Robert A. Anders

Human clinical trials provided tremendous insights to advance novel systemic therapies and to improve treatment outcomes for cancer patients. The few durable treatment options have led to a critical need to advance new therapeutics in hepatocellular carcinoma (HCC). Recent human clinical trials have demonstrated that new combination of immunotherapeutic regimens provide augmented clinical response in a subset of patients. Computational methods that can simulate tumors from mathematical equations describing cellular and molecular interactions are emerging as promising tools to simulate the impact of therapies entirely in silico. To facilitate designing dosing regimens and selecting potential predictive biomarkers, we developed a new computational model to track tumor progression at organ scale while reflecting the spatial heterogeneity in the tumor at cellular and molecular scale in HCC. This …

Radiotherapy is hypothesized to have an immune-modulating effect on the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) to sensitize it to anti–PD-1 antibody (a–PD-1) treatment. We collected paired pre- and posttreatment specimens from a clinical trial evaluating combination treatment with GVAX vaccine, a–PD-1, and stereotactic body radiation (SBRT) following chemotherapy for locally advanced PDACs (LAPC). With resected PDACs following different neoadjuvant therapies as comparisons, effector cells in PDACs were found to skew toward a more exhausted status in LAPCs following chemotherapy. The combination of GVAX/a–PD-1/SBRT drives TME to favor antitumor immune response including increased densities of GZMB+CD8+ T cells, TH1, and TH17, which are associated with longer survival, however increases immunosuppressive M2-like tumor-associated macrophages …

Background: Tertiary lymphoid structures (TLS) are ectopic lymphoid follicles that arise in non-lymphoid tissue. TLS may contribute to response to immune checkpoint blockade (ICB) in solid tumors, but understanding of the life cycle of these structures, particularly the circumstances of their resolution and the functional contribution of this stage to the adaptive immune response, remains incomplete. Methods: We employed a multi-omics approach to evaluate TLS in the tumors of patients with hepatocellular carcinoma (HCC) treated with neoadjuvant ICB (n = 19) and untreated controls (n = 14). TLS density was assessed by immunohistochemistry and correlated with pathologic response, relapse free survival, and overall survival. Imaging mass cytometry was used to characterize distinct TLS morphologies in areas of tumor regression bed and viable tumor. Individual TLS from treated tumors were microdissected and …

506Background: Neoadjuvant use of immune checkpoint inhibitors (ICI) is feasible and achieves pathological responses in a subset of patients with hepatocellular carcinoma (HCC). However, it is not clear whether pathological response to ICI translates into long-term survival benefit. Methods: We analysed patient-level data from 86 subjects recruited to 4 prospective phase I/II clinical trials of ICI prior to liver resection (LR) in 9 centres in the United States, Europe, and Asia and included a cohort of 23 patients (pts) receiving neoadjuvant ICI off trial. Radiological response was assessed with RECISTv1.1. Major (MPR) and complete pathological response (pCR) were considered as ≥70% and 100% non-viable tumour in the resected specimen, respectively. Pathological responses were correlated with radiologic overall response rates (ORR) and relapse-free survival (RFS). Results: Out of 109 pts treated between 10 …

A common precursor of pancreatic adenocarcinoma (PDAC) are microscopic lesions, termed pancreatic intraepithelial neoplasia (or PanIN). These lesions are initiated at least a decade before overt PDAC forms, thus providing a large window of opportunity to modulate the immune microenvironment before significant pro-carcinogenic signals prevail. To best inform strategies for interception of these precursor lesions, it is critical to understand the quantity and spatial localization of the lymphoid compartment recruited to PanINs compared to PDAC. Here, we report the use of spatial–omics (proteomic and transcriptomics) to evaluate the recruitment of lymphoid cells to PanIN lesions compared to immune–enriched regions of PDAC in a unique cohort of 5 treatment–naïve PDAC patients who underwent resection of their primary pancreas tumor. Using imaging mass cytometry, we found lymphoid populations recruited …

