bluuebunny/crossref_metadata_2025_split huggingface dataset:
Albumin-Flt3L-induced cross-presenting dendritic cells promote neoantigen-specific antitumor immunity and subsequent tumor control in murine models of cancer
Authors: Lam Brandon Krishna , Esquivel Daniel , Lee Brandon , Tan Marietta , Wu T.C. , Hung Chien-Fu 
Published: January 2023

Abstract
Central to the long-term success of essentially all cancer treatment strategies is the generation of durable tumor specific cytotoxic CD8+ T cell immunity, which requires uptake and potent antigen cross-presentation by dendritic cells (DCs) since tumor cells do not efficiently present relevant CD8+ T cell epitopes. FMS-like tyrosine kinase 3 ligand (Flt3L) is a cytokine that expands and differentiates DC precursors to murine cross-presenting CD103+ and CD8a+ DCs, but the therapeutic potential of Flt3L is limited because of its short half-life and global distribution in vivo. We have overcome the described issues by generating a novel genetic fusion of Albumin (Alb) to Flt3L, named Albumin-Flt3L (Alb-Flt3L), since Alb has a long half-life and exhibits trafficking to the lymph node (LN) and tumor (TM) as a serum protein. The novel immunotherapeutic Alb-Flt3L fusion protein exhibits increased half-life measured by ELISA, selective accumulation in LN and TM by IVIS imaging compared to native Flt3L, and potently expands cross-presenting DCs with no detectable toxicities. Challenging mice with HPV-associated TC-1 and MC38 adenocarcinoma tumor model, Alb-Flt3L + targeted radiation therapy to release tumor antigen and enhance tumor immunogenicity is able to control tumor progression and extend survival. When analyzing the immune response in mice challenged with MC38 tumor, significant intratumoral neoantigen specific CD8+ T cell responses are seen by tetramer staining, suggesting that Alb-Flt3L expanded DCs are able to engender neoantigen specific T cells without additional peptide vaccination. The therapeutic potential, mechanism of action, and subsequent implications of Alb-Flt3L use are under further investigation.
Mass spectroscopy-defined neoepitopes are a rich source of tumor rejection-mediating neoepitopes in a mouse sarcoma
Authors: Ebrahimi-Nik Hakimeh , Shcheglova Tatiana , Michaux Justine , Pak HuiSong , Sherafat Elham , Al Seesi Sahar , Mandoiu Ion I , Bassani-Sternberg Michal , Srivastava Pramod K 
Published: January 2023

Abstract
Using tandem mass spectroscopy (MS), we identified 3646 unique sequences among peptides eluted from purified Kd and Dd MHC I molecules of the BALB/c fibrosarcoma Meth A. These peptides were cross-referenced with the output of neoepitopes predicted for this tumor by our prediction pipeline CCCP (Cross Consensus Calling Platform). Eleven (11) of the eluted peptides were identified as neoepitopes and eight neoepitopes (of 11) were confirmed by targeted MS.
Each neoepitope was used to immunize BALB/c mice (twice, one week apart, using precise neoepitopes along with bone marrow-derived dendritic cells); mice were challenged with Meth A cells one week after the last immunization, and tumor growth was monitored in individual mice. In parallel, immunized mice were tested for CD8+ T cells to the neoepitopes using tetramer staining and interferon g secretion by CD8 cells.
Four of the eight neoepitopes elicited rejection of Meth A fibrosarcoma; two of the four neoepitopes elicited highly potent tumor rejection, while the other two elicited statistically significant but weaker tumor rejection. Of the two strong neoepitopes, only one elicited a measurable CD8 response. Both weak neoepitopes elicited measurable CD8 responses. Of the four neoepitopes that did not elicit tumor rejection, only one elicited a measurable CD8 response; this CD8 response was the strongest of all CD8 responses detected.
These observations indicate that MS-defined neoepitopes can be a rich source of neoepitopes that can mediate tumor rejection. Further, they highlight the fact that CD8 responses are not a good predictive surrogates for tumor rejection.
Active cancer vaccine targeting carbohydrates for immunotherapy
Authors: Padler-Karavani Vered , Reuven Eliran Moshe , Ben-Arye Shani Leviatan , Yu Hai , Duchi Roberto , Perota Andrea , Conchon Sophie , Soulillou Jean-Paul , Galli Cesare , Chen Xi 
Published: January 2023

