tbuckley/cabot-search huggingface dataset:
Abstract 4097: LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma
Authors: Yongfeng He, Sijin Luo Zhong, Bhavneet Bhinder, Geoffrey Markowitz, Arshdeep Singh, Eric Gardner, Myung Soo Ko, Nasser K. Altorki, Shaoyi Jiang, Vivek Mittal
Journal: Cancer Research (2024)

Abstract The widespread use of chest computed tomography in lung cancer screening has led to the detection of ground-glass opacity (GGO) nodules, which typically harbor pre-invasive or minimally invasive adenocarcinoma and 20-40% of GGO nodules progress to invasive lung adenocarcinoma within 4 years. Lack of approved treatments to intercept disease progression has imposed challenges in the clinical management of patients with GGOs. Previous studies showed that GGO nodules have substantially lower rates of HLA deletions than invasive/metastatic lung cancer, suggesting that GGO nodules constitute a critical window of vulnerability for immune interception. We therefore sought to identify the most immunogenic and cytotoxic neoantigens in patients with GGO nodules and to develop LNP-mRNA cancer vaccines to intercept the disease progression from pre-invasive to invasive adenocarcinoma. Whole exome and RNA sequencing of a large cohort (&amp;gt;300) patients identified potential neoantigen candidates, with KRAS-G12C, KRAS-G12D and EGFR-L858R as the most frequently predicted shared neoantigens consistent with &amp;gt;40% GGO patient population harboring either mutant KRAS or EGFR driver oncogenes. LNP-mRNA vaccines targeting KRAS-G12C and EGFR-L858R showed marked immunogenicity as determined by ELISPOT assays. Moreover, KRAS-G12C vaccination induced CD4+ T cell responses whereas EGFR-L858R vaccination triggered CD8+ T cell responses. Both these vaccines are being tested in GGO immunoprevention studies. Our data suggest the potential of KRAS and EGFR vaccines in the treatment of early disease, particularly in EGFR mutant patients who fail to respond to immunotherapy. Citation Format: Yongfeng He, Sijin Luo Zhong, Bhavneet Bhinder, Geoffrey Markowitz, Arshdeep Singh, Eric Gardner, Myung Soo Ko, Nasser K. Altorki, Shaoyi Jiang, Vivek Mittal. LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4097.
Abstract 2817: Establishment of KRAS G12C mutant brain metastasis models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy
Authors: Qikuan Chen, Guilan Wang, Yingfei Yin
Journal: Cancer Research (2024)

Abstract KRAS is one of the most frequently mutated oncogenes in cancers, especially in lung cancer. Clinical research has shown that about 14% of non-small-cell lung cancers (NSCLCs) carry the KRASG12C mutation, and brain metastases are a relatively common occurrence in KRASG12C-mutated NSCLC. Approximately 30% of patients with KRASG12C mutations develop brain metastases, and those with KRAS-mutated NSCLC and untreated brain metastases have limited treatment options and poor clinical outcomes. AMG510 (Sotorasib) is a small molecule inhibitor of KRASG12C that specifically binds to inactive GDP-bound KRASG12C, preventing its oncogenic signaling. It has been approved for NSCLC by the FDA. Recent clinical studies have shown that Sotorasib exhibits some activity against KRASG12C NSCLC brain metastasis. To evaluate the in vivo activity of AMG510 for NSCLC brain metastasis treatment and provide insights for the preclinical development of new KRAS targeted inhibitors, we established advanced orthotopic models, including intracranial, intracarotid, and intracardiac metastatic models, using the NCI-H358-luc cell line, which harbors the KRASG12C mutation. We validated these models with AMG510 as a single agent or in combination with radiation, which is commonly used in brain tumor therapeutic strategies, to reveal the efficacy and brain concentration of AMG510 in KRASG12C brain metastasis models. Tumor growth and metastasis incidences were assessed using bioluminescence imaging (BLI). All animal studies were performed in an AAALAC accredited facility and aligned with animal welfare regulations. Our preliminary results reveal that AMG510 could penetrate the blood-brain barrier (BBB) and show therapeutic activity for KRASG12C brain metastatic tumors. These models represent powerful tools for clinically relevant assessment of the efficacy of novel KRAS G12C inhibitors and can be expanded for other KRAS mutations-associated brain metastasis or inhibitors. Citation Format: Qikuan Chen, Guilan Wang, Yingfei Yin. Establishment of KRAS G12C mutant brain metastasis models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2817.
Abstract 4092: Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine
Authors: Maria Del Mar Maldonado, Masafumi Iida, Maria Del Mar Gracia Hernandez, Loc Le, Renee N. Donahue, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton
Journal: Cancer Research (2024)

