Phase I/II Open Label Non-randomised Safety and Efficacy Study of the Viral Vectored ChAd-MVA 5T4 Vaccine in Combination With PD-1 Checkpoint Blockade in Low- or Intermediate-risk Localized or Locally Advanced Prostate Cancer and Advanced Metastatic Prostate Cancer

This is a clinical trial of a new treatment for prostate cancer that is a type of vaccine that could be a new way to treat cancer. A vaccine that could alert the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The vaccine is made up of two recombinant viruses ("ChAdOx1"- chimpanzee adenovirus Ox1 and "MVA" - modified vaccinia Ankara) that have been designed to produce the 5T4 protein and have been modified so that they are weakened and cannot reproduce themselves within the body like normal viruses. Once injected into the body, these viruses make the 5T4 protein and help the body's immune system to learn to target this protein and destroy cancer cells.
This vaccine will be used in combination with the immunotherapy drug called nivolumab which is an anti-PD-1 (Programmed Death protein-1) monoclonal antibody. This is a molecule that releases the brakes on the immune system and helps the immune system to kill cancer cells more efficiently. Nivolumab as a monotherapy was approved for treatment of several tumour types but not for the prostate cancer.
This study will evaluate the safety and efficacy of ChAdOx1-MVA 5T4 vaccine in combination with nivolumab in low and intermediate risk prostate cancer patients who have elected to have their prostate removed and in patients with advanced metastatic prostate cancer.

Start Date10 Dec 2018

Sponsor / Collaborator

University of Oxford

[+1]

EUCTR2017-001992-22-GB / Unknown statusPhase 2IIT

Phase II open label randomised safety and efficacy study of the viral vectored ChAd-MVA 5T4 vaccine in combination with PD-1 checkpoint blockade in low- or intermediate-risk localized or locally advanced prostate cancer and advanced metastatic prostate cancer - VAccination in early and ADvanced prostate caNCEr (ADVANCE)

Start Date12 Jun 2018

Sponsor / Collaborator

University of Oxford

NCT02390063 / CompletedPhase 1IIT

A Randomized Phase I Study to Determine the Safety and Immunogenicity of ChAd-MVA Vaccination Compared to MVA Alone With and Without Low Dose Cyclophosphamide in Low and Intermediate Risk Localised Prostate Cancer

This is a clinical trial of a new treatment for prostate cancer that is a type of vaccine that could be a new way to treat cancer. A vaccine that could alert the immune system to the presence of cancer cells in the body may enable the immune system to target and kill those cells effectively. This vaccine is intended to work by making the immune system kill cells that have a special protein (called 5T4) that is present on the surface of cancer cells. The vaccine is made up of two recombinant viruses ("ChAdOx1" and "MVA") that have been designed to produce the 5T4 protein and have been modified so that they are weakened and cannot reproduce themselves within the body like normal viruses. Once injected into the body, these viruses make the 5T4 protein and help the body's immune system to learn to target this protein and destroy cancer cells.
This is a first-in-human study to evaluate the safety and immunogenicity of ChAdOx1.5T4-MVA.5T4 vaccination regime. It is evaluated in neo-adjuvant setting in low and intermediate risk localised prostate cancer patients who have either decided to have their prostate removed or are stable on active surveillance.

Start Date01 Jun 2015

Sponsor / Collaborator

University of Oxford

100 Clinical Results associated with ChAdOx1 MVA 5T4 vaccine (Vaccitech)

100 Translational Medicine associated with ChAdOx1 MVA 5T4 vaccine (Vaccitech)

100 Patents (Medical) associated with ChAdOx1 MVA 5T4 vaccine (Vaccitech)

Literatures (Medical) associated with ChAdOx1 MVA 5T4 vaccine (Vaccitech)

01 Jun 2020·Journal for immunotherapy of cancerQ2 · MEDICINE

Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial

Q2 · MEDICINE

ArticleOA

Author: Mitton, Celia ; Hollidge, Julianne ; Carter, Lucy ; Meier, Armin ; Morgan, Susan ; MacPherson, Ruth ; Redchenko, Irina ; Baker, Megan ; Catto, James ; Baines, Andrea ; Hill, Adrian V S ; Evans, Thomas ; Cappuccini, Federica ; Poulton, Ian ; Vigano, Selena ; Romero, Pedro J ; Harrop, Richard ; Pollock, Emily ; Kennish, Steven ; Verrill, Clare ; Hamdy, Freddie ; Protheroe, Andrew ; Schmidt, Guenter ; Bryant, Richard

Background:

Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity.