Abstract
Transformed cells present cell surface neoantigens, including aberrantly expressed carbohydrates. Targeting tumor-associated carbohydrate antigens could be useful for cancer immunotherapy. N-glycolylneuraminic acid (Neu5Gc) is a non-human carbohydrate consumed in diet and accumulates on human cancer cells, leading to expression of neoantigens. Passive immunotherapy with anti-Neu5Gc antibodies in mice inhibits tumor growth. Here we describe an active cancer vaccination immunotherapy strategy to target Neu5Gc-positive tumors. We generated glyconanoparticles from engineered red blood cells to form nano-ghosts (NGs) that either express (NGpos) or lack expression (NGneg) of Neu5Gc-glycoconjugates. We then show that optimized immunization of Neu5Gc-deficient Cmah-KO mice with NGpos glyconanoparticles induce a robust, diverse and long-lasting anti- Neu5Gc IgG immune response. Anti-Neu5Gc IgG antibodies also migrated into Neu5Gc-positive tumors and inhibited tumor growth in-vivo. Using glycan microarrays we also show that the kinetics and quality of the immune responses influence the efficacy of the vaccine. Hence, immunotherapy targeting Neu5Gc-carbohydrate neoantigens is promising.
Induction of immune responses and clinical efficacy in a pilot personalized trial of 26 multi-epitope immunotherapy using long peptides Th1 and CD8 simultaneously in progressive tumors
Authors: Marquez-Manriquez Juan P , MATUTE-BRISENO JOSE ANTONIO , ICEDO-ZAMORA SALVADOR , DURAZO-ACUNA ALBERTO , Alejandro Lucero-Diaz PEDRO ALEJANDRO , ROSAS-DELGADO MARTIN ORLANDO , CAMACHO-HERNANDEZ ALEJANDRO 
Published: January 2023

Abstract

Background
Most of the immunotherapy trials in progressive cancer are limited targeting few antigens and most of them are not clinically relevant as they are not important for tumor survival. For such reason our approach is to develop multi peptide immunotherapy in order to potentially avoid chemoresistance and target simultaneously several biologically relevant pathways. We treated patients with progressive cancer after failure of the standard of care treatment with this methodology.

Methods
N=12 patients with progressive tumors such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), epithelial ovarian cancer (EOC) and sarcomas (ES) were treated with 26 long-peptides for 3 months until progressive disease. The patients were analyzed initially for several immune parameters such as DTH in both tumor area and non-tumor area, Granzyme B ELISPOT, Antigen-specific ELISA, T-cell expansion using individual peptides and immunohistochemistry.

Results
We were able to improve significant the mOS (38 months) with absence of toxicity. The proteins that we targeted were previously showed that were biologically relevant according with the siRNA studies we were able to silence and kill permanently in vitro different chemoresistant cell lines from the types of tumors treated as following PDAC (n=0.001), CRC (n=p0.005), EOC (P=0.001) and sarcomas (n=0.0001).

Discussion
After we validate this data with a large cohort of progressive tumors we will be able to prepare a clinical trial phase/II I order to accelerate the potential addition of these type of antigen active specific immunotherapy with other treatment modalities such as immunogenic chemotherapy, cytotoxic chemotherapy, radiotherapy, etc.
IL17 depletion enhances the DNA vaccine efficacy in pancreatic ductal adenocarcinoma treatment
Authors: Cappello Paola , Mucciolo Gianluca , Curcio Claudia , Roux Cecilia , Curto Roberta , Barutello Giuseppina , Novelli Francesco 
Published: January 2023

