Publications by authors named "Michael T Lotze"

219 Publications

Baseline Plasma Inflammatory Profile Is Associated With Response to Neoadjuvant Chemotherapy in Patients With Pancreatic Adenocarcinoma.

J Immunother 2021 Jun;44(5):185-192

Departments of Surgery.

Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CJI.0000000000000370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102434PMC
June 2021

Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy.

Front Immunol 2021 18;12:610042. Epub 2021 Feb 18.

Departments of Surgery, University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center, Pittsburgh, PA, United States.

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8 T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8 T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8 T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rα priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.610042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930493PMC
February 2021

ASO Author Reflection: Viruses, the Lung, and Thoracic Neoplasms: Breaking Bad.

Ann Surg Oncol 2021 May 4;28(5):2728-2729. Epub 2021 Mar 4.

University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09484-5DOI Listing
May 2021

Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies.

Ann Surg Oncol 2021 May 11;28(5):2715-2727. Epub 2021 Feb 11.

Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Thoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09477-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043873PMC
May 2021

Intrapleural interleukin-2-expressing oncolytic virotherapy enhances acute antitumor effects and T-cell receptor diversity in malignant pleural disease.

J Thorac Cardiovasc Surg 2020 Dec 13. Epub 2020 Dec 13.

Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pa; Surgical Services Division, VAPHS, Pittsburgh, Pa. Electronic address:

Objective: The mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell-activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus-expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus-expressing interleukin-2 in malignant pleural disease.

Methods: A murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus-expressing interleukin-2), systemic anti-programmed cell death-1 antibody, or combination therapy (vaccinia virus-expressing interleukin-2 and anti-programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed.

Results: Intrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8 T cells (P < .01) and programmed cell death-1 expression on CD8 tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus-expressing interleukin-2 was superior to systemic vaccinia virus-expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus-expressing interleukin-2 alone or combined treatment with systemic anti-programmed cell death-1 reduced tumor burden (P < .01), improved survival (P < .01), and increased intratumoral αβ T-cell receptor diversity (P < .05) compared with systemic anti-programmed cell death-1 monotherapy.

Conclusions: Intrapleural vaccinia virus-expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8 tumor-infiltrating lymphocytes and αβ T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus-expressing interleukin-2 therapy in patients with malignant pleural disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2020.11.160DOI Listing
December 2020

Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer.

J Immunother 2021 Feb-Mar 01;44(2):49-62

DAMP Laboratory, Department of Surgery.

Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%-6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current "state-of-the-art" immunotherapies and define those areas with greatest therapeutic promise for the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CJI.0000000000000357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092416PMC
June 2020

Corrigendum: Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients.

Front Immunol 2020 21;11:633815. Epub 2020 Dec 21.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

[This corrects the article .].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.633815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780884PMC
December 2020

The Unknown Unknowns: Recovering Gamma-Delta T Cells for Control of Human Immunodeficiency Virus (HIV).

Viruses 2020 12 17;12(12). Epub 2020 Dec 17.

Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v12121455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766279PMC
December 2020

HMGB1 as a potential biomarker and therapeutic target for severe COVID-19.

Heliyon 2020 Dec 7;6(12):e05672. Epub 2020 Dec 7.

Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA.

COVID-19 has attracted global attention due to its rapid spread around the world with substantial morbidity and associated mortality. Severe COVID-19 can be complicated by the acute respiratory distress syndrome, sepsis and septic shock leading to death. These complications are thought to result from an overactivation of the immune system, leading to a cytokine storm syndrome associated with multiple organ failure. Here, we report that high mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP) and a central mediator of lethal inflammation, could be a potential target for innovative therapeutic strategies for COVID-19. Serum HMGB1 in severe COVID-19 patients is elevated (189.40 ± 140.88 ng/ml). Exogenous HMGB1 induces the expression of SARS-CoV-2 entry receptor ACE2 in alveolar epithelial cells in an AGER-dependent manner. Importantly, genetic (using AGER siRNA) or pharmacological (using glycyrrhizin, chloroquine, hydroxychloroquine, and FPS-ZM1) inhibition of the HMGB1-AGER pathway blocks ACE2 expression. Thus, HMGB1 inhibitors are likewise promising drug candidates for the treatment of patients suffering from COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heliyon.2020.e05672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720697PMC
December 2020

Outcomes of Neoadjuvant Chemotherapy Versus Chemoradiation in Localized Pancreatic Cancer: A Case-Control Matched Analysis.

