Novel Collaborations Across Training Programs to Support Mentoring in Sex Differences Research.

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.

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions.

Purpose: Although several agents targeting epidermal growth factor receptor () exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) 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 ex20ins-mutant versus WT with potent inhibition of cell growth in ex20ins-positive cell lines.

Methods: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Association of age with survival in older patients with cutaneous melanoma treated with immune checkpoint inhibitors.

Introduction: Several types of immune checkpoint inhibitors (ICIs) are approved to treat advanced melanoma, but their effectiveness has not been compared in older patients treated outside of a clinical trial. Moreover, evidence suggests that a patient's response to ICI therapy may vary by age and type of ICI. The purpose of this study was to compare survival by ICI type in older patients with melanoma and to investigate treatment effect modification by age.

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c.

Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear.

DNA-methylation for the detection and distinction of 19 human malignancies.

The contribution of DNA-methylation based gene silencing to carcinogenesis is well established. Increasingly, DNA-methylation is examined using genome-wide techniques, with recent public efforts yielding immense data sets of diverse malignancies representing the vast majority of human cancer related disease burden. Whereas mutation events may group preferentially or in high frequency with a given histology, mutations are poor classifiers of tumour type.

A Phase 1-2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC.

Introduction: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC).

Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.

Immune checkpoint inhibitors retain effectiveness in older patients with cutaneous metastatic melanoma.

Introduction: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape for advanced melanoma, but their use in older patients remains understudied. An age-related decline in immune function is of concern when treating older patients because host immune factors can influence clinical outcomes with immunotherapy. Therefore, we aimed to evaluate the effectiveness of ICIs in patients 65 years and older.

Epigenetic therapy inhibits metastases by disrupting premetastatic niches.

Cancer recurrence after surgery remains an unresolved clinical problem. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment.

SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors.

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined.

Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response. Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery ( = 24) and validation ( = 142) cohorts.

Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8 T Cells.

Effector CD8 T cells conditioned with IL12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL7-consuming host cells and improve the persistence and antitumor activity of IL12-conditioned CD8 T cells. Using cyclophosphamide, fludarabine, and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T-cell engraftment in mice.

ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.

Background: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC.

IL-2 and Beyond in Cancer Immunotherapy.

The development of the T- and natural killer (NK) cell growth factor IL-2 has been a sentinel force ushering in the era of immunotherapy in cancer. With the advent of clinical grade recombinant IL-2 in the mid-1980s, oncologists could for the first time directly manipulate lymphocyte populations with systemic therapy. By itself, recombinant IL-2 can induce clinical responses in up to 15% of patients with metastatic cancer or renal cell carcinoma.

The clinical implications of immunogenomics in colorectal cancer: A path for precision medicine.

Colorectal cancer (CRC) remains the third most common malignancy and the second-leading cause of cancer-related deaths in the United States. Large multi-omic databases, such as The Cancer Genome Atlas and the International Colorectal Cancer Subtyping Consortium, have identified distinct molecular subtypes related to anatomy. The identification of genomic alterations in CRC is now critical because of the recent success and US Food and Drug Administration approval of pembrolizumab and nivolumab for microsatellite-instable tumors.

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

Background: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.

Methods: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles).

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity.

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells.

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

Adoptive cellular therapy (ACT) with the Th17 subset of CD4 T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells.

Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum.

CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer-specific gene panel to detect DNA methylation in sputum and plasma. This is a case-control study of subjects with suspicious nodules on CT imaging.

Harnessing the IL-7/IL-7Rα axis to improve tumor immunotherapy.

IL-7 and IL-15 are critical for supporting T cells transferred into a lymphopenic environment. As activated CD8(+) T cells downregulate IL-7Rα, it is thought IL-15 is more important. However, we find that CD8(+) T cells activated with IL-12 have elevated IL-7Rα and rely on IL-7 for persistence and antitumor immunity.

Imaging in Advanced Non-Small Cell Lung Cancer: A Medical Oncology Perspective.

Treatment advances have improved outcomes in patients with lung cancer, with a number of targeted therapies and immunotherapies now approved for patients with metastatic disease. Along with longer survival, modern treatment paradigms have increased therapeutic decision-making complexity underscoring informative imaging as paramount in guiding clinical care. In this review, we summarize challenges the thoracic oncologist encounters in common clinical settings.

Neutrophil-to-lymphocyte ratio and overall survival in all sites of head and neck squamous cell carcinoma.

Background: Current prognostic criteria are insufficient in predicting outcomes in head and neck cancer, necessitating new, readily available biomarkers.

Methods: Pretreatment neutrophil and lymphocyte counts and their ratio (NLR) were retrospectively investigated for correlation with overall survival while controlling for demographic and clinical confounders.

Results: Patients in the highest tertile of neutrophil counts and those in the lowest tertile of lymphocytes experienced shorter survival than the rest of the population.