Abstract
Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive cancer with a 5-year survival rate of ~8%. PDA is considered an “immunologically-cold” tumor because of the abundant desmoplastic immune-suppressive microenvironment and low presence of neo-antigens. Moreover, it is characterised by a complex inflammatory response in which the role of the IL17 and T helper-17 remain controversial. We have demonstrated that a DNA-based vaccination strategy targeting a PDA-associated antigen, namely alpha-enolase (ENO1), significantly prolongs survival in genetically engineered mice (GEM). We have also observed that the absence of IL17 strongly modified PDA microenvironment, improving CD8 T cell recruitment. Therefore, the aim of this study is to assess the role of IL17-targeting in combination with the DNA-vaccination. GEM crossed with IL17 knockout mice (GEM/IL17−/−) were vaccinated and monitored weekly to obtain a Kaplan-Meier survival curve. GEM vaccinated in absence of IL17 showed higher level of anti-ENO1 antibodies and IFNγ-secreting ENO1-specific T cells. The analysis of the tumor infiltrating cells revealed an increase of antigen-presenting cells and effector/memory T cells. To translate the experimental model into a clinical setting, mice orthotopically injected with PDA cells, were treated with anti-IL17 mAb in combination or not with ENO1-DNA vaccine. Only the combination elicited a significantly reduction in tumor growth that paralleled the induction of cytotoxic T cells not observed after ENO1-vaccine or anti-IL17 Ab alone. Overall, the depletion of IL17 opens new possibilities for combination to design more effective immunotherapeutic strategies to be associated with conventional one.
A powerful ICOS agonist that enhances anti-tumor immune responses restored by immune checkpoint inhibitors
Authors: Gariepy Jean , Prodeus Aaron , Sparkes Amanda , Fischer Nicholas , Saha Shravasee 
Published: January 2023

Abstract
The Inducible T cell Costimulator (ICOS, CD278) is a receptor in the CD28 family of B7-binding proteins expressed mostly by activated T cells. Upon binding to its ligand ICOS-L expressed on APCs,T cells are further activated by ICOS, resulting in their expansion and production of effector cytokines. Clinical data in patients treated with anti-CTLA-4 or anti-PD-1 mAbs have shown that ICOShiT cells correlated with an increased treatment response in these patients. Here, we report the design of a high avidity pentavalent form of the human ICOS-L extracellular domain fused to a short α-helical peptide from the human cartilage oligomeric matrix protein (COMP). This ICOS agonist, termed ICOS-L.COMP, spontaneously assembles into stable pentamers, binds tightly to both human and murine ICOS (SPR; Kd&lt;10 nM) and co-stimulates (with anti CD3 mAb) the proliferation and cytokine release of both murine and human CD4+ and CD8+ T cells when added as a soluble factor (unlike ICOS-L.Fc). Soluble ICOS-L.COMP also phosphorylates Akt in activated T cells and enhances anti-tumor immune responses in tumor-bearing mice [murine MC38 or CT26 tumors] treated with either anti-murine PD-1 or anti-murine CTLA-4 mAb. Impressively, most mice treated with ICOS-L.COMP combined with an immune checkpoint inhibitor were either cured or displayed a stable tumor burden in contrast to checkpoint monotherapies (delayed tumor progression) or when ICOS-L.COMP was given as a monotherapy (comparable to no treatment). Importantly, ICOS-L.COMP lacks a Fc domain thus eliminating Fc-associated off-target adverse effects. In summary, our results suggest that ICOS-L.COMP represents a new and powerful biologic to be used in combination with existing immune checkpoint inhibitors.
Rejection-resistant off-the-shelf T cells for adoptive cell therapy
Authors: Mo Feiyan , Srinivasan Madhuwanti , Ma Royce , Smith Tyler S , McKenna Mary K , Atilla Erden , Atilla Pinar Ataca , Heslop Helen E , Brenner Malcolm K , Mamonkin Maksim 
Published: January 2023

