Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule

Hörig, Heidi; Lee, David S.; Conkright, William; DiVito, Joe; Hasson, Henry; LaMare, Michelle; Rivera, Audrey; Park, David; Tine, John A.; Guito, Ken; Tsang, Kwong Wong-Yok; Schlom, Jeffrey; Kaufman, Howard L.

doi:10.1007/s002620000146

Cited by 183 publications

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“…These symptoms occur frequently in end-stage colorectal cancer patients. [25][26][27] Mutations in the p53 gene occur in approximately 50% of malignancies and usually result in overexpression in the malignant cells only. 3 The combination of increased steady-state levels and predominant expression by malignant cells provided an opportunity for a p53-specific immunotherapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

“…As we evaluated the tumor response a long time (14 weeks) after completing vaccinations, it is possible that ALVAC-p53 did induce a clinical response, but that this response was no longer detectable 14 weeks later. Other investigators report anti-tumor responses in end-stage patients, but assess these earlier after stopping the experimental treatment, for example, from 0 weeks, 25 2 weeks, 4 weeks, 26 4-6 weeks, 38 or 8 weeks 39 after stopping treatment. However, we observed disease progression at occasional earlier radiographic evaluations, such as in patients 02 (1/10 dose), 09 (1/3 dose) and 17 (full dose) who underwent CT scans on week 2, 4 weeks and 8 weeks after the last vaccination, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients

et al. 2003

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Overexpression of p53 occurs in more than 50% of colorectal cancers. Therefore, p53 represents an attractive target antigen for immunotherapy. We assessed the safety of a canarypox virus encoding the human wild-type p53 gene given intravenously to endstage colorectal cancer patients in a three-step dose escalation study aimed at inducing p53 immune responses. Patients with metastatic disease of p53-overexpressing colorectal cancers were vaccinated three times at 3-week intervals, each time with 10 6.5 CCID 50 (CCID 50 ¼ cell culture infectious dose 50%; group 1, n ¼ 5), 10 7.0 CCID 50 (group 2, n ¼ 5) or 10 7.5 CCID 50 (group 3, n ¼ 6). Vital signs and the occurrence of adverse events were monitored and blood was analyzed for biochemical and hematological parameters as well as signs of auto-immune safety. In all, 16 patients were enrolled and 15 patients completed three vaccinations. No anaphylactic reaction or unwanted auto-immune reactions were observed. A total of 16 serious adverse events (SAEs) occurred: 10 in group 1, three in group 2 and three in group 3. All SAEs were tumor-related complications. There was no difference in the frequency of adverse events between the three groups, except for fever. Fever was the only vaccination-related adverse event consistently observed and was most frequent and outspoken in the group 3 patients. The majority was a grade 1 or 2 fever (93%) and grade 3 fever (7%) was observed in three patients of group 3. Some patients showed humoral and cellular responses against p53, following vaccinations. After having completed his initial treatment cycle, one patient (group 2) received a second treatment cycle of three doses of 10 7.5 CCID 50 and subsequently showed stable disease. All other patients showed progressive disease. We conclude that ALVAC-p53 can be administered intravenously to colorectal cancer patients without serious toxicity or pathological autoimmunity and can induce immune responses against p53.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients

et al. 2003

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“…13 In addition, clinical Phase I trials using B7-1 transduced autologous RCC cells for vaccination or a vaccine with tumor-associated antigen in combination with B7-1 have shown some immunological and clinical responses. 14,26 Allogeneic breast carcinoma cells transfected with B7-1 in addition to influenzaderived protein were able to prime flu-peptide-specific CTL. 27 In this context, our results support the use of B7-engineered tumor cells for vaccination in an allogeneic setting, and, moreover, support the implementation of B7-2 modified tumor cells to obtain a more potent immune response.…”

Section: Discussionmentioning

confidence: 99%

B7‐1 and B7‐2 act differentially in the induction of a T cell response: Their impact for a HLA‐matched and HLA‐mismatched anti‐tumor immunotherapy