Abstract Endogenous retroviruses (ERVs) are remnants of retroviral germline infections which occurred over the course of evolution and constitute between 5-8% of the human genome. Although ERV protein expression is typically silenced epigenetically in normal adult human tissues, previous studies have shown that some ERVSs, can be aberrantly expressed in multiple cancer types. This atypical expression of ERVs in tumors may represent a class of immunologically relevant tumor-associated antigens that can potentially be targeted clinically using therapeutic cancer vaccines. For the first time, this study evaluates the ERV envelope protein ERVMER34-1 as a potential target for a therapeutic cancer vaccine. We first assessed the expression of ERVMER34-1 in multiple tissues and found that ERVMER34-1 protein is absent in most healthy adult tissues and over expressed in multiple types of human carcinomas. ERVMER34-1 specific T-cells were detected in PBMCs of cancer patients but not healthy donors following an overnight stimulation. However, reactive T-cells are readily expanded from both healthy donor and cancer patient PBMCs following a 7-day in-vitro stimulation. Importantly, reactive CD8+ T cells selectively killed human carcinoma cells expressing the target antigen. Based on these findings, we rationally designed a ERVMER34-1 therapeutic cancer vaccine and assessed its immunogenicity and anti-tumor efficacy in established syngeneic murine tumors expressing the full-length ERVMER34-1 protein. Our rationally designed ERVMER34-1 cancer vaccine significantly mediated tumor regression and extended survival as a monotherapy and in combination with checkpoint blockade. Altogether, our work supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1 as a potential first-in-class immunotherapeutic target for the therapy of several carcinoma types. Citation Format: Maria Del Mar Maldonado, Masafumi Iida, Maria Del Mar Gracia Hernandez, Loc Le, Renee N. Donahue, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4092.
Abstract 2157: Evaluating cervical and lung cancer risk among Hispanic and Non-Hispanic Black women in three urban Texas counties
Authors: Megan L. Chu, Irene E. Jayesh
Journal: Cancer Research (2024)

Abstract This study examines if there is a statistically significant difference in the risk of being diagnosed with cervical and lung cancer between Hispanic and Non-Hispanic Black (NHB) women in Tarrant, Dallas, and Bexar county. Pulling from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program, 2000-2020 trends in cancer diagnosis were measured by age-adjusted annual percent change (APC). Data was sorted by county and race/ethnicity and statistically insignificant measures were removed. APC measures were ranked relative to counties across Texas and the US. APC measures with 95% confidence intervals for Hispanic and NHB women in Tarrant, Dallas, and Bexar county were compared for a significant difference. Results from a previous study indicated that the slowest decreases in cervical cancer rates are found among Hispanic and African-American women in Tarrant and Dallas County. We built upon this study to assess if there was a statistically significant difference in the risk of developing cervical and lung cancer between these two groups. In Tarrant County (TC), the cervical cancer APC of Hispanic women was -1.8 [-3.4,0.1] and NHB women was -1.2 [-3.7, 1.3]. In Dallas County, the cervical cancer APC of Hispanic women was -2.1 [-3.4, -0.8] and NHB women was -1.8 [-3, -0.5]. This indicates that for both cities, Hispanic women saw a greater decrease in the APC in cervical cancer rates than NHB women. In Tarrant County (TC), the lung cancer APC of Hispanic women was -2.7 [-4.5, -0.9] and NHB women was -2.1[-3.1, -1.1]. In Dallas County, the lung cancer APC of Hispanic women was -2.3 [-4.2, -0.4] and NHB women was -1.8 [-2.5, -1]. This indicates that for both cities, while Hispanic women saw a greater decrease in the APC in lung cancer rates than NHB women, the decrease is not statistically significant due to the overlap of the confidence intervals. Even though the confidence interval (CI) overlaps indicates insignificance, the APC can still provide valuable information regarding diagnostic trends seen in urban cities. The results showed that there is no significant difference between these two groups, suggesting that other county-level factors may play a role in diagnostic disparities seen between these two racial groups. Citation Format: Megan L. Chu, Irene E. Jayesh. Evaluating cervical and lung cancer risk among Hispanic and Non-Hispanic Black women in three urban Texas counties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2157.
Abstract 1898: LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers
Authors: Daniel P. Fitzgerald, Duc N. Doan, Riley B. Peacock, Shannon M. Kahan, Suvendu Lomash, Stephen Slocum, Kwang Hwa Jung, Hwanhee Oh, Ingrid Meza, Yanira Manzanarez, Shanmugam Selvam, Dallas B. Flies, Chul-Woong Chung, Sol Langermann
Journal: Cancer Research (2024)

