bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1488: Viral molecular mimicry influences the antitumor immune response in murine and human melanoma
Authors: Chiaro Jacopo , Kasanen Henna , Whalley Thomas , Capasso Cristian , Feola Sara , Grönholm Mikaela , Hamdan Firas , Peltonen Karita , Hernberg Micaela , Mäkelä Siru , Karhapää Hanna , Brown Paul , Martins Beatriz , Fusciello Manlio , Ylösmäki Erkko , Kreutzman Anna , Mustjoki Satu , Szomolay Barbara , Cerullo Vincenzo 
Published: July 2021

Abstract
Molecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response.To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T-cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides.In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.
Citation Format: Jacopo Chiaro, Henna Kasanen, Thomas Whalley, Cristian Capasso, Sara Feola, Mikaela Grönholm, Firas Hamdan, Karita Peltonen, Micaela Hernberg, Siru Mäkelä, Hanna Karhapää, Paul Brown, Beatriz Martins, Manlio Fusciello, Erkko Ylösmäki, Anna Kreutzman, Satu Mustjoki, Barbara Szomolay, Vincenzo Cerullo. Viral molecular mimicry influences the antitumor immune response in murine and human melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1488.
Abstract 1494: IgE receptor-activated human mast cells have potent anti-cancer properties
Authors: Kepley Chris , Ferrydouni Mohammad , Motaghed Mona , Dellinger Kristen 
Published: July 2021

Abstract
The purpose of this study was to test the hypothesis that human mast cells (MC) have anti-tumor mediators that can be targeted to tumor specific antigens, induced to release these mediators, and cause cancer cell apoptosis. Breast cancer (BC) continues to be a significant cause of mortality for women in the United States. The oncogene HER2/neu is overexpressed in BC and is validated target for cancer therapeutics. New immunotherapy strategies and combinations of immune agents with non-redundant mechanisms of action are needed. The role of human tissue mast cells (MC) in the pathology of many cancers is not known. Nonetheless, high densities of MC are associated with favorable prognosis in certain types of cancer such as BC suggesting an anti-tumor effect. We previously reported that human adipose cells can be differentiated into autologous, fully functional MC (ADMC) capable of releasing mediators upon FcϵRI stimulation that induce BC cell death of cell suspensions of SK-BR3. Further data is presented demonstrating the anti-tumor effects of ADMC using BC tumor masses. The ADMC, sensitized with breast cancer-specific IgE anti-HER2/neu, bound to and were activated by, HER2/neu-positive human BC cells. The anti-HER2/neu IgE-sensitized ADMC bound to, infiltrated, and induced apoptosis of HER2/neu-positive BT-474 BC tumor masses as determined by time-lapse, live cell confocal imaging. Specific, HER2/neu IgE-mediated binding was also verified in vivo using immunocompromised xenograft models. Further studies are warranted to determine if tumor-targeted, autologous MC may be a new way to treat solid tumors.
Citation Format: Chris Kepley, Mohammad Ferrydouni, Mona Motaghed, Kristen Dellinger. IgE receptor-activated human mast cells have potent anti-cancer properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1494.
Abstract 1498: Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer
Authors: Li Dan , Wang RuiXue , Liang Tianyuzhou , Croix Brad St. , Ho Mitchell 
Published: July 2021

Abstract
Pancreatic cancer is a common cause of cancer-related mortality worldwide with a poor 5-year survival rate. Adoptive transfer of T cells engineered with chimeric antigen receptors (CAR T cells) have shown promising potency in hematological malignancies, but it is more challenging to apply CAR T cells in the treatment of solid tumors. One of the major barriers is the lack of appropriate therapeutic targets. B7-H3 (CD276) is an emerging and promising pan-cancer target that is overexpressed in multiple solid tumors including pancreatic ductal adenocarcinoma (PDAC) and neuroblastoma (NB) but limited in normal tissues. Interestingly, it is highly expressed in not only tumor cells but also tumor-associated myeloid cells in the tumor microenvironment. In this study, we isolated a panel of novel B7-H3 specific nanobodies from our camel VHH single domain phage libraries. These nanobodies bind to human B7-H3-expressing tumor cell lines and cross-react with B7-H3 of different species. Notably, three nanobody-based CAR T cells (B12, C4 and G8) demonstrate potent cytolytic effects on B7-H3 positive PDAC and NB cell lines in vitro. In particular, CAR T cells have been tested in a metastatic PDAC model and a NB model in mice, showing that C4 and B12 nanobody-based CAR T cells have potent antitumor efficacy without evident side effects. Therefore, we conclude that our new B7-H3 targeted nanobody-based CAR T cells, in particular C4 and B12 derived CAR T cells, are promising for treating solid tumors such as pancreatic cancer and other deadly solid tumors.
Citation Format: Dan Li, RuiXue Wang, Tianyuzhou Liang, Brad St. Croix, Mitchell Ho. Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1498.
Abstract 1502: Pre-conditioning modifies the tumor microenvironment to enhance solid tumor CAR T cell efficacy and endogenous immunity
Authors: Murad John P. , Tilakawardane Dileshni , Park Anthony K. , Kennewick Kelly T. , Lopez Lupita S. , Lee Hee J. , Gittins Brenna J. , Chang Wen-Chung , Tran Chau P. , Martinez Catalina , Wu Anna M. , Reiter Robert E. , Dorff Tanya B. , Forman Stephen J. , Priceman Saul J. 
Published: July 2021