Ann Surg Oncol 2020 Nov 24. Epub 2020 Nov 24.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC.

Patients And Methods: Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case-control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS).

Results: Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (-)0.24, p = 0.007] and lymphovascular invasion [ATE = (-)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32).

Conclusion: Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09391-9DOI Listing
November 2020

Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case-Control Studies.

Cancer Epidemiol Biomarkers Prev 2021 Feb 17;30(2):388-395. Epub 2020 Nov 17.

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

Background: IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma.

Methods: Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma.

Results: The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg.

Conclusions: Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development.

Impact: IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867592PMC
February 2021

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

J Immunother Cancer 2020 11;8(2)

Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670953PMC
November 2020

Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients.

Front Immunol 2020 30;11:582010. Epub 2020 Sep 30.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Severe COVID-19 is associated with profound lymphopenia and an elevated neutrophil to lymphocyte ratio. We applied a novel dimer avoidance multiplexed polymerase chain reaction next-generation sequencing assay to analyze T (TCR) and B cell receptor (BCR) repertoires. Surprisingly, TCR repertoires were markedly diminished during the early onset of severe disease but recovered during the convalescent stage. Monitoring TCR repertoires could serve as an indicative biomarker to predict disease progression and recovery. Panoramic concurrent assessment of BCR repertoires demonstrated isotype switching and a transient but dramatic early IgA expansion. Dominant B cell clonal expansion with decreased diversity occurred following recovery from infection. Profound changes in T cell homeostasis raise critical questions about the early events in COVID-19 infection and demonstrate that immune repertoire analysis is a promising method for evaluating emergent host immunity to SARS-CoV-2 viral infection, with great implications for assessing vaccination and other immunological therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.582010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561365PMC
November 2020

HMGB1 Promotes Myeloid Egress and Limits Lymphatic Clearance of Malignant Pleural Effusions.

Front Immunol 2020 4;11:2027. Epub 2020 Sep 4.

Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States.

Pleural effusions, when benign, are attributed to cardiac events and suffusion of fluid within the pleural space. When malignant, lymphatic obstruction by tumor and failure to absorb constitutively produced fluid is the predominant formulation. The prevailing view has been challenged recently, namely that the lymphatics are only passive vessels, carrying antigenic fluid to secondary lymphoid sites. Rather, lymphatic vessels can be a selective barrier, efficiently coordinating egress of immune cells and factors within tissues, limiting tumor spread and immune pathology. An alternative explanation, offered here, is that damage associated molecular pattern molecules, released in excess, maintain a local milieu associated with recruitment and retention of immune cells associated with failed lymphatic clearance and functional lymphatic obstruction. We found that levels of high mobility group box 1 (HMGB1) were equally elevated in both benign and malignant pleural effusions (MPEs) and that limited diversity of T cell receptor expressing gamma and delta chain were inversely associated with these levels in MPEs. Acellular fluid from MPEs enhanced γδ T cell proliferation , while inhibiting cytokine production from γδ T cells and monocytes as well as restricting monocyte chemotaxis. Novel therapeutic strategies, targeting HMGB1 and its neutralization in such effusions as well as direct delivery of immune cells into the pleural space to reconstitute normal physiology should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.02027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498625PMC
April 2021

Actin-binding protein profilin1 promotes aggressiveness of clear-cell renal cell carcinoma cells.