Abstract The B7 family protein B7-H4 is highly expressed on a range of solid tumors including breast, ovarian, and endometrial cancers, where it may play a role in immune evasion. In non-cancerous tissues, B7-H4 expression is limited, suggesting it may be a potential target for an antibody drug conjugate (ADC). LNCB74 is a human IgG1 antibody conjugated to the potent microtubule disrupting payload monomethyl auristatin E (MMAE) with a drug-to-antibody ratio of 4 (DAR4). The ADC employs a highly selective B7-H4 antibody based upon NextCure’s expertise in B7-H4 tumor biology coupled with a glucuronidase-cleavable, site-specific linkage to an engineered cysteine in the antibody light chain via LegoChem Biosciences’ ConjuAllTM technology. This improves the safety profile and therapeutic index of the agent by a) increasing stability in circulation, b) selectively releasing payload in tumor cells, and c) reducing payload release in off-target cells. LNCB74 was further engineered with a “LALA”-mutant Fc region to minimize uptake and toxicity to immune cells. In a nonhuman primate (NHP) toxicity study, LNCB74 was well tolerated for repeat dosing and provides evidence for a superior safety profile without noticeable side effects. LNCB74 is rapidly internalized by B7-H4-expressing tumor cells, and demonstrates potent, target-specific cytotoxicity on multiple cancer cell lines. In vivo studies demonstrate a strong bystander effect following a single dose administration of LNCB74. A rapid and durable anti-tumor response has been demonstrated in multiple cell-line derived (CDX) and patient-derived xenograft (PDX) tumor models. In summary, LNCB74 is a promising ADC enabling specific targeting of B7-H4 positive cancers across a spectrum of indications. Citation Format: Daniel P. Fitzgerald, Duc N. Doan, Riley B. Peacock, Shannon M. Kahan, Suvendu Lomash, Stephen Slocum, Kwang Hwa Jung, Hwanhee Oh, Ingrid Meza, Yanira Manzanarez, Shanmugam Selvam, Dallas B. Flies, Chul-Woong Chung, Sol Langermann. LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1898.
Abstract 2828: Combining neratinib with trastuzumab deruxtecan to treat HER2;TP53 co-mutated breast cancers
Authors: Xiaoqing (Cathy) Cheng, Maureen Highkin, Jacob Hsia, Julie L. Prior, Ian S. Hagemann, Ron Bose
Journal: Cancer Research (2024)