Cancer immunotherapy has ushered in a new era for treatment of many difficult to treat cancers such as Leiomyosarcoma (LMS), one of the most common subtypes of sarcomas. There are few biomarkers which can be used to identify patients who might benefit from immunotherapy. There is an urgent need to discover novel biomarkers which might be prognostic of a strong anti-tumor response. We thus sought to comprehensively profile the microenvironment of LMS tumors to identify features which might be suggestive of an active immune response and molecular features prognostic of response to immunotherapy. We began our analysis by classifying the LMS tumors from The Cancer Genome Atlas (TCGA) into 4 subtypes based on previously identified molecular features and comparing the enrichment of various immune gene signatures. Two of the subtypes had a high expression of various immune gene …

Metabolic reprogramming is a necessary component of oncogenesis and cancer progression that solid tumors undergo when their growth outstrips local nutrient supply. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including brain, breast, colon, liver, and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Highlighting the clinical importance of this pathway, the SREBP pathway is broadly required for cancer cell growth, SREBP target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets …

BackgroundTumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.MethodsMultiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell …

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in …

Background: In pancreatic ductal adenocarcinoma (PDAC), rare long-term survivors correlate with high intratumoral tertiary lymphoid structure (TLS) density. This finding prompted our investigation of clinically viable strategies to induce TLS in patients with immune-excluded tumors. We previously reported the induction of intratumoral TLS following administration of a neoadjuvant GM-CSF-secreting allogeneic vaccine (GVAX) to PDAC patients (NCT00727441). However, no clinical benefit was observed, likely owing to immune tolerance mechanisms governing the PDAC tumor microenvironment (TME). We previously observed upregulation of both the PD-1 and 4-1BB pathways with GVAX, and thus in a subsequent neoadjuvant trial combined GVAX with PD-1 blockade and 4-1BB agonism (NCT02451982) which was associated with pathologic responses. We hypothesized this combination strategy induced TLS of …

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 (NCT02453620). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however …

Simple Summary This study aims to compare the performance of the standardized consensus Immunoscore (IS) digital pathology assay to an evaluation of the immune response via visual examination of hematoxylin–eosin (H&E) slides and CD3+/CD8+ stained slides, achieved by expert pathologists. Herein, we report the evaluation of 540 stained images by multi-institutional pathologists to determine the concordance between pathologist assessment before and after training. The results show that the IS assay outperformed expert pathologists’ T-score evaluation in the clinical setting. This reveals the potential of the IS as an immune pathology tool, critical for reproducible quantitative analysis of tumor-infiltrated immune cells. These findings can contribute to a better diagnosis, allowing one to stratify cancer patients into reliable prognostic groups, based on the immune parameters quantified by IS. This work will likely impact the management of colon cancer patients as it raises the importance of the implementation of digital pathology in cancer diagnosis to provide appropriate personalized therapeutic decisions. Abstract Background: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists’ visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. Methods: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists’ T-score, corresponding hematoxylin–eosin (H&E …

Background Pathologic response assessment after neoadjuvant treatment is the potential analog to radiographic response for advanced disease, with regard to study design, clinical care, and accelerated regulatory approvals. A standardized system for assessing degree of pathologic response in the primary tumor (PT) and lymph nodes (LNs) as a survival surrogate is an unmet need. It is also a prerequisite for determining whether patients with versus without LN involvement benefit from neoadjuvant therapy. Here, in a pre-specified exploratory analysis from CheckMate 816, we report the first in-depth assessment of the full spectrum of percent residual viable tumor (RVT; beyond pathologic complete response) in both the PT and LNs and its association with event-free survival (EFS). This study represents the first prospective use of such a pan-tumor scoring system in a phase 3 registrational trial.Methods Pathologic …

BackgroundProstate-specific membrane antigen (PSMA) is highly and specifically upregulated in active-inflamed mucosa of patients with inflammatory bowel disease (IBD). We hypothesized that this upregulation would be detectable using a PSMA-targeted positron emission tomography/computed tomography (PET/CT) imaging agent, [18F]DCFPyL, enabling non-invasive visualization of inflammation. A noninvasive means of detecting active inflammation would have high clinical value in localization and management of IBD.StudyWe performed [18F]DCFPyL imaging in three IBD patients with active disease. Abnormally increased gastrointestinal [18F]DCFPyL uptake was observed in areas with endoscopic, histologic, and immunohistochemical inflammation, demonstrating partial overlap of segments of bowel with abnormal [18F]DCFPyL uptake and active inflammation.ConclusionThis study demonstrates that …