Abstract
Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.
Citation Format: John P. Murad, Dileshni Tilakawardane, Anthony K. Park, Kelly T. Kennewick, Lupita S. Lopez, Hee J. Lee, Brenna J. Gittins, Wen-Chung Chang, Chau P. Tran, Catalina Martinez, Anna M. Wu, Robert E. Reiter, Tanya B. Dorff, Stephen J. Forman, Saul J. Priceman. Pre-conditioning modifies the tumor microenvironment to enhance solid tumor CAR T cell efficacy and endogenous immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1502.
Abstract 1526: Single-step precision genome engineering platform enables versatile generation of personalized (neoTCR) adoptive cell therapy T cells with supplementary anti-tumor attributes
Authors: Dubreuil Michael M. , Tran Charles W. , Purandare Bhamini , Lu William , Byers James , Mass Michal , Jacoby Kyle , Sennino Barbara , Franzusoff Alex , Mandl Stefanie J. 
Published: July 2021

Abstract
Personalized autologous TCR-T cell therapies targeting neoE-specific neoepitopes (NeoE) derived from tumor-exclusive mutations are a compelling approach for the treatment of patients with solid tumors. Using the ultra-sensitive imPACT Isolation Technology®, antigen-experienced neoE-specific CD8 T cells are captured from the blood of patients with solid cancers followed by cloning of the cognate neoepitope-specific HLA class I-restricted T cell receptors (HLA-I neoTCRs). Using DNA-mediated (non-viral) precision genome engineering technology, fresh CD8 and CD4 T cells from the same patient with cancer are engineered to express the HLA-I neoTCR. We have further innovated this platform of precision genome engineering to confer neoTCR-T cells with supplementary gene edits to address the array of potential sources for tumor immune evasion. Two examples of the versatility of this single step gene editing platform are described in this study: 1) concurrent expression of a CD8 co-receptor (CD8coR) to augment activity of CD4 T cells engineered with lower affinity HLA-I neoTCRs; and 2) simultaneous disruption of TET2 expression in T cells, which has previously been reported to positively affect T cell differentiation and persistence. The data shows that these simultaneous supplemental gene modifications were achieved with high efficiency, resulting in fully functional CD8 and CD4 neoTCR-T cells. Surface expression of CD8coR together with the neoE-targeted TCR increased T cell effector function and antigen-specific tumor cell killing. NeoTCR-T cells with concomitant deletion of TET2-expression exhibited enhanced cytotoxicity against neoantigen-expressing tumor cells. Together, these results demonstrate the applicability of this versatile precision genome engineering platform technology to yield enhanced next generation neoTCR-T cell therapies to expand the potential for clinical benefit in treating persons with solid cancers.
Citation Format: Michael M. Dubreuil, Charles W. Tran, Bhamini Purandare, William Lu, James Byers, Michal Mass, Kyle Jacoby, Barbara Sennino, Alex Franzusoff, Stefanie J. Mandl. Single-step precision genome engineering platform enables versatile generation of personalized (neoTCR) adoptive cell therapy T cells with supplementary anti-tumor attributes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1526.
Abstract 1528: Discovery and preclinical characterization of fratricide-resistant TRuC T-cells targeting CD70
Authors: Ding Jian , Watt Amy , Liu Erica , Adam Zieba , McCarthy Derrick , Gierut Jessica , Schrand Brett , Lofgren Michael , Lajoie Jason , Kenanova Vania , Kiefer-Kwon Philippe , Horton Holly , Gutierrez Dario A. , Hofmeister Robert , Tighe Robert 
Published: July 2021

