogenous neoantigen-specific T cell immunity in immunotherapy refractory tumors remains poorly characterized. Pancreatic ductal adenocarcinoma (PDAC) is the prototypical immunotherapy refractory cancer: response rates to single-agent checkpoint blockade are &lt;2%, and 5-year survival with conventional therapies remains &lt;7%. In these rare 7% of PDAC patients that survive &gt; 5 years, T cell immunity has been linked to their exceptional outcome however the relevant antigens remained unknown. We sought to identify the landscape, antigenic potential, and T cell functional states induced by neoantigens in rare long-term pancreatic cancer survivors. Using genetic, immunologic, and computational techniques, we recently reported that tumors with the highest predicted neoantigen number and the greatest density of CD3+CD8+ infiltrates together, but neither parameter alone, could identify long-term survivors, suggesting differential inherent neoantigen immunogenicity. To investigate the specific neoantigen qualities promoting differential immunogenicity, we developed a fitness model that quantifies neoantigen immunogenicity based on estimations of the relative MHC binding affinity of each neoantigen to its wild type counterpart, as well as a nonlinear dependence on sequence similarity of neoantigens to known antigens. Our neoantigen quality fitness model identified long-term survivors in two independent PDAC datasets, as well as predicted survival in anti-CTLA4 treated melanoma patients, and anti-PD-1 treated lung cancer patients. In long-term PDAC survivors, we detected high quality neoantigen-specific intratumoral T cell clones persisting in the blood up to 12 years after primary tumor removal, with both unique clonal and phenotypic profiles. Our results identify neoantigens with unique qualities as T cell targets in both endogenous and immunotherapy treated cancers. Neoantigen quality can therefore inform rational neoantigen immunogenicity predictions that may guide patient and target selection for immunotherapies.
Citation Format: Marta Luksza, Joanne P. Leung, Alexander Solovyov, David Redmond, Miriam Merad, Sacha Gnjatic, Christine Iacubuzio-Donohue, Ronald P. DeMatteo, Timothy A. Chan, Jedd Wolchock, Steven D. Leach, Benjamin D. Greenbaum, Taha Merghoub, Vinod P. Balachandran. Mapping immune recognition of non-self neoantigens in human pancreatic cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA34.
Abstract IA35: Determinants of effective tumor immunity
Authors: Hacohen Nir 
Published: February 2019

Abstract
Treatment of solid tumors has been revolutionized by immune checkpoint blockade therapies; yet even for melanoma, for which high response rates are observed, the majority of tumors continue to grow after therapy. To identify immune cell states associated with success or failure of immunotherapy, we profiled the single-cell transcriptomes of immune cells from tumor samples obtained from melanoma patients treated with checkpoint inhibitors. We defined specific activation states of CD8+ T cells that associate with tumor growth post-therapy, delineated their epigenetic landscape and clonality, and demonstrated enhanced immunity by targeting a novel combination of T cell factors. We also found that expression of a single T cell gene was predictive of tumor regression in response to therapy. Our study thus reveals immune cell states and molecules that help explain effective immunotherapy in humans.
Citation Format: Nir Hacohen. Determinants of effective tumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA35.
Abstract IA37: Enhancing the function of CAR T cells via a universal vaccine strategy
Authors: Irvine Darrell J. 
Published: February 2019

Abstract
We recently developed a strategy to target peptide vaccines to lymph nodes, by linking peptide antigens to albumin-binding phospholipid-polymers. Small peptides are normally rapidly dispersed in the bloodstream following parenteral injection, but binding of amphiphile-peptides to endogenous albumin, which constitutively traffics from blood to lymph, retargeted these molecules to lymph nodes. However, these lipid-polymer conjugates bind to albumin with a relatively low affinity, and these molecules can also partition into cell membranes. We hypothesized that by attaching a small molecule, peptide, or protein ligand for a chimeric antigen receptor (CAR) to the same polymer-lipid tail (forming an “amph-vax” molecule), CAR ligands could be delivered efficiently to lymph nodes by albumin and subsequently partition into membranes of resident antigen presenting cells (APCs), thereby co-displaying a CAR T cell ligand from the cell surface together with native cytokine/receptor costimulation. In syngeneic mouse models of adoptive cell therapy, we demonstrated that this approach effectively concentrates CAR T ligands on the surfaces of dendritic cells in lymph nodes, leading to profound expansion of amph-vax-boosted CAR T cells in vivo. Amph-vax boosting safely increased the polyfunctionality of CAR T cells in parallel with T cell expansion. In a syngeneic model of melanoma, this converted a CAR T treatment that had no impact on tumor progression to a therapy that strongly delayed tumor outgrowth and enhanced survival. We have reduced to practice three different strategies to generalize this approach to any CAR of interest. This concept provides a strategy to regulate the expansion and function of CAR T cells directly in vivo to enhance adoptive cell therapy of cancer.
Citation Format: Darrell J. Irvine. Enhancing the function of CAR T cells via a universal vaccine strategy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA37.
Abstract IA38: Manipulating the gut microbiome to improve immunotherapy of melanoma
Authors: Davar Diwakar , Vetizou Marie Anne , Dzutsev Amirin , Badger Jonathan , McCullogh John , Menna Carmine , Pagliano Ornella , Kirkwood John M. , Trinchieri Giorgio , Zarour Hassane M. 
Published: February 2019

