Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy.

Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers.

Leveraging oncology collaborative networks and biomedical informatics data resources to rapidly recruit and enroll rural residents into oncology quality of life clinical trials.

Purpose: This study assesses the feasibility of biomedical informatics resources for efficient recruitment of rural residents with cancer to a clinical trial of a quality-of-life (QOL) mobile app. These resources have the potential to reduce costly, time-consuming, in-person recruitment methods.

Methods: A cohort was identified from the electronic health record data repository and cross-referenced with patients who consented to additional research contact.

Multicellular immune ecotypes within solid tumors predict real-world therapeutic benefits with immune checkpoint inhibitors.

Background: Cancer initiation, progression, and immune evasion depend on the tumor microenvironment (TME). Thus, understanding the TME immune architecture is essential for understanding tumor metastasis and therapy response. This study aimed to create an immune cell states (CSs) atlas using bulk RNA-seq data enriched by eco-type analyses to resolve the complex immune architectures in the TME.

T-cell help in the tumor microenvironment enhances rituximab-mediated NK-cell ADCC.

Rituximab (RTX) and other monoclonal antibodies (mAbs) that bind directly to malignant cells are of great clinical value but are not effective for all patients. A major mechanism of action of RTX is antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells. Prior in vitro studies in our laboratory demonstrated that T cells contribute to maintaining the viability and cytotoxic potential of NK cells activated by anti-CD20-coated target B cells.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States.

The T Cell Immunoscore as a Reference for Biomarker Development Utilizing Real-World Data from Patients with Advanced Malignancies Treated with Immune Checkpoint Inhibitors.

Background: We aimed to determine the prognostic value of an immunoscore reflecting CD3+ and CD8+ T cell density estimated from real-world transcriptomic data of a patient cohort with advanced malignancies treated with immune checkpoint inhibitors (ICIs) in an effort to validate a reference for future machine learning-based biomarker development.

Methods: Transcriptomic data was collected under the Total Cancer Care Protocol (NCT03977402) Avatar project. The real-world immunoscore for each patient was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells utilizing CIBERSORTx and the LM22 gene signature matrix.

Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers.

Disparate groups share cancer disparities.

Due to historical and structural factors, underserved rural and racial/ethnic minorities suffer a disproportionate cancer burden based in part on common disparities they share. The time is ripe for cancer researchers to engage with these underserved populations to build trust in science and improve care for those they serve.

Bispecific antibody-activated T cells enhance NK cell-mediated antibody-dependent cellular cytotoxicity.

Resistance to anti-cancer monoclonal antibody (mAb) therapy remains a clinical challenge. Previous work in our laboratory has shown that T cell help in the form of interleukin-2 maintains long-term NK cell viability and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Lack of such T cell help may be a potential mechanism for resistance to mAb therapy.

Monocytes Exposed to Immune Complexes Reduce pDC Type 1 Interferon Response to Vidutolimod.

Vidutolimod, also known as CMP-001, is a virus-like particle composed of the Qβ bacteriophage coat protein encasing a TLR9 agonist. Vidutolimod injected intratumorally is showing promise in early phase clinical trials based on its ability to alter the tumor microenvironment and induce an anti-tumor immune response. We previously demonstrated that the in vivo efficacy of vidutolimod is dependent on the presence of anti-Qβ antibodies that enhance opsonization and uptake of vidutolimod by TLR9-expressing plasmacytoid dendritic cells (pDCs).

Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma.

Unlabelled: Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy.

Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer.

Background: Though the gut microbiome has been associated with efficacy of immunotherapy (ICI) in certain cancers, similar findings have not been identified for microbiomes from other body sites and their correlation to treatment response and immune related adverse events (irAEs) in lung cancer (LC) patients receiving ICIs.

Methods: We designed a prospective cohort study conducted from 2018 to 2020 at a single-center academic institution to assess for correlations between the microbiome in various body sites with treatment response and development of irAEs in LC patients treated with ICIs. Patients must have had measurable disease, ECOG 0-2, and good organ function to be included.

T cells, particularly activated CD4 cells, maintain anti-CD20-mediated NK cell viability and antibody dependent cellular cytotoxicity.