Abstract
‘Off-the-shelf’ (OTS) chimeric antigen receptor (CAR) T cells pre-manufactured from healthy donors are a readily available and less expensive alternative to autologous products. However, immune rejection of OTS cells by host T- and NK-cells may limit their persistence and reduce therapeutic effect. Here, we engineered rejection-resistant OTS T cells that recognize and eliminate alloreactive lymphocytes while retaining desired anti-tumor activity. As T- and NK-cells transiently upregulate 4-1BB after activation, T cells expressing a 4-1BB-specific alloimmune defense receptor (ADR) selectively eliminated activated T- and NK-cells while sparing resting lymphocytes. Using this mechanism, ADR-expressing T cells suppressed alloimmune activation and resisted rejection in a mixed lymphocyte reaction (MLR) model in vitro. Further, T cells co-expressing the ADR and a CD19 CAR retained undiminished activity through both receptors in vitro and in vivo. We established a mouse model of allogeneic cell therapy in which NSG mice were engrafted with systemic CD19+ leukemia and normal human T cells. In this model, adoptively transferred unmodified CD19 CAR T cells from an HLA mismatched donor produced only transient anti-tumor activity and were rapidly rejected by pre-engrafted alloreactive T cells within 7 days, leading to fatal leukemia relapse. In contrast, T cells co-expressing both CAR and ADR were protected from immune rejection, resulting in long-term persistence (&gt;9 weeks) and durable leukemia eradication in most animals. These data support the feasibility of using ADR to generate highly potent OTS CAR T cell products that suppress immune rejection to produce long-term therapeutic benefit even in immunocompetent patients.
Modulating Interlukin-7 (IL-7) cytokine receptor signaling to enhance the persistence and anti-tumor efficacy of Epstein-Barr Virus (EBV) specific T-cells in EBV positive malignancies
Authors: Sharma Sandhya , Shum Thomas , Parikh Kathan , Omer Bilal , Rooney Cliona 
Published: January 2023

Abstract
EBV-specific T-cells (EBVSTs) targeting viral proteins in EBV+ lymphoma patients have produced 50% clinical response. Limited T-cell expansion and persistence attributed to lack of cytokines in the tumor microenvironment (TME) remains a major challenge. IL-7 signaling has survival and anti-apoptotic effects on T-cells, however, IL-7 availability in vivo is limited and the IL7 receptor is downregulated on activated T-cells. We aim to overcome this limitation of suppressive TME by augmenting IL-7 signaling.
We recently reported the transgenic expression of a constitutively active IL-7 receptor (C7R) to provide the proliferative and survival advantage in T-cells. Hence, we hypothesize that EBVSTs endowed with cytokine-independent C7R signaling will have resistance to the immunosuppressive TME and increased persistence and anti-tumor potency.
C7R expressing EBVSTs demonstrated enhanced antigen-specific IFN-γ release and superior target specific cytotoxicity in-vitro. In contrast to unmodified EBVSTs, C7R-EBVSTs demonstrated EBV antigen dependent, cytokine-independent proliferation and survival, associated with increased phosphorylated STAT5. Furthermore, C7R signaling provided resistance against TGFβ, Arginase-I, and M2 macrophages, as demonstrated by increased proliferation attributed to decreased apoptosis in C7R-EBVSTs. Following adoptive transfer in an EBV+ murine xenograft model, C7R-EBVSTs persisted significantly longer and demonstrated tumor clearance, while unmodified EBVSTs failed.
C7R signaling augments EBVSTs potency and persistence against suppressive components of TME in our preclinical models. Once effective, the findings will be translated to clinical trials in EBV+ malignancies.
Assessing the in-vitro effects of anti-PD-L1 (Avelumab) and recombinant human rhIL-15 in CD8 T cell function from HIV infected patients
Authors: Goshu Bruktawit , Lane Clifford , Catalfamo Marta 
Published: January 2023