Methods:

In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells.

Results:

The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2–8 weeks following vaccination, possibly indicating an inflammatory response in the target organ.

Conclusions:

An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab.

Trial registration:

The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063).

18 Jul 2017·Oncotarget

5T4 oncofoetal glycoprotein: an old target for a novel prostate cancer immunotherapy

Article

Author: Redchenko, Irina ; Cappuccini, Federica ; Stribbling, Stephen ; Pollock, Emily ; Hill, Adrian V.S.

The tumour-associated antigen 5T4 is an attractive target for cancer immunotherapy. However to date, reported 5T4-specific cellular immune responses induced by various immunisation platforms have been largely weak or non-existent. In the present study, we have evaluated a heterologous prime boost regime based on the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA) expressing 5T4 for immunogenicity and tumour protective efficacy in a mouse cancer model. Vaccination-induced immune responses were strong, durable and attributable primarily to CD8+ T cells. By comparison, homologous MVA vaccination regimen did not induce detectable 5T4-specific T cell responses. ChAdOx1-MVA vaccinated mice were completely protected against subsequent B16 melanoma challenge, but in therapeutic settings this regime was only modestly effective in delaying tumour outgrowth. Concomitant delivery of the vaccine with monoclonal antibodies (mAbs) targeting immune checkpoint regulators LAG-3, PD-1 or PD-L1 demonstrated that the combination of vaccine with anti PD-1 mAb could significantly delay tumour growth and increase overall survival of tumour-bearing mice. Our findings support a translation of the combinatorial approach based on the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade into the clinic for the treatment of 5T4-positive tumours such as prostate, renal, colorectal, gastric, ovarian, lung cancer and mesothelioma.

Frontiers in oncology

Role of Adenoviruses in Cancer Therapy

Review

Author: Tseha, Sintayehu Tsegaye

Cancer is one of the leading causes of death in the world, which is the second after heart diseases. Adenoviruses (Ads) have become the promise of new therapeutic strategy for cancer treatment. The objective of this review is to discuss current advances in the applications of adenoviral vectors in cancer therapy. Adenoviral vectors can be engineered in different ways so as to change the tumor microenvironment from cold tumor to hot tumor, including; 1. by modifying Ads to deliver transgenes that codes for tumor suppressor gene (p53) and other proteins whose expression result in cell cycle arrest 2. Ads can also be modified to express tumor specific antigens, cytokines, and other immune-modulatory molecules. The other strategy to use Ads in cancer therapy is to use oncolytic adenoviruses, which directly kills tumor cells. Gendicine and Advexin are replication-defective recombinant human p53 adenoviral vectors that have been shown to be effective against several types of cancer. Gendicine was approved for treatment of squamous cell carcinoma of the head and neck by the Chinese Food and Drug Administration (FDA) agency in 2003 as a first-ever gene therapy product. Oncorine and ONYX-015 are oncolytic adenoviral vectors that have been shown to be effective against some types of cancer. The Chiness FDA agency has also approved Oncorin for the treatment of head and neck cancer. Ads that were engineered to express immune-stimulatory cytokines and other immune-modulatory molecules such as TNF-α, IL-2, BiTE, CD40L, 4-1BBL, GM-CSF, and IFN have shown promising outcome in treatment of cancer. Ads can also improve therapeutic efficacy of immune checkpoint inhibitors and adoptive cell therapy (Chimeric Antigen Receptor T Cells). In addition, different replication-deficient adenoviral vectors (Ad5-CEA, Ad5-PSA, Ad-E6E7, ChAdOx1–MVA and Ad-transduced Dendritic cells) that were tested as anticancer vaccines have been demonstrated to induce strong antitumor immune response. However, the use of adenoviral vectors in gene therapy is limited by several factors such as pre-existing immunity to adenoviral vectors and high immunogenicity of the viruses. Thus, innovative strategies must be continually developed so as to overcome the obstacles of using adenoviral vectors in gene therapy.

