Development of the PANVAC™-VF vaccine for pancreatic cancer

Petrulio, Christian; Kaufman, Howard L.

doi:10.1586/14760584.5.1.9

Cited by 60 publications

(24 citation statements)

References 62 publications

(51 reference statements)

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“…Three phase III trials of PC vaccines have been conducted previously, all of which did not meet their primary objective [31-33]. Over 20 vaccine immunotherapy clinical trials are currently ongoing in various stages of completion (http://clinicaltrials.gov) examining varying iterations of the above approaches for cancers including but not limited to PC, including novel peptides (e.g., mesothelin, VEGFR1/VEGFR2 and survivin), DNA-based vaccines, and combinations of vaccines with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

Geynisman¹,

Zha²,

Kunnavakkam³

et al. 2013

J Immunother Cancer

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BackgroundCEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8+ T cell response.MethodsPatients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression.ResultsSixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 104 CD8+ cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease.ConclusionsThe T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts.Trial registrationClinicalTrials.gov NCT00203892

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Section: Discussionmentioning

confidence: 99%

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

Geynisman¹,

Zha²,

Kunnavakkam³

et al. 2013

J Immunother Cancer

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“…Oncolytic adenovirus and replication-impaired HSV and vaccinia virus vectors expressing B7 molecules have also been tested as treatments for cancers. The B7-modified viruses enhance antitumor immunity (36,63) and promote regression following direct intratumoral injection (25,30,46,60). These studies suggest expression of host B7 costimulation molecules by a live attenuated vaccine virus could also potentially be used to induce more vigorous immunity to the homologous viral pathogen.…”

mentioning

confidence: 99%

B7 Costimulation Molecules Expressed from the Herpes Simplex Virus 2 Genome Rescue Immune Induction in B7-Deficient Mice

Thebeau

Vagvala

Wong

et al. 2007

J Virol

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The interaction between B7 costimulation molecules on antigen-presenting cells and CD28 on antigenresponsive T cells is essential for T-cell activation and maturation of immune responses to herpes simplex virus (HSV) infection. Vaccine-induced immune responses also depend upon adequate upregulation of B7 costimulation molecules, but this signal may be limiting for replication-defective virus vaccines. We investigated whether expression of B7 costimulation molecules by a prototypical replication-defective antiviral vaccine could enhance immune responses to the vaccine and whether B7-1 and B7-2 would be similarly effective. We altered an ICP8؊ replication-defective strain of HSV type 2 (HSV-2), 5BlacZ, to encode either murine B7-1 or B7-2. B7 molecule expression was detected on the surface of cells infected in vitro and at the RNA level in tissue of immunized mice. Immunization of B7-1/B7-2 knockout mice with B7-encoding virus modestly expanded the number of gamma interferon-producing T cells and significantly augmented class-switched HSV-specific antibody responses compared with the parental virus. Mice immunized with either B7-expressing virus showed less replication of challenge virus in the genital mucosa than mice immunized with 5BlacZ, markedly fewer signs of genital and neurological disease, and little weight loss. Virtually all mice immunized with B7-encoding virus survived challenge with a large dose of HSV-2, whereas most 5BlacZ-immunized mice succumbed to infection. These results indicate that protective immune responses can be enhanced by the inclusion of host B7 costimulation molecules in a prototypical replication-defective HSV vaccine against HSV-2 genital infection and that B7-1 and B7-2 induce immune responses with similar capacities to fight HSV-2 infection.

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“…Most viruses engineered to express B7 molecules have been used to enhance responses to coexpressed heterologous antigens such as tumor-specific epitopes (18,27,36,40). We have notably extended this work by demonstrating that virus-encoded B7 costimulation molecules enhance protective immune responses to the homologous viruses.…”

Section: Discussionmentioning

confidence: 99%

Virus-Encoded B7-2 Costimulation Molecules Enhance the Protective Capacity of a Replication-Defective Herpes Simplex Virus Type 2 Vaccine in Immunocompetent Mice

Vagvala

Thebeau

Wilson

et al. 2009

J Virol

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Herpes simplex virus 2 (HSV-2) and, to a lesser extent, HSV-1 cause the majority of sexually transmitted genital ulcerative disease. No effective prophylactic vaccine is currently available. Replication-defective HSV stimulates immune responses in animals but produces no progeny virus, making it potentially useful as a safe form of live vaccine against HSV. Because it does not replicate and spread in the host, however, replicationdefective virus may have relatively limited capacity to solicit professional antigen presentation. We previously demonstrated that in mice devoid of B7-1 and B7-2 costimulation molecules, replication-defective HSV-2 encoding B7-1 or B7-2 induces stronger immune responses and protection against HSV-2 challenge than immunization with replication-defective virus alone. Here, we vaccinated wild-type mice fully competent to express endogenous B7 costimulation molecules with replication-defective HSV-2 or replication-defective virus encoding B7-2 and compared their capacities to protect against vaginal HSV-2 infection and disease. Replication-defective virus encoding B7-2 induced more IFN-␥-producing CD4 T cells than did replication-defective virus alone. Immunization with B7-2-expressing virus decreased challenge virus replication in the vaginal mucosa, genital and neurological disease, and mortality more effectively than did immunization with the parental replication-defective virus. Prior immunization with B7-expressing, replication-defective virus also effectively suppressed infection of the nervous system compared to immunization with the parental virus. Thus, B7 costimulation molecules expressed at the site of HSV infection can enhance vaccine efficacy even in a fully immunocompetent host.

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Development of the PANVAC™-VF vaccine for pancreatic cancer

Cited by 60 publications

References 62 publications

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

B7 Costimulation Molecules Expressed from the Herpes Simplex Virus 2 Genome Rescue Immune Induction in B7-Deficient Mice

Virus-Encoded B7-2 Costimulation Molecules Enhance the Protective Capacity of a Replication-Defective Herpes Simplex Virus Type 2 Vaccine in Immunocompetent Mice

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