Abstract
Persistent immune activation in chronic HIV infection leads to exhaustion/activation of virus-specific CD8 T cells accompanied by expression of checkpoint receptors such as PD1. Here, we hypothesized that blockade of the PD1/PD-L1 pathway in combination with IL-15 (known to induce proliferation of CD8 T cells) may have a higher impact in improving HIV-specific responses. We assessed the in vitro effects of a checkpoint inhibitor, anti-PD-L1 (Avelumab), in combination with rhIL15 in HIV-specific CD8 T cell proliferation and cytokine secretion. Cell Trace Violet (CTV) labeled PBMCs from HIV infected patients (HIV+, n= 15) and healthy controls (HC, n= 7) were stimulated with HIVGag and CEF-peptides in the following conditions: rhIL-15, anti-PD-L1, and combination rhIL- 15/anti-PD-L1. After 5 days of culture, cells were re-stimulated and analyzed by flow cytometry. We found that rhIL-15 promoted higher antigen-independent proliferation (CTVlow) and cytokine secretion IFNg+ (p=0.009) and TNFa+ (p=0.01) in CD8 T cells from HIV+ patients than HC. In addition, rhIL-15 induced an increased trend in HIVGag-specific CD8 T cells (CTVlowIFNg+) but did not reach significance (p=0.1250). In HC, rhIL15 increased CEF-specific CD8 T cell CTVlowIFNg+ (p=0.03) and TNFa+ (p=0.03). Anti-PD-L1 alone did not show any effect in CD8 T cells from HIV+ patients and HC. In contrast, the combined treatment increased the CTVlowIFNg+ HIVGag-specific CD8 T cells in HIV+ patients (p=0.039) and CTVlowIFNg+ CEF-specific CD8 T cells in HC (p= 0.031). Overall, there was a synergistic effect in HIV-specific CD8 T cell function with the combined treatment. Further studies should assess the potential use of this combined treatment in the context of HIV infection.
Passive infusion of Fc-modified neutralizing antibodies does not affect the dynamics of plasma virus decay in SHIV-infected macaques
Authors: Asokan Mangaiarkarasi , Maximova Anna , Dias Joana , Crowley Andrew R , Pegu Amarendra , Ambrozak David , McKee Krisha , Shi Wei , Todd John-Paul , Ackerman Margaret E , Gama Lucio , Keele Brandon F , Lifson Jeffrey D , Perelson Alan S , Mascola John R , Koup Richard 
Published: January 2023

Abstract
Passive neutralizing antibody (NAb) infusion leads to a reduction of HIV plasma viremia in infected people as well as in SHIV-infected rhesus macaques. Potential mechanisms of viral reduction include neutralization of free virus as well as Fc-dependent effector functions that can clear infected cells. We generated several Fc variants of the human IgG1 NAb VRC07-523LS and characterized them for neutralization, complement binding, ADCC, phagocytosis, and binding to rhesus FcgR. Based on these assays, we down selected two variants, LALA and DEL, that showed knock-out or increase in ADCC and phagocytosis respectively, with complement binding knocked out in both. The parental, LALA and DEL variants of VRC07-523LS were administered at a single dose of 20 mg/kg i.v. to rhesus macaques chronically infected with SHIV-SF162P3 for 6–14 weeks (n=6 to 10 per group). Animals were followed for rate of plasma virus decay and antibody PK. All groups showed similar characteristics: 1) plasma virus decay was delayed for 24h after NAb infusion 2) the rate of plasma virus decay was the same between day 1 and day 5, and 3) plasma virus decay was independent of FcgRIII genotype. Pharmacokinetic analysis showed that serum NAb concentrations in the VRC07-523LS, LALA and DEL groups were maintained at greater than ten-fold excess of the in vitro IC80 against SHIV SF162P3 throughout the period of investigation. Further, unlike VRC07-523LS-LALA, VRC07-523LS-DEL was able to engage natural killer cells and monocytes and mediate both HIV envelope-dependent ADCC and phagocytosis. These results show that the initial impact on plasma viremia by passive NAb therapy is predominantly mediated by virus neutralization rather than ADCC or phagocytosis.
Characterization of heterologous HIV-1 Tier 2 neutralizing mAbs cloned from a macaque immunized with viral quasispecies present in a human subject with neutralization breadth
Authors: Spencer David A , Malherbe Delphine C , Henderson Heidi , Pandy Shilpi , Bernat Néstor Vázquez , Àdori Monika , Goldberg Ben , Dambrauskas Nicholas , Sutton William , Sather Noah , Kobie James , Ackerman Margaret E , Karlsson Hedestam Gunilla B , Haigwood Nancy Logan , Hessell Ann Jones 
Published: January 2023

