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Articles by Patrick A. Ott
Personalized neoantigen-targeting cancer vaccines in ovarian cancer: a phase 1 trial
Abstract Personalized neoantigen-targeting cancer vaccines in the adjuvant setting are of increasing interest across malignancies. Here we report the results of a phase 1 clinical trial testing the feasibility and safety of personalized neoantigen-targeting cancer vaccines for high-grade epithelial ovarian cancer.
The Moderna cancer vaccine offers hope — now we must speed up personalized therapies
Skin cancer cells viewed under a microscope. Such images can reveal how the cancer spreads.Credit: NCI Center for Cancer Research/NCI/SPL The announcement on 19 August that people with melanoma who received a personalized vaccine lived longer without a cancer recurrence than those who didn’t have the vaccine is a sensation for the field.
Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells
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Abstract Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue.
By Adi Nagler, Amit Sud, Jack Ghannam, Lucas Pomerance, Camila Robles-Oteiza, Alexander B. Afeyan, Jackson A. Weir, Andrew Russell, Wesley Lu, McKayla Van Orden, Giovanni J. Marrero, Qiyu Gong, vipin kumar, Kun Huang, Chloe R. Tu, Emma Lin, Bohoon Shim, Gabriel De Oliveira, MacLean Sellars, Charles H. Yoon, David A Reardon, Toni K. Choueiri, Lars R. Olsen, Sabina Signoretti, Patrick A. Ott, David Braun, Giacomo Oliveira, Shuqiang Li, Kenneth J. Livak, Nir Hacohen, fei chen, Catherine J. Wu, Andrea Sonnenholzner
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Nature
Verified
Tertiary lymphoid structures harbour stem-like tumour-specific T cells
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Abstract Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS− tumours.
By Alexander B. Afeyan, Adi Nagler, Chloe R. Tu, Gabriel De Oliveira, Berkay Simsek, Maxwell D. Seager, Haley E. Sax, Emma Lin, Amit Sud, Mehdi Borji, Cleo Forman, Sophia Liu, Patrick A. Ott, Toni K. Choueiri, Jennifer G. Abelin, Richard Burack, Shuqiang Li, Kenneth J. Livak, Svitlana Tyekucheva, Derin B. Keskin, fei chen, Jeremy Simon, Sabina Signoretti, Giacomo Oliveira, David Braun, Catherine J. Wu, Nourhan El Ahmar
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Nature
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Bridging clinical gaps in personalized cancer neoantigen vaccines
Keywords personalized cancer vaccine neoantigen neoepitope Introduction The concept of vaccination against cancer has long captivated the immunology and oncology communities.
Clinical validation of a high-performance somatic exome sequencing assay: from target-enrichment strategy to variant calling
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Abstract Clinical whole-exome sequencing (WES) has revolutionized clinical diagnostics by enabling scalable, cost-effective molecular profiling to detect somatic variants and identify novel therapeutic targets. In particular, the clinical evaluation of somatic variants relies on both high-quality sequencing data and robust variant detection with rapid turnaround times.
By Junko Tsuji, Micah Rickles-Young, Justin Abreu, Alyssa Friedman, Caroline Petersen, J. Bryan, Konrad Scheffler, Edyta Malolepsza, Mark Fleharty, Katie Larkin, Kenneth J. Livak, Shuqiang Li, David A Reardon, Catherine J. Wu, Patrick A. Ott, Heidi Rehm, Max Jan, Chip Stewart, Gad Getz, Varun Jain, Severine Catreux, Carrie L. Cibulskis, Niall J Lennon, Taylor O’Connell, Theo Heyns, Fanny Dao
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Nature
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Thymic health and immunotherapy outcomes in patients with cancer
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Abstract Although immunotherapy has revolutionized cancer treatment, many patients still experience limited benefit, highlighting the urgent need for improved biomarkers1. Although immunotherapy is founded on unleashing T cells2, most existing biomarkers remain tumour-centric and mainly overlook host immune competence. The thymus is a key immune organ that is crucial for T cell maturation, and we hypothesized that thymic functionality is associated with immunotherapy outcomes3.
By Simon Bernatz, Vasco Prudente, Suraj Pai, Asbjørn K. Attermann, Alessandro Di Federico, Andrew Rowan Verified, Selvaraju Veeriah, Lars Dyrskjøt, Leonard Nürnberg, Joao V Alessi, Patrick A. Ott, Elad Sharon, Allan Hackshaw, Nicholas McGranahan, Christopher Abbosh, Raymond Mak, Danielle S Bitterman, Mark Awad, Biagio Ricciuti, Charles Swanton, Mariam Jamal-Hanjani, Nicolai J. Birkbak, Hugo J. W. L. Aerts
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Nature
Verified
The promises and challenges of neoantigen cancer vaccines
Abstract Transformational advances in genomic sequencing capabilities, vastly improved HLA class I epitope prediction algorithms and powerful delivery platforms have facilitated the clinical development of vaccines targeting neoantigens encoded by tumor mutations. Early clinical trials indicate that vaccination against neoantigens can induce robust and durable T cell immunity that may persist for decades.
Sensitive detection of cancer antigens enabled by user-defined peptide libraries - Nature Biotechnology
Abstract Human leukocyte antigen (HLA)-bound tumor peptides can be routinely isolated from cancer samples and identified using mass spectrometry (MS). However, MS approaches can be stochastic or rely on spectral libraries, which are not customarily available for individual-specific peptides, thus limiting the ability to discover novel peptides.
A neoantigen vaccine generates antitumour immunity in renal cell carcinoma - Nature
Abstract Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1,2,3,4,5,6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient’s tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden.
Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors
Discussion We report here data from two phase 1/2 trials that aimed to evaluate the safety, tolerability, PK, PD, immunogenicity, and preliminary efficacy of novel combinations of urelumab with cetuximab (CA186-018) or nivolumab (CA186-107). The combination of urelumab-0.1 or urelumab-8 with cetuximab-240 was well tolerated and did not appear to have additive toxicity profiles beyond the expected safety profile of cetuximab.
Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers
The following protocol information is provided solely to describe how the authors conducted the research underlying this article. The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors, JCO requests only specific elements of the most recent version of the protocol.
Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy - Nature Communications
Abstract Kidney transplant recipients are at particular risk for developing tumors, many of which are now routinely treated with immune checkpoint inhibitors (ICIs); however, ICI therapy can precipitate transplant rejection. Here, we use TCR sequencing to identify and track alloreactive T cells in a patient with melanoma who experienced kidney transplant rejection following PD-1 inhibition.
Landscape of helper and regulatory antitumour CD4+ T cells in melanoma - Nature
Abstract Within the tumour microenvironment, CD4+ T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules1,2, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood.
Capitalizing on the messenger: Intra-tumoral delivery of RNA with a systemic effect
As reported recently in Science Translational Medicine, intra-tumoral administration of mRNAs that encode four cytokines formulated in saline mediates regression of injected and distant murine tumors. The anti-tumor effect, which is also seen in the anti-PD-1-resistant setting and enhanced by checkpoint blockade, is mediated by tumor-specific T cells and natural killer cells.
A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer
Highlights • The personalized neoantigen vaccine Neo-PV-01 plus nivolumab is feasible and safe • NEO-PV-01 plus nivolumab stimulates durable neoantigen-specific T cell reactivity • NEO-PV-01-specific T cells have cytotoxic potential and can traffic to the tumor • NEO-PV-01 induces epitope spreading consistent with vaccine-mediated tumor cytotoxicity Summary Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity.
A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer
Highlights • The personalized neoantigen vaccine Neo-PV-01 plus nivolumab is feasible and safe • NEO-PV-01 plus nivolumab stimulates durable neoantigen-specific T cell reactivity • NEO-PV-01-specific T cells have cytotoxic potential and can traffic to the tumor • NEO-PV-01 induces epitope spreading consistent with vaccine-mediated tumor cytotoxicity Summary Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity.
Directing Traffic: How to Effectively Drive T Cells into Tumors
Mini Review Annabelle J. Anandappa, Catherine J. Wu and Patrick A. Ott DOI: 10.1158/2159-8290.CD-19-0790 Published February 2020 This article requires a subscription to view the full text. You may purchase access to this article or login to access your subscription using the links below. Abstract Although immune checkpoint inhibitors (ICI) have demonstrated clinical activity in multiple tumor types, the majority of patients do not respond to ICI monotherapy.
Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort
Introduction Patients with recurrent small cell lung cancer (SCLC) have limited treatment options and poor survival.1x1Byers, L.A. and Rudin, C.M. Small cell lung cancer: where do we go from here?. Cancer. 2015; 121: 664–672 Crossref | PubMed | Scopus (176) | Google ScholarSee all References Nivolumab, an anti–programmed death-1 antibody, and ipilimumab, an anti–cytotoxic T-lymphocyte associated protein 4 antibody, are immune checkpoint inhibitors with complementary mechanisms of action.
FDA approves Keytruda for metastatic small cell lung cancer
The FDA approved pembrolizumab monotherapy for patients with metastatic small cell lung cancer that progressed on or after platinum-based chemotherapy and at least one other prior line of therapy. This marks the first approval of pembrolizumab (Keytruda, Merck), an anti-PD-1 therapy, for small cell lung cancer.
Cancer Vaccines: Steering T Cells Down the Right Path to Eradicate Tumors
In Focus Patrick A. Ott and Catherine J. Wu DOI: 10.1158/2159-8290.CD-18-1357 Published April 2019 Abstract Summary: Lack of tumor T-cell infiltration is a barrier to the efficacy of immune checkpoint inhibitors and other immunotherapies in patients with cancer. Because of their ability to activate and augment tumor-specific T cells, vaccines are an attractive approach to direct T-cell responses into the tumor.
Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028
To view the full text, please login as a subscribed user or purchase a subscription. Click here to view the full text on ScienceDirect. Fig. 1 Treatment exposure and duration of response in responders (N = 26). The length of the bars corresponds with time to the last tumor assessment. Only PR, CR, disease progression, and ongoing response are displayed for each subject. *Response presumed to be ongoing; patient had ≥2 consecutive missed assessments.
Immunotherapy: Immune-modified response criteria — an iterative learning process?
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Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors
Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points.
Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial
Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries.
The B7-H1/PD-1 pathway in cancers associated with infections and inflammation: opportunities for therapeutic intervention
Abstract Almost one fifth of malignancies worldwide and about one quarter in China are associated with viral or bacterial infections, mediating an inflammatory environment in the tumor. Hepatitis viruses (B and C), Epstein Barr Virus (EBV), and helicobacter pylori have been linked to liver, gastric, and nasopharyngeal cancer.
The B7-H1/PD-1 pathway in cancers associated with infections and inflammation: opportunities for therapeutic intervention
Review Article Epidemiology of cancers associated with inflammation Approximately 16% of all malignancies world-wide are linked to viral and bacterial infections, which cause chronic inflammation (1,2).
Management of Ipilimumab-Related Toxicities
Melanoma Ipilimumab, a monoclonal antibody that blocks the negative costimulatory molecule CTLA-4 on T cells, leading to augmented T-cell activation and proliferation, improves overall survival (OS) in patients with metastatic melanoma and was approved by the regulatory agencies in the United States and several other countries for the treatment of unresectable melanoma.
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