Abstract Introduction Cervical cancer is the fourth most commonly diagnosed cancer in women worldwide and in some countries is the most lethal cancer in women. Ninety-nine percent of cervical cancers are attributable to HPV infection, which has decreased dramatically with the introduction of HPV vaccines. However, the incidence of cervical cancer remains high in generations of women for whom the vaccine was not available as well as in unvaccinated women, as up to 40% of eligible individuals did not receive an HPV vaccination. There is a critical unmet need for noninvasive treatment options among these groups. Methods A hallmark of HPV-mediated oncogenesis is dysregulated E2F transcription factor activity. Leveraging this, we developed a rationally designed series of synthetic AAV transgene promoters for specific activity in HPV-positive cervical cancer cells, which can then be used to deliver therapeutic payloads to tumor tissue. Our panel of candidate promoter sequences was assessed for activity in HPV+ cervical cancer cell lines as well as normal epithelial cells for expression of a luciferase reporter, as determined by comparative expression in a dual-luciferase system. Results Testing our candidate promoters in a dual luciferase reporter assay we identified a construct with activity in multiple cell lines. This candidate achieved an 18.31-fold and a 4.45-fold increase in reporter expression in HPV16+ CaSki and SiHa cancer lines compared to normal controls, respectively. Further, it produced a 15.18-fold increase in the HPV18+ C4I line compared to normal controls. By modulating the levels of activating E2F family members in normal cells, we have shown a positive relationship between E2F levels and reporter expression. Conclusion Based upon our results in vitro we have developed a candidate AAV transgene construct for specific delivery of a therapeutic payload to cervical cancer cells in vivo. Funding Source T32 Postdoctoral Fellowship Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

PURPOSE Although several agents targeting epidermal growth factor receptor ( EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. METHODS This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non–small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. RESULTS Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. CONCLUSION Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

This cross-sectional study evaluates differences between cervical cancer incidence and mortality in counties with high vs low screening rates.

PURPOSE:To evaluate the safety and efficacy of zipalertinib, an irreversible epidermal growth factor receptor (EGFR) inhibitor, in pretreated patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins) mutations. METHODS:REZILIENT1 (ClinicalTrials.gov identifier: NCT04036682) is a phase I/II open-label trial enrolling patients with locally advanced or metastatic EGFR ex20ins-mutant NSCLC previously treated with platinum-based chemotherapy with/without ex20ins-targeted therapies. Asymptomatic, treated and untreated stable CNS metastases are permitted. We report data from patients treated with zipalertinib 100 mg twice daily. The primary end points are objective response rate (ORR) and duration of response (DOR) by independent central review. RESULTS:At data cutoff (December 10, 2024), 244 patients had received treatment with zipalertinib 100 mg twice daily. The primary efficacy population (8 months' follow-up) comprised patients who had received prior platinum-based chemotherapy without ex20ins-targeted therapy (125 patients), with amivantamab only (30 patients), or with amivantamab and other ex20ins-targeted therapy (21 patients). The confirmed ORR was 35.2% (95% CI, 28.2 to 42.8); median DOR was 8.8 months (95% CI, 8.3 to 12.7). Among patients who received prior platinum-based chemotherapy without ex20ins-targeted therapy, amivantamab only, or amivantamab and other ex20ins-targeted therapy, the confirmed ORR was 40%, 30%, and 14.3%, and median DOR was 8.8, 14.7, and 4.2 months, respectively. Among 68 patients with CNS metastases, the ORR was 30.9%. The most common grade ≥3 treatment-related adverse events were anemia (7%), pneumonitis and rash (2.5% each), and diarrhea, ALT increased, and platelet count decreased (2% each). CONCLUSION:Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in patients with EGFR ex20ins-mutant NSCLC who received prior platinum-based chemotherapy with or without amivantamab.

Leukemia stem cells (LSCs) are a small yet powerful subset of leukemic cells that possess the ability to self-renew and have a long-term tumorigenic capacity, playing a crucial role in both leukemia development and therapy resistance. These LSCs are influenced by external and internal factors within the bone marrow niche. By delving into the intricate interplay between LSCs and their immune environment, we can pave the way for innovative immunotherapies that target both the malignant stem cells and the suppressive immune microenvironment, addressing both the "seed" and the "soil" simultaneously. Through the analysis of public datasets and patient samples, we show that elevated IL1RL1 expression correlates with poor prognosis and therapy resistance in acute myeloid leukemia (AML). At the core of this process, stem cell leukemogenesis initiation and maintenance signals are driven by a stress-induced IL-33/IL1RL1 autocrine loop. This LSC-induced IL-33/IL1RL1 signaling fosters an immune regulatory microenvironment. Therefore, IL1RL1 emerges as a promising therapeutic target, with IL1RL1-specific T cell-engaging bispecific antibodies holding great potential as cutting-edge immunotherapeutics for AML.

