A Phase I Study of Guanylyl Cyclase C (GCC)-Encoding Replication-Deficient Human Type 5 Recombinant Adenovirus Vaccine (Ad5-hGCC-PADRE) in Stage I and II Colon Cancer Patients

The purpose of this study is to determine the safety, tolerability and ability to stimulate hGCC-specific antibody and killer T cell immune responses of an Ad5-hGCC-PADRE vaccine in stage I and stage II Caucasian and African American colon cancer patients.

Start Date01 Oct 2013

Sponsor / Collaborator

Sidney Kimmel Cancer Center at Thomas Jefferson University

100 Clinical Results associated with Ad5-hGCC-PADRE vaccine(Sidney Kimmel Cancer Center at Thomas Jefferson University)

100 Translational Medicine associated with Ad5-hGCC-PADRE vaccine(Sidney Kimmel Cancer Center at Thomas Jefferson University)

100 Patents (Medical) associated with Ad5-hGCC-PADRE vaccine(Sidney Kimmel Cancer Center at Thomas Jefferson University)

Literatures (Medical) associated with Ad5-hGCC-PADRE vaccine(Sidney Kimmel Cancer Center at Thomas Jefferson University)

01 Dec 2019·Journal for ImmunoTherapy of CancerQ2 · MEDICINE

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients

Q2 · MEDICINE

ArticleOA

Author: Snook, Adam E ; Waldman, Scott A ; Baybutt, Trevor R ; Abraham, Tara S ; Zhan, Tingting ; Flickinger, John C ; Kraft, Walter K ; Hyslop, Terry ; Xiang, Bo ; Sato, Takami

BACKGROUNDThe colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8⁺, but not CD4⁺, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy.METHODSTen patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 10¹¹ viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes.RESULTSAll patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8⁺ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4⁺ T cells are eliminated by self-tolerance, while CD8⁺ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies.CONCLUSIONSSplit tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8⁺, but not autoimmune CD4⁺, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector.TRIAL REGISTRATIONThis trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737.

01 Jan 2017·Cell ReportsQ1 · BIOLOGY

Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1

Q1 · BIOLOGY

ArticleOA

Author: Katja Närhi ; Teijo Pellinen ; Jenni Lahtela ; Emmy W. Verschuren ; Kaisa Salmenkivi ; Mikko I. Mäyränpää ; Ashwini S. Nagaraj ; Jennifer R. Devlin ; Annabrita Hemmes ; Olli Kallioniemi ; Sami Blom

Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of Kras^G12D and loss of Lkb1 (Kras;Lkb1). Using progenitor cell-type-restricted adenoviral Cre to target cells expressing surfactant protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre-infected mice exhibit a shorter latency compared with Ad5-SPC-Cre cohorts. We further demonstrate that CC10⁺ cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas. Transcriptome analysis shows ASC histotype-specific upregulation of pro-inflammatory and immunomodulatory genes. This is accompanied by an ASC-specific immunosuppressive environment, consisting of downregulated MHC genes, recruitment of CD11b⁺ Gr-1⁺ tumor-associated neutrophils (TANs), and decreased T cell numbers. We conclude that progenitor cell-specific etiology influences the Kras;Lkb1-driven tumor histopathology spectrum and histotype-specific immune microenvironment.

01 Dec 2016·Human Gene Therapy MethodsQ4 · MEDICINE

Preclinical Evaluation of a Replication-Deficient Recombinant Adenovirus Serotype 5 Vaccine Expressing Guanylate Cyclase C and the PADRE T-helper Epitope

Q4 · MEDICINE

Article

Author: Snook, Adam E. ; Waldman, Scott A. ; Baybutt, Trevor R. ; Hyslop, Terry

There is an unmet need for improved therapeutics for colorectal cancer, the second leading cause of cancer mortality worldwide. Adjuvant chemotherapy only marginally improves survival in some patients and has no benefit in others, underscoring the clinical opportunity for novel immunotherapeutic approaches to improve survival in colorectal cancer. In that context, guanylate cyclase C (GUCY2C) is an established biomarker and therapeutic target for metastatic colorectal cancer with immunological characteristics that promote durable antitumor efficacy without autoimmunity. Preliminary studies established non-replicating human type 5 adenovirus (Ad5) expressing GUCY2C as safe and effective to induce GUCY2C-specific immune responses and antitumor immunity in mice. This study characterized the biodistribution, immunogenicity, and safety of a vector expressing GUCY2C fused with the human CD4⁺ T helper cell epitope PADRE (Ad5-GUCY2C-PADRE) to advance this vaccine into clinical trials in colorectal cancer patients. Ad5-GUCY2C-PADRE levels were highest in the injection site and distributed in vivo primarily to draining lymph nodes, the liver, spleen and, unexpectedly, to the bone marrow. Immune responses following Ad5-GUCY2C-PADRE administration were characterized by PADRE-specific CD4⁺ T-cell and GUCY2C-specific B-cell and CD8⁺ T-cell responses, producing antitumor immunity targeting GUCY2C-expressing colorectal cancer metastases in the lungs, without acute or chronic autoimmune or other toxicities. Collectively, these data support Ad5-GUCY2C-PADRE as a safe and effective vaccination strategy in preclinical models and position Ad5-GUCY2C-PADRE for Phase I clinical testing in colorectal cancer patients.

100 Deals associated with Ad5-hGCC-PADRE vaccine(Sidney Kimmel Cancer Center at Thomas Jefferson University)

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