News (Medical) associated with ChAdOx1 MVA 5T4 vaccine (Vaccitech)

13 Jun 2023

·pipelinereview.com

Vaccitech Doses First Patient in PCA001, a Prostate Cancer Phase 1/2 Clinical Trial of VTP-850 Immunotherapeutic Candidate in Men with Rising PSA after Definitive Local Therapy

OXFORD, UK I June 12, 2023 I Vaccitech plc (NASDAQ: VACC) (the Company, we or us), a clinical-stage biopharmaceutical company engaged in the discovery and development of novel immunotherapeutics for the treatment of autoimmunity, chronic infectious diseases and cancer, today announced the dosing of the first patient in the PCA001 clinical trial (NCT05617040). PCA001 is a multi-centre, Phase 1/2 clinical trial designed to determine the recommended Phase 2 regimen and evaluate the safety, efficacy, as measured by prostate-specific antigen (PSA) response, and T cell response of VTP-850 monotherapy in men with rising PSA after definitive local therapy for their disease ( i.e. , biochemical recurrence). VTP-850 is a next-generation prostate cancer immunotherapeutic candidate which utilizes Vaccitech’s sequential dosing approach of two proprietary nonreplicating viral vectors, ChAdOx and MVA. PCA001 builds on the previous promising data from the University of Oxford VANCE01 (NCT02390063) and ADVANCE (NCT03815942) trials, Phase 1 and Phase 1/2 clinical trials respectively, of VTP-800, the first-generation product candidate which encoded 5T4, an antigen expressed by most prostate cancers. 1,2 VTP-850 is a multi-antigen immunotherapeutic candidate containing four prostate-associated antigens: PSA, PAP, STEAP1 and 5T4. The first phase of the trial is enrolling participants in the US, with plans to open further sites in Italy and Spain. “20-40% of patients will unfortunately experience biochemical recurrence following initial local therapy for prostate cancer with the potential to experience metastases. 3 VTP-850 is our next-generation, multi-antigen product candidate designed to induce a targeted polyclonal T cell response to kill remaining tumor cells and prevent advancement to metastatic disease,” said Bill Enright, Chief Executive Officer of Vaccitech. “We saw very encouraging data from the VANCE01 and ADVANCE trials, and we are excited to begin PCA001 where VTP-850 will be evaluated as a monotherapy in a patient population with important unmet medical needs.” “VTP-850 encodes four prostate cancer antigens and is designed to induce a broader T cell response to tumor cells,” said Dr. Meg Marshall, Chief Medical Officer of Vaccitech. “When the immune system targets multiple molecules on tumor cells, it is generally harder for tumor cells to escape destruction by the immune system.” About Prostate Cancer In 2020, prostate cancer was the fourth most common cancer worldwide, with 1.4 million new cases diagnosed. 4 In the US, out of every 100 American men, about 13 will get prostate cancer during their lifetime. 5 In the UK, prostate cancer is the most common cancer in men, with more than 52,000 people diagnosed with the disease on average each year. 6 20-30% of patients experience rising levels of PSA after local therapy (e.g. prostatectomy), indicating that disease was not cured by local therapy. 7 Of men who do experience biochemical recurrence, there is a 1 in 9 chance of developing metastases. 8 About Vaccitech Vaccitech is a clinical-stage biopharmaceutical company focused on the development of novel T cell immunotherapeutics designed to harness the power of the immune system to treat and cure chronic infectious diseases, autoimmune diseases, and cancer. The Company stands apart through a proprietary, multi-platform approach that has shown the ability to induce higher magnitudes of T cells compared with other technologies. Vaccitech is uniquely positioned to address the needs of large, underserved patient populations through a diverse clinical-stage pipeline of investigational therapies targeting diseases that pose significant public health risk and have limited treatment options. The Company’s lead product candidates include VTP-300, an immunotherapy product candidate designed as a component of a potential functional cure for chronic hepatitis B viral (HBV) infection; VTP-200, a non-invasive, early-stage investigational treatment for persistent, high-risk human papillomavirus (HPV) infection; VTP-850, a novel T cell investigational therapy for prostate cancer; and VTP-1000, a preclinical T cell therapeutic candidate designed to restore immune tolerance in celiac disease. Vaccitech has proven drug development and scientific expertise in the field of immunization, co-inventing a COVID-19 vaccine with the University of Oxford, which is now approved and exclusively licensed worldwide to AstraZeneca. For more information, visit www.vaccitech.co.uk . SOURCE: Vaccitech