J Biol Chem 2020 11 3;295(46):15636-15649. Epub 2020 Sep 3.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address:

Clear-cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, has a poor clinical outcome. A hallmark of ccRCC is genetic loss-of-function of (von Hippel-Lindau) that leads to a highly vascularized tumor microenvironment. Although many ccRCC patients initially respond to antiangiogenic therapies, virtually all develop progressive, drug-refractory disease. Given the role of dysregulated expressions of cytoskeletal and cytoskeleton-regulatory proteins in tumor progression, we performed analyses of The Cancer Genome Atlas (TCGA) transcriptome data for different classes of actin-binding proteins to demonstrate that increased mRNA expression of profilin1 (Pfn1), Arp3, cofilin1, Ena/VASP, and CapZ, is an indicator of poor prognosis in ccRCC. Focusing further on Pfn1, we performed immunohistochemistry-based classification of Pfn1 staining in tissue microarrays, which indicated Pfn1 positivity in both tumor and stromal cells; however, the vast majority of ccRCC tumors tend to be Pfn1-positive selectively in stromal cells only. This finding is further supported by evidence for dramatic transcriptional up-regulation of Pfn1 in tumor-associated vascular endothelial cells in the clinical specimens of ccRCC. studies support the importance of Pfn1 in proliferation and migration of RCC cells and in soluble Pfn1's involvement in vascular endothelial cell tumor cell cross-talk. Furthermore, proof-of-concept studies demonstrate that treatment with a novel computationally designed Pfn1-actin interaction inhibitor identified herein reduces proliferation and migration of RCC cells and RCC tumor growth Based on these findings, we propose a potentiating role for Pfn1 in promoting tumor cell aggressiveness in the setting of ccRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.RA120.013963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667959PMC
November 2020

Characteristics of Malignant Pleural Effusion Resident CD8 T Cells from a Heterogeneous Collection of Tumors.

Int J Mol Sci 2020 Aug 27;21(17). Epub 2020 Aug 27.

Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 10 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8 T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8 T cells with autologous CD45 tumor containing cells demonstrated cytotoxicity ( = 0.030) and IFNγ production ( = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8 T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21176178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503595PMC
August 2020

Autophagy inhibition is the next step in the treatment of glioblastoma patients following the Stupp era.

Cancer Gene Ther 2020 Aug 5. Epub 2020 Aug 5.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

It has now been nearly 15 years since the last major advance in the treatment of patients with glioma. "The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity". Autophagy is primarily a survival pathway, literally self-eating, that is utilized in response to stress (such as radiation and chemotherapy), enabling clearance of effete protein aggregates and multimolecular assemblies. Promising results have been observed in patients with glioma for over a decade now when autophagy inhibition with chloroquine derivatives coupled with conventional therapy. The application of autophagy inhibitors, the role of immune cell-induced autophagy, and the potential role of novel cellular and gene therapies, should now be considered for development as part of this well-established regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41417-020-0205-8DOI Listing
August 2020

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy.

Biomedicines 2020 Jul 10;8(7). Epub 2020 Jul 10.

Icell Kealex Therapeutics, Houston, TX 77021, USA.

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8070204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400484PMC
July 2020

Oncolytic virus promotes tumor-reactive infiltrating lymphocytes for adoptive cell therapy.

Cancer Gene Ther 2021 Feb 7;28(1-2):98-111. Epub 2020 Jul 7.

Department of Surgery, University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1Tim-3 CD8 T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41417-020-0189-4DOI Listing
February 2021

Boning up: amino-bisphophonates as immunostimulants and endosomal disruptors of dendritic cell in SARS-CoV-2 infection.

J Transl Med 2020 06 29;18(1):261. Epub 2020 Jun 29.

Department of Surgery, UPMC Hillman Cancer Center, Rm G.27A, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.