Abstract In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the TP53 gene and patients with these two co-occuring mutations have a lower response rate to neratinib. In order to address this clinical problem, we bred HER2 activating mutant transgenic mice with two different alleles of TP53. We used mice with the TP53 R172H mutation, which is the murine homolog of the human hotspot TP53 R175H mutation, and mice with TP53flox/flox allele, which mimics TP53 truncating mutations seen in human breast cancers. All three H53 genotypes (H53null, H53172/WT, and H53172/null) developed breast cancers faster than H mice, with H53172/null mice developing breast tumors the fastest, at just 6 weeks after adenoviral-Cre injection into the mammary fat pad. We developed organoids from these murine breast cancers and found that all H53 genotype organoids were less sensitive to neratinib compared to H, however, neratinib was able to synergize with trastuzumab deruxtecan (T-DXd), likely through neratinib mediated increased internalization of T-DXd. Prior literature studies suggest TP53 mutant cancer cells may have therapeutic vulnerabilities to the topoisomerase 1 (Top1) inhibitors. Organoids from all three H53 genotypes were sensitive to the Top1 inhibitor, exatecan. H53172/WT behaved like H organoids with G1 phase cell cycle arrest and induction of p21 expression after exatecan treatment. In contrast, H53null and H53172/null failed to induce p21 and arrested at late-S/G2 phase. Additional animal experiments with these H53 genotypes are in progress and results will be presented at the AACR Annual Meeting. Abbreviation Genotype Median tumor formation (weeks) Neratinib IC50 (nM) Neratinib +T-DXd H HER2V777L 28 10 Not determined H53null HER2V777L;TP53flox/flox 10 240 Synergy H53172/WT HER2V777L;TP53R172H/WT 11 100 Synergy H53172/null HER2V777L;TP53R172H/flox 6 150 Synergy Citation Format: Xiaoqing (Cathy) Cheng, Maureen Highkin, Jacob Hsia, Julie L. Prior, Ian S. Hagemann, Ron Bose. Combining neratinib with trastuzumab deruxtecan to treat HER2;TP53 co-mutated breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2828.
Abstract 4104: Randomized phase II trial of imiquimod with or without 9vHPV vs observation in patients with CIN 2 and 3
Authors: Sangini S. Sheth, Ji Eun Oh, Stefania Bellone, Eric R. Siegel, Natalia Buza, Akiko Iwasaki, Alessandro D. Santin
Journal: Cancer Research (2024)

Abstract Introduction: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator, vs imiquimod plus a 9-valent human papillomavirus vaccine (9vHPV) vs surveillance in cervical intraepithelial neoplasia (CIN) 2 and 3 patients. Methods: We randomly allocated 133 patients with untreated CIN 2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (arm B) or imiquimod plus 9vHPV (arm C) vs clinical surveillance (arm A). The main outcome was efficacy, defined as histologic regression to CIN 1 or less. Secondary outcomes were HPV clearance and treatment tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and post-treatment by flow-cytometry. Results: Of the 114 evaluable patients 77% and 23% had CIN2 and CIN3, respectively. Histologic regression to CIN1 or less was observed in 95% of patients in the Arm B: imiquimod group and 84% in the Arm C: imiquimod+9vHPV compared with 79% in Arm A: surveillance (p=0.043 and 0.384, respectively). The difference between either treatment arm compared with control did not reach the prespecified α=0.025. No significant differences were noted in HPV clearance. The number of tissue-resident memory CD4/CD8 T-cells in cytobrush samples demonstrated a &amp;gt;5-fold increase in Arm-B: imiquimod when compared to Arm-A: surveillance (p&amp;lt;0.01). Imiquimod treatment was well tolerated. In contrast, there was no significant difference in T-cell responses among participants in Arm-C compared to Arm-A. Imiquimod treatment was well-tolerated. Conclusions: Although imiquimod induced a higher percentage of regression to CIN1 or less and significant increases in CD4/CD8 T-cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trial with imiquimod targeting CIN3 patients are warranted. Citation Format: Sangini S. Sheth, Ji Eun Oh, Stefania Bellone, Eric R. Siegel, Natalia Buza, Akiko Iwasaki, Alessandro D. Santin. Randomized phase II trial of imiquimod with or without 9vHPV vs observation in patients with CIN 2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4104.
Abstract 4098: A citrullinated-ENO1 peptide vaccine delayed tumor growth and markedly improved overall survival in a mouse model of triple-negative breast cancer
Authors: Ricardo A. Leon Letelier, Hiroyuki Katayama, Yihui Chen, Yinning Cai, Fuchung Hsiao, Banu Arun, Samir Hanash
Journal: Cancer Research (2024)