ImmunotherapyVaccineClinical StudyPhase 2Clinical Result

12 Jun 2023

·www.globenewswire.com

Vaccitech Doses First Patient in PCA001, a Prostate Cancer Phase 1/2 Clinical Trial of VTP-850 Immunotherapeutic Candidate in Men with Rising PSA after Definitive Local Therapy

OXFORD, United Kingdom, June 12, 2023 (GLOBE NEWSWIRE) -- Vaccitech plc (NASDAQ: VACC) (the Company, we or us), a clinical-stage biopharmaceutical company engaged in the discovery and development of novel immunotherapeutics for the treatment of autoimmunity, chronic infectious diseases and cancer, today announced the dosing of the first patient in the PCA001 clinical trial (NCT05617040). PCA001 is a multi-centre, Phase 1/2 clinical trial designed to determine the recommended Phase 2 regimen and evaluate the safety, efficacy, as measured by prostate-specific antigen (PSA) response, and T cell response of VTP-850 monotherapy in men with rising PSA after definitive local therapy for their disease (i.e., biochemical recurrence). VTP-850 is a next-generation prostate cancer immunotherapeutic candidate which utilizes Vaccitech’s sequential dosing approach of two proprietary nonreplicating viral vectors, ChAdOx and MVA. PCA001 builds on the previous promising data from the University of Oxford VANCE01 (NCT02390063) and ADVANCE (NCT03815942) trials, Phase 1 and Phase 1/2 clinical trials respectively, of VTP-800, the first-generation product candidate which encoded 5T4, an antigen expressed by most prostate cancers.1,2 VTP-850 is a multi-antigen immunotherapeutic candidate containing four prostate-associated antigens: PSA, PAP, STEAP1 and 5T4. The first phase of the trial is enrolling participants in the US, with plans to open further sites in Italy and Spain. “20-40% of patients will unfortunately experience biochemical recurrence following initial local therapy for prostate cancer with the potential to experience metastases.3 VTP-850 is our next-generation, multi-antigen product candidate designed to induce a targeted polyclonal T cell response to kill remaining tumor cells and prevent advancement to metastatic disease,” said Bill Enright, Chief Executive Officer of Vaccitech. “We saw very encouraging data from the VANCE01 and ADVANCE trials, and we are excited to begin PCA001 where VTP-850 will be evaluated as a monotherapy in a patient population with important unmet medical needs.” “VTP-850 encodes four prostate cancer antigens and is designed to induce a broader T cell response to tumor cells,” said Dr. Meg Marshall, Chief Medical Officer of Vaccitech. “When the immune system targets multiple molecules on tumor cells, it is generally harder for tumor cells to escape destruction by the immune system.” About Prostate Cancer In 2020, prostate cancer was the fourth most common cancer worldwide, with 1.4 million new cases diagnosed.4 In the US, out of every 100 American men, about 13 will get prostate cancer during their lifetime.5 In the UK, prostate cancer is the most common cancer in men, with more than 52,000 people diagnosed with the disease on average each year.6 20-30% of patients experience rising levels of PSA after local therapy (e.g. prostatectomy), indicating that disease was not cured by local therapy.7 Of men who do experience biochemical recurrence, there is a 1 in 9 chance of developing metastases.8 About Vaccitech Vaccitech is a clinical-stage biopharmaceutical company focused on the development of novel T cell immunotherapeutics designed to harness the power of the immune system to treat and cure chronic infectious diseases, autoimmune diseases, and cancer. The Company stands apart through a proprietary, multi-platform approach that has shown the ability to induce higher magnitudes of T cells compared with other technologies. Vaccitech is uniquely positioned to address the needs of large, underserved patient populations through a diverse clinical-stage pipeline of investigational therapies targeting diseases that pose significant public health risk and have limited treatment options. The Company’s lead product candidates include VTP-300, an immunotherapy product candidate designed as a component of a potential functional cure for