Amino-bisphosphonates such as zoledronic acid (ZA) can possibly ameliorate or prevent severe COVID-19 disease by at least three distinct mechanisms: (1) as immunostimulants which could boost γδ T cell expansion, important in the acute response in the lung; (2) as DC modulators, limiting their ability to only partially activate T cells; and (3) as prenylation inhibitors of small GTPases in the endosomal pathway of the DC to prevent expulsion of lysosomes containing SARS-CoV-2 virions. Use of ZA or other amino-bisphosphonates as modulators of COVID-19 disease should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-020-02433-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322393PMC
June 2020

Ratcheting down the virulence of SARS-CoV-2 in the COVID-19 pandemic.

J Med Virol 2020 11 3;92(11):2379-2380. Epub 2020 Jun 3.

Department of Surgery, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.26067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283725PMC
November 2020

DC/L-SIGNs of hope in the COVID-19 pandemic.

J Med Virol 2020 Sep 19;92(9):1396-1398. Epub 2020 Jun 19.

Department of Surgery, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.25980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267543PMC
September 2020

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

J Immunother Cancer 2020 03;8(1)

Program of Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2019-000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064135PMC
March 2020

A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients.

Clin Cancer Res 2020 07 10;26(13):3126-3134. Epub 2020 Mar 10.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Purpose: We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel.

Patients And Methods: Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines.

Results: Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses ( = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival ( < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, = 0.027, as well as increased immune cell tumor infiltration, = 0.033). Overall survival ( = 0.59) and relapse-free survival ( = 0.55) did not differ between the two arms.

Conclusions: The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-4042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086597PMC
July 2020

Prognostic Value of the Systemic Immune-Inflammation Index (SII) After Neoadjuvant Therapy for Patients with Resected Pancreatic Cancer.

Ann Surg Oncol 2020 Mar 2;27(3):898-906. Epub 2019 Dec 2.

Department of Surgery, West Virginia University, Morgantown, WV, USA.

Background: The systemic immune-inflammation index (SII), calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently emerged as a predictor of survival for patients with pancreatic ductal adenocarcinoma (PDAC) when assessed at diagnosis. Neoadjuvant therapy (NAT) is increasingly used in the treatment of PDAC. However, biomarkers of response are lacking. This study aimed to determine the prognostic significance of SII before and after NAT and its association with the pancreatic tumor biomarker carbohydrate-antigen 19-9 (CA 19-9).

Methods: This study retrospectively analyzed all PDAC patients treated with NAT before pancreatic resection at a single institution between 2007 and 2017. Pre- and post-NAT lab values were collected to calculate SII. Absolute pre-NAT, post-NAT, and change in SII after NAT were evaluated for their association with clinical outcomes.

Results: The study analyzed 419 patients and found no significant correlation between pre-NAT SII and clinical outcomes. Elevated post-NAT SII was an independent, negative predictor of overall survival (OS) when assessed as a continuous variable (hazard ratio [HR], 1.0001; 95% confidence interval [CI] 1.00003-1.00014; p = 0.006). Patients with a post-NAT SII greater than 900 had a shorter median OS (31.9 vs 26.1 months; p = 0.050), and a post-NAT SII greater than 900 also was an independent negative predictor of OS (HR, 1.369; 95% CI 1.019-1.838; p = 0.037). An 80% reduction in SII independently predicted a CA 19-9 response after NAT (HR, 4.22; 95% CI 1.209-14.750; p = 0.024).

Conclusion: Post-treatment SII may be a useful prognostic marker in PDAC patients receiving NAT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-08094-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879583PMC
March 2020

Different measures of HMGB1 location in cancer immunology.

Methods Enzymol 2019 29;629:195-217. Epub 2019 Oct 29.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

HMGB1 is the most abundant non-histone nuclear protein. It regulates transcriptional access to open areas of chromatin and limits release of DNA with apoptotic death, serving to both inhibit apoptosis and promote DNA repair. When HMGB1 is translocated to the cytosol with many types of cellular stress, it is a powerful inducer of autophagy. It can also be released by activated immune cells and damaged or dying cells into the extracellular space, where it acts as a damage associated molecular pattern (DAMP) molecule, contributing to the pathogenesis and progression of cancer. Here, the most common methodologies to not only measure HMGB1 but also to effectively determine its subcellular localization, which dictates many of HMGB1's different functions, are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.mie.2019.10.011DOI Listing
June 2020

A peaceful death orchestrates immune balance in a chaotic environment.