Abstract
Previously we have described the design and antitumor activity of T cell receptor fusion constructs (TRuC™) that tether an antibody-derived binder to one of the TCR subunits to achieve redirected T cell killing of tumor cells independent of HLA. Different from CAR-T cells, TRuCs are integrated into the full TCR complex and thus harness its full signaling capacity. The cell surface antigen CD70 represents a promising target for cancer immunotherapy for its selective overexpression in various hematological and solid tumor indications. Because the normal tissue expression of CD70 occurs on activated lymphocytes, including activated T cells, fratricide (self-killing) has been recognized as a significant challenge for CD70-targeted T cell therapies. To address this challenge, we discovered a diverse pool of fully human anti-CD70 scFv binders that were used to make TRuC-T cells and then functionally screened for fratricide-resistance in vitro. We successfully identified a CD70-targeted TRuC-T cell candidate that exhibits normal T cell expansion and an improved memory phenotype, clearly differentiating from fratricide-prone candidates, all while maintaining potent cytotoxicity and cytokine production against tumor cells expressing both low and high levels of CD70. In addition, our CD70-targeted TRuC-T cells showed significant anti-tumor efficacy in multiple xenograft mouse models with no evidence of in vivo fratricide. In summary, we have engineered a fratricide-resistant CD70-directed TRuC-T cell therapy that has the potential to treat a wide range of both hematologic and solid cancers.
Citation Format: Jian Ding, Amy Watt, Erica Liu, Zieba Adam, Derrick McCarthy, Jessica Gierut, Brett Schrand, Michael Lofgren, Jason Lajoie, Vania Kenanova, Philippe Kiefer-Kwon, Holly Horton, Dario A. Gutierrez, Robert Hofmeister, Robert Tighe. Discovery and preclinical characterization of fratricide-resistant TRuC T-cells targeting CD70 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1528.
Abstract 1542: A FasL-targeted immunomodulatory fusion protein replaces a pro-death with a costimulatory signal, enhancing T cell function, adoptive cell therapy, and altering the tumor microenvironment
Authors: McMurray Margot , Oda Shannon 
Published: July 2021

Abstract
Improved therapies are urgently needed for several cancers, including acute myeloid leukemia (AML) and pancreatic cancers. Adoptive cell therapy (ACT) with genetically-modified T cells has shown impressive results against B cell malignancies, but limited efficacy in other hematologic and solid tumors. To address this need, we have developed immunomodulatory fusion proteins (IFPs) that combine the ectodomain of an inhibitory receptor with a costimulatory endodomain, providing positive signals exclusively delivered to the T cells concurrently engineered to target tumor-expressed antigens, avoiding the systemic T cell activation seen with immune checkpoint-blocking therapies. We developed an IFP to target Fas ligand (FasL), which is commonly over-expressed in TMEs and induces apoptosis in tumor-infiltrating T cells. We replaced the Fas intracellular tail with the costimulatory, pro-survival 4-1BB signaling domain since both Fas and 4-1BB signal as trimers. After exposure to a murine AML cell line, IFP-transduced murine T cells effectively generated 4-1BB signaling, with metabolic reprogramming, and showed enhanced in vitro proliferation, accumulation and function. IFP T cells resisted exhaustion and effectively eradicated AML, improving survival to 71% in the FBL disseminated AML murine model (vs.11% survival with control T cells). We next engineered T cells with a single-vector that combined the IFP with a tumor-targeted mesothelin-targeted T cell receptor (TCR), for studies with the KPC mouse model of PDA that recapitulates the immunosuppressive characteristics of human disease. TCR/Fas-4-1BB T cells showed increased intratumoral concentration over control TCR-only T cells and increased median survival (65 vs. 37 days, P=0.0042). Human TCR/Fas-4-1BB T cells induced significantly more PDA tumor cell lysis than a dominant negative Fas receptor, supporting the increased benefit of the costimulatory signal. Single-cell RNA sequencing results suggest that IFP-ACT can also improve endogenous antitumor immunity, and Fas-4-1BB primary human T cells showed increased in vitro expansion and cytokine production, relative to TCR-only human T cells. We have now developed a toolbox of IFPs with distinct costimulatory domains and we show that IFPs can substantially improve therapeutic efficacy against liquid and solid tumors, supporting clinical translation.
Citation Format: Margot McMurray, Shannon Oda. A FasL-targeted immunomodulatory fusion protein replaces a pro-death with a costimulatory signal, enhancing T cell function, adoptive cell therapy, and altering the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1542.
Abstract 1544: Generation of ALK CAR-T cells for neuroblastoma therapy
Authors: Bergaggio Elisa , Tai Wei-Tien , Aroldi Andrea , Mota Ineês , Alvarado Diego , Landoni Elisa , Metovic Jasna , Nüesch Manuel , Blasco-Patiño Rafael , Papotti Mauro , Dotti Gianpietro , Chiarle Roberto 
Published: July 2021