chronic hepatitis B viral (HBV) infection; VTP-200, a non-invasive, early-stage investigational treatment for persistent, high-risk human papillomavirus (HPV) infection; VTP-850, a novel T cell investigational therapy for prostate cancer; and VTP-1000, a preclinical T cell therapeutic candidate designed to restore immune tolerance in celiac disease. Vaccitech has proven drug development and scientific expertise in the field of immunization, co-inventing a COVID-19 vaccine with the University of Oxford, which is now approved and exclusively licensed worldwide to AstraZeneca. For more information, visit www.vaccitech.co.uk. Forward Looking Statements This press release contains forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, which can generally be identified as such by use of the words “may,” “will,” “plan,” “forward,” “intend,” “promising,” “believe,” “potential,” and similar expressions, although not all forward-looking statements contain these identifying words. These forward-looking statements include, without limitation, express or implied statements regarding: the Company’s plans and strategy with respect to VTP-850 and the PCA001 clinical trial, including plans for patient enrollment in Italy and Spain, the potential benefits of VTP-850 for the treatment of prostate cancer and expected patient population of VTP-850. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to numerous risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks and uncertainties related to the success, cost and timing of the Company’s product development activities and planned and ongoing clinical trials, the Company’s ability to execute on its strategy, regulatory developments, the Company’s ability to fund its operations, global economic uncertainty, including disruptions in the banking industry, the impact that the COVID-19 pandemic may have on the Company’s clinical trials and preclinical studies, and access to capital and other risks identified in the company’s filings with the Securities and Exchange Commission (the “SEC”), including its Annual Report on Form 10-K for the year ended December 31, 2022, its Quarterly Reports on Form 10-Q and subsequent filings with the SEC. The Company cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. The Company expressly disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. References Cappuccini. F, et al, J Immunother Cancer, 2020. DOI: 10.1136/jitc-2020-000928Tuthill, M, et al, Ann. Oncol. 2020. DOI: https://doi.org/10.1016/j.annonc.2020.08.2076Artibani, W, et al, Urol Int, 2017. DOI: https://doi.org/10.1159/000481438WHO, Cancer, 2022.CDC, Prostate Cancer, 2022.Prostate Cancer UK, About Prostate Cancer, 2022.Johns Hopkins Medicine, Prostate Cancer Prognosis, 2023.Stensland. KD, et al, J Clin Onc, 2022. DOI: 10.1200/JCO.2022.40.16_suppl.5090 IR contacts: Christopher M. Calabrese  Managing Director  LifeSci Advisors 917-680-5608 ccalabrese@lifesciadvisors.com  Kevin Gardner Managing Director LifeSci Advisors 617-283-2856 kgardner@lifesciadvisors.com     Media contact: Mike Beyer SAM BROWN, INC 312-961-2502 mikebeyer@sambrown.com       Company contact: Jonothan Blackbourn IR & PR Manager Vaccitech IR@vaccitech.co.uk

ImmunotherapyVaccine

100 Deals associated with ChAdOx1 MVA 5T4 vaccine (Vaccitech)

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Phase 2	GB	Vaccitech (UK) Ltd.	04 May 2019
Castration-Resistant Prostatic Cancer	Phase 2	GB	University of Oxford	10 Dec 2018
Locally Advanced Prostate Carcinoma	Phase 2	GB	University of Oxford	10 Dec 2018

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02390063 (VANCE, Pubmed \| J Immunother Cancer)	Phase 1	Prostatic Cancer	40	ChAdOx1-MVA 5T4 vaccine	xisdoszhpl(zvztsgisnd) = Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ lffyaihkcq (uevbntsvfp )	-	01 Jun 2020
ASCO2008	Not Applicable	Metastatic Renal Cell Carcinoma	25	MVA-5T4 vaccine	rfytstisuq(anclvdruro) = zaonywnzjl ozzamfrqth (jetnaquawu )	-	20 May 2008
ASCO2008	Not Applicable	Metastatic Renal Cell Carcinoma	25	High-dose interleukin-2	rfytstisuq(anclvdruro) = ubyswraflt ozzamfrqth (jetnaquawu )	-	20 May 2008

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