Proc Natl Acad Sci U S A 2019 11 25;116(46):22901-22903. Epub 2019 Oct 25.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1916211116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859350PMC
November 2019

The Adaptome as Biomarker for Assessing Cancer Immunity and Immunotherapy.

Methods Mol Biol 2020 ;2055:369-397

University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

In terms of diagnosing and treating diseases, our adaptive immune system is the "best doctor." It carries out these tasks with unmatched precision, with the help of both T and B cell receptors, our most diverse set of genes, distinguishing one individual from another. It does this by generating autologous extraordinary diversity in the receptors, ranging from 10 to 10 for each chain of the rearranged receptors. By combining multiplex PCR and next-generation sequencing (NGS), we have developed high throughput methods to study adaptive immunity. The adaptome is the sum-total of expressed T and B cell receptor genes in a sample, composed of seven chains, including the alpha/beta and gamma/delta chains for T cells, and heavy/lambda or kappa chains for B cells. Immune repertoire is the sum-total of the individual clonotypes within one chain, including individual complementarity-determining regions (CDR) 3 sequences. In order to reflect the breadth and depth of the true adaptome, the following criteria assessing any method needs to be ascertained: (1) Methods need to be inclusive and quantitative; (2) Analysis should consider what questions need to be addressed and whether bulk or single cell sequencing provide the best tools for assessing the underlying biology and addressing important questions; (3) Measures of clonal diversity are key to understand the underlying structure and providence of the repertoire; and (4) Convergent evolution may allow a surprising degree of homologous or identical CDR3s associated with individual disease entities, creating hope for novel diagnostics and/or disease burden assessments. Integrating studies of the peripheral blood, lymph nodes, and tumor allows dynamic interrogation of the alterations occurring with age, treatment, and response to emergent and established therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-9773-2_17DOI Listing
November 2020

DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth.

Oncoimmunology 2019;8(9):e1605822. Epub 2019 Jun 11.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Neutrophil extracellular trap (NET) formation results in the expulsion of granulocyte proteins and DNA into the extracellular space. This process is mediated by the enzyme peptidyl arginine deiminase 4 (PADI4) and translocation of elastase to the nucleus. NET formation, marked by increased levels of extracellular DNA, promotes pancreatic cancer proliferation and metastasis. Mice deficient in Padi4 demonstrate decreased pancreatic tumor growth, associated with a reduction in circulating extracellular DNA levels, diminished pancreatic stromal activation and improved survival in murine orthotopic pancreatic adenocarcinoma. Transplantation of Padi4 bone marrow into genetically engineered mice with Kras driven pancreatic adenocarcinoma (Pdx1-Cre:Kras, KC mice) limits the frequency of invasive cancers when compared with syngeneic controls. DNA from neutrophils activates pancreatic stellate cells that form dense, fibrous stroma which can promote and enable tumor proliferation. DNase treatment diminishes murine tumor growth and stromal activation to reverse the effect of NETs within the tumor microenvironment. Furthermore, deletion of the receptor for advanced glycation end products (RAGE) in pancreatic stellate cells abrogates the effects of DNA in promoting stellate cell proliferation and decreases tumor growth. Circulating neutrophil-derived DNA correlates with the stage in patients with pancreatic ductal adenocarcinoma, confirming the role of NETs in human pancreatic cancer. These findings support further investigation into targeting of NETs, PADI4 and extracellular DNA as a potential treatment strategy in patients with pancreatic cancer. : This study reports correlative data from a clinical trial registered with clinicaltrials.gov, NCT01978184 (November 7, 2013).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2019.1605822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685506PMC
February 2021