2619 Background: IL-15 is a member of the IL-2 common gamma chain family of cytokines. N-803 is IL-15 administered in complex with IL-15 receptor alpha. Lung cancer, despite advances in targeted therapies and immunotherapy, remains the leading cause of cancer related death in the United States. Strategies to improve the performance of immunotherapy in advanced NSCLC is a clinical unmet need. Methods: Lung-MAP S1800D was a randomized study comparing N-803 plus pembrolizumab (NP) to investigators’ choice standard-of-care chemotherapy (SoC) for previously treated advanced NSCLC. Patients were enrolled into an Acquired Resistance Cohort (ARC) if disease progression on prior anti-PD-(L)1 occurred > 84 days from start of treatment and otherwise into a Primary Resistance Cohort (PRC). The ARC was a phase II/III study with a sample size goal of 334 patients. The PRC was a phase II with sample size of 134 patients. The first interim analysis (IA1) in the ARC evaluated futility among the first 25 patients treated with NP which required ≥1 response and ≥50% with disease control at 12 weeks to continue accrual. The primary endpoint in both cohorts was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response, and toxicity. Results: Accrual in the ARC and PRC were closed at the IA1 in the ARC with 74 pts in the ARC and 8 in the PRC. Of the 74 ARC patients, 71 met eligibility (36 SoC, 35 NP), and 32 pts on each arm received treatment. With 44 events, OS was not significantly different between the two arms (HR (95%CI: 0.73(0.40-1.36), p=0.32) with a 12-month OS rate of 25% with SoC and 44% with NP. With 61 events, PFS was not significantly different but numerically worse (HR (95% CI): 1.29 (0.78-2.13, 95% CI), p=0.33). There were 3 unconfirmed partial responses and 1 confirmed complete response with NP and 3 unconfirmed partial responses and 2 confirmed partial responses with SoC. On the NP arm, there were 10 Grade 3 (1 hematologic) and 1 Grade 5 treatment-related adverse events reported as Disease Progression (34% Grade 3+ TRAE). The Grade 3+ TRAE rate on the SoC arm was 53% with 10 Grade 3+ hematologic toxicities. Conclusions: While the study failed to continue accrual past IA1, there is an indication of a subgroup that might benefit from NP with a potential OS difference at 12 months. NP was safe when compared to SoC, and responses were seen in both treatment arms, including partial and complete responses in the NP group. Evaluation of tumor and patient characteristics will be critical to define if there are those who may benefit from N-803 plus pembrolizumab. Clinical trial information: NCT05096663 .