Abstract
Eliciting Abs that efficiently neutralize multi-clade HIV strains will likely be necessary for an effective HIV-1 vaccine. Such broadly neutralizing Abs have been cloned from a minority of chronically infected patients but have yet to be generated through pre-clinical vaccine regimens in NHPs. Here we characterize the Env-specific mAb response in an NHP with autologous Tier 2 neutralizing activity after co-immunization with plasmid gp160 DNA(x6) + gp140 trimeric protein(x2), using viral quasispecies present in a human subject immediately prior to and concurrent with the development of neutralizing breadth. In brief, 46 mAbs were cloned from single IgG+, antigen-specific, memory B cells, 12 of which neutralized heterologous Tier 1 and Tier 2 virus at IC50s &lt; 4.2 mg/ml in a TZM-bl assay. These mAbs bound SHIVSF162P3-infected rhesus PBMCs significantly more than non-neutralizers (p &lt; 0.001). Octet measurements and peptide mapping revealed the strongest neutralizers bound autologous F8 SOSIP with high affinity (KD ≤ 1.32×10−9), and 10 of these mAbs targeted the viral V3 region in the VH5.51 “cradle” orientation. Interestingly, non-neutralizing mAbs demonstrated high in vitroEnv binding (EC50s &lt; 0.001 mg/ml) via ELISA, and several mediated ADCP against HIVSF162gp120 coated beads. Additionally, ADCC activity was observed with select neutralizing and non-neutralizing mAbs via KHYG-1/NKR24 SHIV-infected reporter assay. Collectively, these results suggest this immunization strategy recapitulated in part the clonal neutralization expansion and Env targeting observed in the patient and provide insights into effector functions of both neutralizing and non-neutralizing HIV-1 Env-specific mAbs elicited during vaccination.
Low weight piglets show differences in intestinal microbiota, intestinal transcriptome and immune cell profile compared to high weight piglets during the first two weeks of lactation
Authors: Blais Mylene , Morissette Bruno , Talbot Guylaine , Beaudoin Frederic , Deschene Karine , Verso Luca Lo , Bissonnette Nathalie , Lauzon Karoline , Guay Frederic , Lessard Martin 
Published: January 2023

Abstract
Piglets born with lower weight and showing low performances during the first weeks of lactation are associated with higher risks of gastroenteric diseases after weaning. Therefore, we investigated the developmental differences between these pigs compared to the high weight piglets. Eight litters adjusted to 12 piglets were used. In each litter, piglets showing the lowest weight gain (LWG) or the highest weight gain (HWG)in the first week of life were selected. For each piglets enrolled, ileal gene expression, immune cell populations and microbiota profiles were studied. Results obtained from microarray and Q-PCR analysis showed that, at 16 days of age, the expression of genes involved in oxidative stress and immune response was altered in LWG piglets’ ileum. Analysis of the LH-PCR data of the microbiota using non-metric multidimensional scaling (NMS) and blocked multiresponse permutation procedure (MRBP) revealed that the microbiota of the HWG and LWG piglets tended to differ in ileal mucosa (p = .097) and differed incolonic lumen (p = .024). From day 8 to 16, LWG piglets failed to show an increase of CD21+ B cells in their blood (P weight × day = 0.01), but showed an increase of CD4+CD8α-Th cells (P = 0.002), unlike the HWG piglets. Percentages of CD14+ monocytes and other MHC-II+ cells were respectively higher and lower on day 8 compared to day 16 (P &lt; 0.01). Moreover, LPS activated PBMC from LWG piglets produced less IL-6 (P &lt; 0.05). These results suggest that piglets low performances during lactation affect the development of their immune system and is associated with differences in intestinal gene expression profile and microbiota.