Kronfeld

Abken

Seliger

2005

Intl Journal of Cancer

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The efficacy of T cell-based immunotherapy is primarily due to efficient cellular activation that requires the engagement of 2 separate signals, i.e., via the T cell receptor complex and via costimulatory molecules the prototype of which is CD28. In cellular activation, the CD28 ligands B7-1 (CD80) and B7-2 (CD86) are thought to play nearly identical roles in T cell activation. We monitored the T cell response upon co-culture with HLA Class I-matched and mismatched renal carcinoma cells, respectively, that express different levels of B7-1 and B7-2, respectively. In a HLA Class I-mismatched co-culture, T cell proliferation, IFN-c and GM-CSF secretion equally depend on the levels of B7-1 and B7-2 on tumor cells. In contrast, in a HLA Class I-matched situation, B7-2 is more effective in the induction of IFN-c and GM-CSF secretion than B7-1, but both B7 molecules induce T cell proliferation equally efficient. B7-2 is more effective than B7-1 in inducing TNF-a and IL-10 secretion in both HLA Class Imatched and mismatched situations. The distinct patterns of cytokine induction by B7-1 and B7-2 obviously depend on the HLA Class I compatibility. These conclusions have substantial implications for the development of B7-based vaccines used for immunotherapies. ' 2005 Wiley-Liss, Inc.

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“…The viral transfer of CEA and B7.1 into T cells was tested in a phase I trial but the results were not spectacular with only 3 out of 12 stable disease [65]. More promising results have been reported when several tumor-directing antigens, including CEA, together with co-stimulatory molecules were delivered to T cells with poxviruses since the overall survival was significantly increased in the patient demonstrating efficient immunization [66].…”

Section: Clinical Trials Completed and Ongoingmentioning

confidence: 91%

Gene Therapy of Pancreatic Cancer

Dabernat¹,

Lafitte²,

Bedel³

et al. 2013

J Genet Syndr Gene Ther

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a 5-year survival rate of less than 5%. The poor prognosis of the disease is associated with late diagnosis and a high degree of drug resistance has not been overcome during the past decades. Gemcitabine-based regimens are the first line therapy for advanced pancreatic cancer but are not curative. Recent new combination chemotherapies achieved significant benefits but toxicity makes their use controversial. Novel approaches are currently being developed; in particular cancer gene therapies are undergoing preclinical and clinical validation and are the topic of the present review. We will present different ways to design gene therapy against pancreatic cancers that have been validated in preclinical studies. We also reviewed the clinical trials already published or still ongoing.Citation: Dabernat S, Lafitte M, Bedel A, de Verneuil H, Moreau-Gaudry F (2013) Gene Therapy of Pancreatic Cancer. J Genet Syndr Gene Ther 4: 138. doi:10.4172/2157-7412.1000138 Page 2 of 6Volume 4 • Issue 4 • 1000138 Suicide Gene Therapy of Cancer J Genet Syndr Gene Ther ISSN: 2157-7412 JGSGT, an open access journal gene restoration efficiency [12]. Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers. Among them, mutations in the KRAS oncogene occur in almost all pancreatic adenorcinomas [9]. Thus, it is tempting to use direct anti-KRAS strategies to inhibit tumor growth (Figure 1b), since disappointing results have been obtained with inhibition of farnesyl transferases [1]. RNAi directed against mutated KRAS showed anti-tumor activity [15], limited the aggressive phenotype of the tumor cells [16] and potentiated gemcitabine antitumor activity [17]. Preclinical studies showed encouraging results with viral delivery systems such as oncolytic adenovirus [18]. However, this strategy has not been further tested in phase I clinical trials.In fact, pancreatic adenocarcinomas present very complex genetic alterations profiles. The Pancreatic Cancer Genome project has analyzed 23,219 transcripts and identified an average of 63 somatic mutations per PDAC affecting 12 core signaling pathways and the overexpression of 500 different genes in 24 tumors [19]. These highly versatile and unpredictable molecular patterns can explain the failure of single gene/pathway targeted adjuvant therapies. It is now critical to test therapies targeting several pathways or therapies that induce specific tumor cell death. Delivering a Suicide GeneWith the suicide gene approach, a gene that encodes a protein triggering tumor cell death is delivered to the tumor cells ( Figure 1c). The expression of the therapeutic gene can directly kill the cells (diphtheria toxin, [20]), or can render the cells sensitive to certain otherwise non toxic prodrugs (Gene Directed Enzyme Prodrug Therapy, GDEPT,[21]), or based on gemcitabine association ...

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Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule

Cited by 183 publications

References 0 publications

Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients

Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients

B7‐1 and B7‐2 act differentially in the induction of a T cell response: Their impact for a HLA‐matched and HLA‐mismatched anti‐tumor immunotherapy

Gene Therapy of Pancreatic Cancer

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