Anti-CD20 monoclonal antibody (mAb) therapy is a mainstay of therapy for B cell malignancies, however many patients fail to respond or eventually develop resistance. The current understanding of mechanisms responsible for this resistance is limited. When peripheral blood mononuclear cells of healthy donors were cultured with Raji cells for 7 days, rituximab (RTX) induced NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), enhanced NK cell viability and increased or maintained NK expression of CD56, CD16, CD57 and KIR.

Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist.

Background: CMP-001, also known as vidutolimod, is a virus-like particle containing a TLR9 agonist that is showing promise in early clinical trials. Our group previously demonstrated that the immunostimulatory effects of CMP-001 are dependent on an anti-Qβ antibody response which results in opsonization of CMP-001 and uptake by plasmacytoid dendritic cells (pDCs) that then produce interferon (IFN)-α. IFN-α then leads to an antitumor T-cell response that is responsible for the in vivo efficacy of CMP-001.

Status of Cancer Care at Network Sites of the Nation's Academic Cancer Centers.

Background: Cancer care coordination across major academic medical centers and their networks is evolving rapidly, but the spectrum of organizational efforts has not been described. We conducted a mixed-methods survey of leading cancer centers and their networks to document care coordination and identify opportunities to improve geographically dispersed care.

Methods: A mixed-methods survey was sent to 91 cancer centers in the United States and Canada.

Immune checkpoint markers and anti-CD20-mediated NK cell activation.

Anti-CD20 mAb is an effective therapy for most B-cell malignancies. Checkpoint blockade has been used to enhance T-cell-mediated antitumor response. Little is known about the biologic significance of immune checkpoints expressed by NK cells in anti-CD20-based therapy.

Combining Doxorubicin-Loaded PEGylated Poly(Lactide-co-glycolide) Nanoparticles with Checkpoint Inhibition Safely Enhances Therapeutic Efficacy in a Melanoma Model.

Doxorubicin (DOX) has been widely used for the treatment of various cancers, however, the use of soluble DOX is limited by its low therapeutic index and improved formulations are therefore sought. Aside from its tumoricidal properties, DOX has also been shown to cause an immunogenic form of cell death, however, it is becoming abundantly clear that in situ immune stimulation alone is insufficient to cause significant immune based antitumor activity and that immune checkpoint modulation is also required. In this study, DOX-loaded nanoparticles were made by nanoprecipitation of DOX with a PEGylated poly(lactide--glycolide) copolymer (DOX-PLGA-PEG NPs) and were then tested in combination with immune checkpoint blockade (antiprogrammed death (anti-PD-1)) in a murine melanoma model to enhance antitumor effectiveness.

The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent.

The Toll-like receptor 8 (TLR8) agonist VTX-2337 (motolimod) is an anti-cancer immunotherapeutic agent that is believed to augment natural killer (NK) and dendritic cell (DC) activity. The goal of this work is to examine the role of TLR8 expression/activity in head and neck squamous cell carcinoma (HNSCC) to facilitate the prediction of responders to VTX-2337-based therapy. The prognostic role of TLR8 expression in HNSCC patients was assessed by TCGA and tissue microarray analyses.

Quantification of Receptor Occupancy by Ligand-An Understudied Class of Potential Biomarkers.

Molecular complexes, such as ligand-receptor complexes, are vital for both health and disease and can be shed into the circulation in soluble form. Relatively little is known about the biology of soluble ligand-receptor complexes. The functional importance of such complexes and their potential use as clinical biomarkers in diagnosis and therapy remains underappreciated.

immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy.

Background: CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model.

A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors.

T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment.

Intraperitoneal CMP-001: A Novel Immunotherapy for Treating Peritoneal Carcinomatosis of Gastrointestinal and Pancreaticobiliary Cancer.

Background: The treatment options for patients with peritoneal carcinomatosis (PC) of gastrointestinal and pancreaticobiliary origins are limited. The virus-like particle, CMP-001, composed of the Qβ bacteriophage capsid protein encapsulating a CpG-A oligodeoxynucleotide, activates plasmacytoid dendritic cells (pDCs) and triggers interferon alpha (IFNα) release, leading to a cascade of anti-tumor immune effects.

Methods: To evaluate the ability of CMP-001 to trigger an immune response in patients with PC, peritoneal cells were isolated and stimulated ex vivo with CMP-001.