Background Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor to preferentially activate antitumor CD8+ T cells and natural killer cells, with minimal expansion of immunosuppressive regulatory T cells. The first-in-human study, ARTISTRY-1, demonstrated antitumor activity with intravenous (IV) nemvaleukin (6 µg/kg on days 1–5 per 21-day cycle) monotherapy and nemvaleukin + pembrolizumab, with manageable safety in heavily pretreated adults with advanced solid tumors.1 ARTISTRY-2 (NCT03861793) is a phase 1/2 study evaluating the safety, antitumor activity, and pharmacokinetics/pharmacodynamics of subcutaneous (SC) nemvaleukin + pembrolizumab in patients with advanced solid tumors. Methods In ARTISTRY-2, the recommended phase 2 dose (RP2D) of SC nemvaleukin was identified as 3 mg every 7 days (Q7D).2 In phase 2, SC nemvaleukin + pembrolizumab was administered in the following cohorts: non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), gastric and gastroesophageal junction cancer (G/GEJ), and ovarian cancer Cohorts 1 (OC1) and 2 (OC2). OC2 cohort included definition of platinum resistance, number of prior lines of therapy and requirement for prior treatment with bevacizumab, reflecting baseline characteristics associated with higher likelihood of clinical benefit. Investigator-assessed antitumor activity (RECIST v1.1) and safety are reported as of April 21, 2023. Results In phase 2, 59 patients (11 NSCLC, 10 SCCHN, 13 G/GEJ, 17 OC1, 8 OC2) received SC nemvaleukin + pembrolizumab. Antitumor activity was observed, including 2 partial responses (PRs) in OC (ORR 15.4% [OC1, 2/13]) and 1 PR in NSCLC (ORR 10% [NSCLC, 1/10]); responders were checkpoint inhibitor-naive. The most frequent treatment-related adverse events (TRAEs) of any grade (>40%) included pyrexia (50.8%) and injection-site reactions (45.8%), and of grade 3/4 (>5%) were fatigue (6.8%), lymphocyte count decreased (6.8%), and lymphopenia (5.1%). A total of 7 patients (11.9%) discontinued the study due to TRAEs. There was 1 treatment-related grade 5 event of pneumonitis (NSCLC cohort). The safety profile of SC nemvaleukin + pembrolizumab was consistent with that reported for IV dosing, except for injection-site reactions. Conclusions SC nemvaleukin 3 mg Q7D with pembrolizumab was generally well tolerated and demonstrated antitumor activity in patients with refractory solid tumors. Although antitumor activity was observed, the robustness of this activity was less than that observed with the daily ×5 IV dosing; therefore, a less frequent IV dosing schedule of nemvaleukin is being explored in ARTISTRY-3 (NCT04592653). Acknowledgements The authors would like to thank all the patients who are participating in this study and their families. The study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel International and funded by Alkermes, Inc. Trial Registration Clinicaltrials.gov NCT03861793 References Vaishampayan U, Tomczak P, Muzaffar J, et al. Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1. J Clin Oncol. 2022;40(16_suppl). Abstract #2500. Hamid O, Liu SV, Boccia RV, et al. Selection of the recommended phase 2 dose (RP2D) for subcutaneous nemvaleukin alfa: ARTISTRY-2. J Clin Oncol. 2021;39(15_suppl). Abstract #2552. Ethics Approval The study protocol and its amendments, patient informed consent form, and all relevant documents were approved by an institutional review board or local ethics committee. This study is being conducted according to Declaration of Helsinki and all applicable guidelines from the International Council on Harmonisation (ICH) E6 Good Clinical Practice, US Code of Federal Conduct, and state, local and federal laws. All patients are required to provide written informed consent to participate.

mp3 file (49.6MB). Patients with recurrent metastatic non-small cell lung cancer have a morbid prognosis, but a new epigenetic therapy may have potential for this population. Cancer Discovery Editors-in-Chief Jose Baselga, M.D., Ph.D. and Lewis C. Cantley, Ph.D. moderated a press conference about this research on Wednesday, Nov. 9, 2011.

Variable importance plot for random forest prediction

PDF file - 287KB, DNA Methylation of CDO1, HOXA9, and TAC1 is Highly Sensitive for Stage I NSCLC in the Cancer Genome Atlas.

<p>This file contains the following figures: Supplemental Figure 1. The return of host lymphocytes is affected by the type of donor CD8+ T cells. Supplemental Figure 2. Return of myeloid cells after CTX leads to more rapid host cell reconstitution than TBI-containing regimens. Supplemental Figure 3. CTX and TBI differentially affect host T cells and NK cells. Supplemental Figure 4. Donor CD8+ T cells transferred into a TBI-conditioned host maintain functional efficacy. Supplemental Figure 5. ALT-803 (IL-15/IL-15Ra complexes) augment the persistence of Tc1 cells in irradiated hosts.</p>

PDF file - 2177KB, Scatter Plots of Gene Re-expression with Decitabine or Trichostatin-A in Eight Non-Small Cell Lung Cancer Cell Lines.

PDF file - 100KB, DNA Methylation of CDO1, HOXA9, and TAC1 is Highly Sensitive for Stage I NSCLC in the Cancer Genome Atlas.

Supplemental Tables and figures legends

There is a critical need to develop a capable and well-trained workforce dedicated to the systematic study of sex differences and examination of sex as a biological variable. Through the support of the Office of Research on Women's Health and partner National Institute of Health centers, the Specialized Centers of Research Excellence (SCORE) on Sex Differences Career Enhancement Cores (CECs) were established to help address this need. We describe the integration of the Medical University of South Carolina SCORE CEC with other National Institutes of Health (NIH)-funded and institutional training programs to promote training synergies, share resources, and enhance mentorship opportunities. Benefits of developing an intrainstitutional training platform have included facilitating cross-disciplinary interactions, encouragement of peer mentorship, and reduced burden on training program leadership.