Abstract Purpose: To evaluate the impact of a novel citrullinated-enolase 1 (cit-ENO1) peptide-based vaccine on the immune response, tumor growth and overall survival in a mouse model of triple-negative breast cancer (TNBC). Background: Cancer vaccines have consisted primarily of mutated or overexpressed proteins in cancer. We have uncovered dysregulated protein citrullination by peptidyl arginine deiminases (PADI) as a feature of triple negative breast cancer inducing immunogenicity to citrullinated proteins. On the basis of these findings, we investigated a novel vaccine based on cancer-selective cit-ENO1 peptides that we identified from mass spectrometry analysis of the surfaceome and immunopeptidome in TNBC. We assessed the extent to which the vaccine elicited an immune response and delayed tumor growth and improved overall survival in a syngeneic mouse model of TNBC. Experimental Design: We immunized female B6129SF1/J mice with cit-ENO1 peptides or corresponding unmodified ENO1 (unm-ENO1) peptides as antigens, together with the TLR3 agonist poly I:C as an adjuvant, once a week, for three weeks. PBS or poly I:C alone were used as controls. One week post the last round of immunization, draining lymph nodes (LN) and immunized skin were harvested, and T cell phenotypes evaluated using flow cytometry. To assess anti-cancer efficacy, mice were immunized with cit-ENO1 or unm-ENO1 peptides, followed by orthotopic implantation with murine BRCA1co/co; MMTV-Cre; p53+/- TNBC cells. Tumor growth and overall survival were assessed. Results: Cit-ENO1 peptide vaccination induced a statistically significantly greater percentage of activated CD8+ PD-1+ effector T cells as well as CD8+ CD44+ CD62L- effector memory T cells in the LNs compared with either the control groups or the unm-ENO1 peptide. CD8+ PD-1+ T-cells were also significantly elevated in immunized skin of cit-ENO1 vaccinated mice. Both cit-ENO1 and unm-ENO1 vaccine increased CD4+ PD-1+ T cells from the LNs and immunized skin. Remarkably, the cit-ENO1 vaccine but not the um-ENO1 vaccine significantly delayed tumor growth and markedly improved overall survival compared to respective controls. Conclusion: Cancer-selective cit-ENO1 peptides induced a potent anti-cancer immune response and significantly delayed tumor initiation and progression in a preclinical, immune competent mouse model of TNBC. Citation Format: Ricardo A. Leon Letelier, Hiroyuki Katayama, Yihui Chen, Yinning Cai, Fuchung Hsiao, Banu Arun, Samir Hanash. A citrullinated-ENO1 peptide vaccine delayed tumor growth and markedly improved overall survival in a mouse model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4098.
Abstract 6728: Preclinical development of QL325, a novel T cell engager targeting CLEC12A-positive AML
Authors: Shenda Gu, Hieu V. Tran, Shihao Chen, Ke Liu, Xin Zhang, Linchao Jia, Ruixue Ma, Jiayu Fu
Journal: Cancer Research (2024)

Abstract Despite advancement in targeted therapies, treatment options for patients with acute myeloid leukemia (AML) that provide a tolerable and durable response remain elusive. We have developed a CD3 bispecific antibody, QL325, targeting CLEC12A, a c-type lectin protein that is highly expressed on AML blasts. Normally, CLEC12A expression is mostly confined to the CD34+CD38- progenitor population and largely absent on normal and regenerating bone marrow stem cells. Our bispecific antibody is configured in a 2 + 1 format, with bivalent avidity binding to CLEC12A, monovalent low affinity binding to CD3, and an effector-null Fc for extending half-life. In our preclinical studies, QL325 induced CLEC12A -dependent activation and proliferation of T cells. Redirected T cell-dependent cytotoxicity mediated by QL325 was restricted to AML cancer cells expressing CLEC12A. QL325 demonstrated dose dependent suppression of tumor growth in xenograft models of AML, significantly more potent than a clinical benchmark antibody. In non-human primates, QL325 was tolerated up to 0.03 mg/kg for IV dosing and under 0.1 mg/kg for SC dosing, well above the predicted effective therapeutic dose. A phase 1 clinical trial is currently ongoing to determine the safety and early efficacy in patients with refractory or relapsed AML. Citation Format: Shenda Gu, Hieu V. Tran, Shihao Chen, Ke Liu, Xin Zhang, Linchao Jia, Ruixue Ma, Jiayu Fu. Preclinical development of QL325, a novel T cell engager targeting CLEC12A-positive AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6728.