Abstract
Neuroblastoma (NB) is the most deadly cancer in children with dismal survival in high-risk patients. The majority of NB express the full length anaplastic lymphoma kinase (ALK) receptor, that typically acts as driver oncogene together with MYCN. In contrast to ALK-driven lung cancer or lymphoma, targeted therapies with ALK tyrosine kinase inhibitors (TKIs), despite encouraging, induce only partial responses in NB. Therefore, additional tools to improve NB treatment are strongly needed. To specifically target NB cells, we developed a series of ALK chimeric antigen receptor (CAR) T constructs from antibodies that recognize both human and mouse ALK. Murine ALK CAR-T cells are able to control the growth of ALK+ leukemia and NB in syngeneic tumor models without detectable toxicity. From the leading candidate, we generated fully humanized ALK CAR-T cells that showed potent in vitro killing activity against a large panel of human NB lines, with activity comparable to GD2 CAR-T cells that are currently in clinical trials for NB patients. Remarkably, ALK CAR-T treatment synergized in vivo with the ALK inhibitor lorlatinib. Mechanistically, lorlatinib not only reduced tumor growth, but enhanced ALK expression on the surface of tumor cells, thereby facilitating ALK CAR-T targeting. Combination of ALK CAR-T cells with lorlatinib resulted in enhanced killing of NB cells and cure or markedly increased survival in mouse models of human metastatic NB even with low ALK expression. These findings support the clinical development of ALK CAR-T cells for NB therapy.
Citation Format: Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Ineês Mota, Diego Alvarado, Elisa Landoni, Jasna Metovic, Manuel Nüesch, Rafael Blasco-Patiño, Mauro Papotti, Gianpietro Dotti, Roberto Chiarle. Generation of ALK CAR-T cells for neuroblastoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1544.
Abstract 1557: Intratumoral plasmid IL-12 enhanced the systemic anti-tumor effect of anti-PD-1 antibody in triple-negative breast cancer
Authors: Nagata Hiroshi , Osada Takuya , Crosby Erika J. , Canton David A. , Twitty Chris G. , Lyerly H. Kim 
Published: July 2021

Abstract
Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Although immune checkpoint inhibitors (ICI) have entered the therapeutic landscape in TNBC, their benefits are limited to a minority of patients. We hypothesized the combination of ICI with the intratumoral administration of plasmid IL-12 (tavokinogene telseplasmid; TAVOTM) followed by electroporation could enhance the therapeutic efficacy based on our previous observation of the anti-tumor effect of TAVO in TNBC. The purpose of this study was to clarify the potency of TAVO as an additive local treatment to systemic anti-PD-1 immunotherapy.
Methods: A murine TNBC cell line, E0771, was implanted bilaterally into flanks of female C57BL/6 mice, which were randomized into four groups: control (control plasmid + control antibody), anti-PD-1 (control plasmid + anti-PD-1), Tavo (Tavo + control antibody), and combination (TAVO + anti-PD-1). TAVO or control plasmid (50 µg/injection) was administered into a single tumor followed by electroporation on days 0, 3, and 7, as we previously reported (SITC abstract), while tumors on the other side were left untreated. Anti-PD-1 or control antibody (200 µg/injection) was administered by intraperitoneal injection on days 2, 6, 9, and 13. Tumor volume was measured every other day, and the survival of mice was monitored. The local microenvironment of both treated and untreated tumors and systemic effect on splenocytes were evaluated using flow cytometry and single-cell RNA-sequencing.
Results: The combination of intratumoral administration of TAVO with anti-PD-1 suppressed the tumor growth more effectively compared to the other groups not only in treated local tumors but also in untreated remote tumors. Higher rates of tumor regression and better survival were observed in the combination group. TAVO locally increased effector CD8+ T cells while reducing regulatory T cells in both treated tumors and distant untreated tumors. The systemic expansion of effector CD8+ T cells was also observed in splenocytes.
Conclusions: Intratumoral electroporation of TAVO with anti-PD-1 improved systemic anti-tumor efficacy by modifying the immunosuppressive tumor microenvironment. Clinical studies of this combination treatment in TNBC are underway.
Citation Format: Hiroshi Nagata, Takuya Osada, Erika J. Crosby, David A. Canton, Chris G. Twitty, H. Kim Lyerly. Intratumoral plasmid IL-12 enhanced the systemic anti-tumor effect of anti-PD-1 antibody in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1557.