Introduction: Pancreatic ductal adenocarcinomas (PDACs) are immunogenically “cold” tumors that lack effector T cell infiltration associated with immune checkpoint inhibitor (ICI) responsiveness. Neoadjuvant immunotherapy clinical trials facilitate understanding of the complexities of combination treatment strategies on immunosuppressive mechanisms. Our recent multi-omics analysis of a neoadjuvant trial comparing the GVAX vaccine alone or with nivolumab and supporting preclinical data uncovered crosstalk between CD8+CD137+ T cells and neutrophils as an axis for therapeutic intervention. These studies have formed the foundation for the addition of the CD137 agonist, urelumab, to our combination regimen to improve T cell activation in PDACs. Methods: Patients were enrolled on NCT02451982 and initiated treatment 2 weeks prior to surgical resection. We compared specimens from 3 treatment arms for …

BackgroundDespite the efficacy of immune checkpoint inhibitors (ICIs), adverse events including hepatotoxicity limit their ongoing use. We investigated the outcomes and management of patients with immune-mediated hepatitis (IMH) and clinical predictors of toxicity resolution.MethodsPatients referred to our multidisciplinary immunotherapy-related toxicity group from August 2017 to December 2020 for IMH were evaluated. Toxicity was defined according to CTCAEv4.0. IMH resolution was defined as liver enzyme normalization after steroid initiation.ResultsThirty-three patients were included in the study, 62% female, and 71% Caucasian. The most common ICI used was PD-1/PD-L1 (76%). Peak IMH occurred at a median of 89 [45,193] days, for which most patients received 1–2 mg/kg/day prednisone equivalent with 35% requiring MMF. Median follow-up was 123 [33,472] days with IMH resolution seen in 48% of …

2625Background: FLX475 is a potent and selective CCR4 antagonist, designed to block the recruitment of immunosuppressive regulatory T cells (Treg) into tumors without affecting healthy tissues. Blocking migration of Treg into the tumor microenvironment (TME) has the potential to restore antitumor immunity and synergize with a variety of conventional and immunotherapy-based approaches to overcome immune resistance and broaden clinical efficacy. In a recent interim clinical update from the ongoing FLX475-02 Phase 1/2 trial, evidence of monotherapy and combination activity were reported. FLX475 monotherapy induced complete responses in two of the six evaluable subjects enrolled with EBV+ NK/T cell lymphoma. In checkpoint inhibitor naïve non-small-cell lung cancer (NSCLC), 4/13 subjects (31%) had confirmed partial responses (PRs) following treatment with the combination of FLX475 and …

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Neoadjuvant immunotherapy is thought to produce long-term remissions through induction of antitumor immune responses before removal of the primary tumor. Tertiary lymphoid structures (TLS), germinal center-like structures that can arise within tumors, may contribute to the establishment of immunological memory in this setting, but understanding of their role remains limited. Here, we investigated the contribution of TLS to antitumor immunity in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy. We found that neoadjuvant immunotherapy induced the formation of TLS, which were associated with superior pathologic response, improved relapse free survival, and expansion of the intratumoral T and B cell repertoire. While TLS in viable tumor displayed a highly active mature morphology, in areas of tumor regression we identified an involuted TLS morphology, which was characterized by …

ObjectivesTo identify the most suitable size of imaging-visible embolic agents with balanced safety and efficacy for bariatric arterial embolization (BAE) in a preclinical model.Materials and MethodsTwenty-seven pigs were divided into 3 cohorts. In Cohort I, 16 pigs were randomized to receive (n = 4 each) 40–100-μm microspheres in 1 or 2 fundal arteries, 70–340-μm radiopaque microspheres in 2 fundal arteries, or saline. In Cohort II, 3 pigs underwent renal arterial embolization with either custom-made 100–200-μm, 200–250-μm, 200–300-μm, or 300–400-μm radiopaque microspheres or Bead Block 300–500 μm with microsphere distribution assessed histologically. In Cohort III, 8 pigs underwent BAE in 2 fundal arteries with tailored 100–200-μm radiopaque microspheres (n = 5) or saline (n = 3).ResultsIn Cohort I, no significant differences in weight or ghrelin expression were observed between BAE and control …