PURPOSE OF REVIEWThis review discusses select recent data that suggest that indeed it is possible to make a clinically useful preventive vaccine for HIV-1 and outlines some of the remaining obstacles that stand in the way of success.RECENT FINDINGSPassive protection studies, with broad neutralizing antibodies for mucosal simian-HIV challenges, in nonhuman primates have suggested that lower doses of neutralizing antibodies than previously thought may be effective in preventing HIV-1 infection. The use of recombinant antibody technology coupled with the ability to culture single memory B cells has yielded new broad neutralizing antibodies and new targets for vaccine design. The success of the RV144 Thai HIV-1 efficacy trials with a replication-defective recombinant canarypox vector (ALVAC)/gp120 prime, clade B/E recombinant gp120 protein boost showing 31% efficacy has given hope that indeed a protective HIV-1 vaccine can be made.SUMMARYRecent data in the last year have provided new hope that a clinically useful preventive HIV-1 vaccine can potentially be made. The path forward will require development of improved immunogens, understanding the correlates of protection to HIV-1, and development of immunogens to induce antibodies that can prevent the initial stages of HIV-1 infection at mucosal sites, in order to improve on the RV144 trial results.

01 Jul 2003·Cancer Gene TherapyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Peter J K Kuppen ; Rob A E M Tollenaar ; Anand G Menon ; Hein Putter ; Sjoerd H van der Burg ; Rienk Offringa ; Marie Claude Bonnet ; Hans Morreau ; Philippe Moingeon ; Bert I J Harinck ; Anke Redeker ; Cornelis J M Melief ; Cornelis J H van de Velde

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 end-stage 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)=cell culture infectious dose 50%; group 1, n=5), 10(7.0) CCID(50) (group 2, n=5) or 10(7.5) CCID(50) (group 3, n=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.

01 Feb 2001·Cancer Gene TherapyQ2 · MEDICINE

Canarypox virus expressing wild type p53 for gene therapy in murine tumors mutated in p53

Q2 · MEDICINE

Article

Author: James Tartaglia ; Marie Favrot ; Isabelle Puisieux ; Laurence Odin ; Jean-Philippe Michot ; Philippe Moingeon ; Dominique Poujol

The antitumor activity of a recombinant canarypox virus expressing wild type murine p53 (ALVAC-p53) was investigated in two murine syngeneic tumors harboring an endogenous p53 mutation (CMS4 and TS/A). Direct intratumor injections of ALVAC-p53 in CMS4 pre-established subcutaneous tumors induced total tumor regression in 66% of mice. Furthermore, 100% of the cured mice was protected against a contralateral subsequent challenge with the parental tumor cells. The intravenous treatment of experimental lung metastasis by ALVAC-p53 also induced significant tumor growth inhibition in both models. The antitumor effect of ALVAC-p53 was only observed in immunocompetent animals and was associated with the generation of a specific antitumor immune response. ALVAC-p53 induced the expression of a functional p53 wild type protein as demonstrated by up-regulation of p21waf1 and induction of apoptosis. A vaccine strategy using intravenous or subcutaneous ALVAC-p53/NYVAC-p53 prime boost protocol failed to induce CTL against p53 wild type used as target tumor antigen, and failed to protect mice against challenge with the mutated tumor cells. The mechanism of the curative and protective effects observed after direct intratumor injections results from the induction of a specific antitumor response directed against other antigens than p53. Our results suggest that the local induction of tumor apoptosis, combined with the adjuvant effect of ALVAC vector, enhances the immunogenicity of the intratumor environment and allows induction of specific antitumor immune response.

100 Deals associated with ALVAC-p53(Sanofi Pasteur SA)

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	-	Sanofi Pasteur	-

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