Abstract
Immunotherapy with blocking anti-PD1 monoclonal antibodies (a PD1 mAbs) has become one of the most potent therapies of melanoma, providing extended clinical benefits to 30-40% advanced melanoma patients. There is substantial evidence that pre-existing tumor-infiltrating CD8+T cell infiltrates correlate with clinical antitumor response to PD1 blockade. However, not all T cell-inflamed tumors respond to PD1 blockade and not all melanomas are inflamed. Hence, the mechanisms supporting response or resistance to PD1 blockade remain to be precisely determined. One intriguing finding in the field of cancer immunotherapy is the recent demonstration that the gut microbiome regulates immune and clinical responses to PD1 blockade in murine tumor models. Mice with distinct gut microbiota profiles exhibited differential tumor growth, eliminated upon cohousing. This difference was transmittable and augmented the clinical efficacy of PD1 blockade. Interestingly, fecal microbiota transplant (FMT) together with aPD1 mAbs resulted in nearly full tumor rejection in mice with melanoma. Multiple studies have recently correlated the presence of specific bacterial commensal profile with response to PD-1 blockade in melanoma. To investigate the relevance of these findings in melanoma patients, we have collected stool from melanoma patients treated with aPD-1 mAbs. Using metagenomics, we evaluated whether PD-1 responders and PD-1 non-responders exhibited a distinct gut microbiota profile and whether the gut microbiota profile overlaps with previously published studies. We have also implemented a novel clinical trial with fecal microbiota transplant (FMT) FMT obtained from long-term PD1 responders combined with PD1 blockade in melanoma patients who failed to respond to PD1 blockade alone. This trial will determine whether the administration of a single PD1 responder-derived FMT to PD1 non-responders together with PD1 blockade is safe and can promote clinical and immune antitumor response to melanoma.
Citation Format: Diwakar Davar, Marie Anne Vetizou, Amirin Dzutsev, Jonathan Badger, John McCullogh, Carmine Menna, Ornella Pagliano, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour. Manipulating the gut microbiome to improve immunotherapy of melanoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA38.
Abstract PR02: Neoadjuvant immunotherapy pre-cancer surgery relieves tumor-specific CD8+ T-cell dysfunction and restores memory differentiation potential
Authors: O'Donnell Jake S. , Liu Jing , Allen Stacey , Mueller Scott , Smyth Mark J. , Teng Michele W.L. 
Published: February 2019

Abstract
Recent preclinical and clinical results indicate that neoadjuvant immunotherapy pre-surgery may be superior to surgery followed by adjuvant immunotherapy, however it is unclear why. Using preclinical mouse models of spontaneously metastatic cancer, we dissected the mechanisms underpinning the improved efficacy of neoadjuvant immunotherapy. Compared to adjuvant treatment, neoadjuvant treatment promoted the expansion, subsequent contraction, and memory differentiation of tumor-specific CD8+ T-cells. This process “resets” the antitumor immune response to one more reminiscent of that which occurs during an acute viral infection. These effects required the presence of the primary tumor followed by its timely resection but was independent of de novo priming of tumor-specific CD8+ T-cells. This understanding allowed us to identify an on-treatment biomarker within the blood that predicted long-term survival among neoadjuvant-treated mice. These findings may enable selective targeting of key pathways activated and further improvement of front-line cancer immunotherapies.
Citation Format: Jake S. O'Donnell, Jing Liu, Stacey Allen, Scott Mueller, Mark J. Smyth, Michele W.L. Teng. Neoadjuvant immunotherapy pre-cancer surgery relieves tumor-specific CD8+ T-cell dysfunction and restores memory differentiation potential [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR02.
Abstract PR05: T-cells engineered to overcome death signaling within the tumor microenvironment enhance adoptive cancer immunotherapy
Authors: Klebanoff Christopher A. 
Published: February 2019

Abstract
Across clinical trials, T-cell expansion and persistence following adoptive cell transfer (ACT) has correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis across human tumors to identify potentially actionable ligand/receptor pairs that might limit T-cell function and persistence following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments. Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T-cells used for ACT. We hypothesized that a cognate Fas-FasL interaction within the tumor microenvironment might limit both T-cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired the ability to bind FADD function as dominant negative receptors (DNRs) in Fas-competent mouse and human T-cells, rescuing cells from FasL-induced apoptosis. Fas DNR-engineered T-cells exhibited enhanced persistence within tumors following ACT, resulting in superior cancer regression and overall survival in solid and hematologic malignancies treated with TCR or CAR-modified cells. Despite enhanced longevity, Fas DNR-engineered T-cells did not undergo aberrant clonal expansion, demonstrating the safety of this approach. Thus, cell-intrinsic “insulation” of T-cells from the negative influence of FasL is a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.
Citation Format: Christopher A. Klebanoff. T-cells engineered to overcome death signaling within the tumor microenvironment enhance adoptive cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR05.
Abstract PR06: Dual-specific T-cells and an indirect vaccine eradicate large solid tumors
Authors: Slaney Clare Y. , Scheidt Bianca von , Darcy Phillip K. , Kershaw Michael H. 
Published: February 2019

Abstract
While immunotherapy can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors and metastases for most cancers. Here we generate dual-specific T-cells expressing a chimeric antigen receptor (CAR) specific for Her2 and a TCR specific for the melanocyte protein (gp100). Injection of T-cells, together with a vaccine that contains a recombinant vaccinia virus expressing gp100, induced durable complete remission of a variety of Her2+ tumors and established metastases, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues. Tumor destruction occurred rapidly over seven days and was associated with an extensive infiltrate of T-cells. Mice that had rejected tumors were resistant to rechallenge with the same Her2+ tumor cells, indicating the formation of immune memory. Furthermore, we have established methods to transduce dual-specific T-cells from human peripheral blood with both a TCR specific for gp100 and a CAR for Her2. From as little as 1 ml of human buffy coat, we could generate sufficient numbers of cells for a course of treatment for a patient. The stimulation of gp100 through TCR enhanced the human dual-specific CAR T-cell proliferation, secretion of IFN-γ and killing of Her2+ human cancer cells in vitro. These characteristics were identified to be important for eradicating tumors in the mouse models. Taken together, our data provide valuable information for the development of CAR T-cell therapies for patients with solid cancers and evidence for pursuing a phase I clinical trial.
Citation Format: Clare Y. Slaney, Bianca von Scheidt, Phillip K. Darcy, Michael H. Kershaw. Dual-specific T-cells and an indirect vaccine eradicate large solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR06.
Abstract PR12: Functional identification and therapeutic targeting of tumor neoantigens
Authors: Schoenberger Stephen Phillip , Miller Aaron M. , Sternberg Luise A. , Cuencac Leslie Montero , Bahmanof Milad , Koasaloglu-Yalcin Zeynep , Lanka Manasa , Premlal Ashmitaa , Vijayanand Pandurangan , Greenbaum Jason , Seatte Allesandro , Cohen Ezra E.W. , Peters Bjoern 
Published: February 2019

Abstract
Accurate identification of tumor-specific neoantigens (NeoAg) is essential for the development of effective personalized cancer vaccines and cellular immunotherapies. The success rates for purely computational approaches which rely on predicted HLA-binding have been disappointing, as these generally ignore 85-90% of total mutations and find less than 5% of those selected can be confirmed as T-cell targets. We have developed a novel NeoAg identification platform in which WES and RNAseq metadata is used to nominate mutations for subsequent functional T-cell analysis using autologous PBMC and/or TIL. Applying this platform to tumors of low mutational burden including PDAC, HNSCC, and MSS-CRC, we report that an average of 35% of expressed mutations selected for functional testing can be verified as neoantigens, and that a significant number of these would be missed by HLA-binding algorithms. Responses comprise both type I and type 2 CD4+ and CD8+ effector T-cells recognizing both “passenger” mutations and known activating mutations in driver oncogenes such as KRAS, PIK3CA, and NRAS. Additionally, we have established a single-cell platform for isolation of T-cell receptors (TCR) against these shared recurrent mutations, and have opened a phase 1b clinical trial to evaluate the efficacy of personalized NeoAg vaccination in solid tumors.
Citation Format: Stephen Phillip Schoenberger, Aaron M. Miller, Luise A. Sternberg, Leslie Montero Cuencac, Milad Bahmanof, Zeynep Koasaloglu-Yalcin, Manasa Lanka, Ashmitaa Premlal, Pandurangan Vijayanand, Jason Greenbaum, Allesandro Seatte, Ezra E.W. Cohen, Bjoern Peters. Functional identification and therapeutic targeting of tumor neoantigens [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR12.