Preclinical qualification of a new multi-antigen candidate vaccine for metastatic melanoma.

New therapies are urgently required for the treatment of patients with melanoma. Here we describe the generation and preclinical evaluation of 3 new recombinant ALVAC(2) poxviruses vCP2264, vCP2291, and vCP2292 for their ability to induce the desired cellular immune responses against the encoded melanoma-associated antigens. This was done either in HLA-A2/K transgenic mice or using in vitro antigen-presentation studies. These studies demonstrated that the vaccine was able to induce HLA-A*0201-restricted T-cell responses against gp100 and NY-ESO-1, detectable directly ex vivo, in HLA-A2/K-transgenic mice. The in vitro antigen presentation studies, in the absence of appropriate animal models, demonstrated that target cells infected with the vaccine construct were lysed by MAGE-1, MAGE-3 or MART-1 peptide-specific T cells. These data indicate that ALVAC(2)-encoded melanoma-associated antigens can be properly processed and presented to induce antigen-specific cytotoxic T-cell responses. To enhance the immunogenicity of the melanoma antigens, a TRIad of COstimulatory Molecules (TRICOM) were also cloned into all 3 vectors. Increased in vitro proliferation and IFN-γ production was observed with all ALVAC(2) poxviruses encoding TRICOM, confirming the immune-enhancing effect of the ALVAC-encoded TRICOM. These studies demonstrated that all components of the vaccine were functionally active and provide a rationale for moving this candidate vaccine to the clinic.

The nonprofit sector's $100 billion opportunity.

Imagine what an extra $100 billion a year could do for philanthropic and other nonprofit institutions. According to a new study, the nonprofit sector could free that amount--maybe even more--by making five changes in the way it operates. The study asked two central questions: Does the sector's money flow from its source to its ultimate use as efficiently and effectively as possible? If not, where are the big opportunities to increase social benefit? According to former senator Bill Bradley and McKinsey's Paul Jansen and Les Silverman, nonprofits could save roughly $25 billion a year by changing the way they raise funds. By distributing funds more quickly, they could put an extra $30 billion to work. Organizations could generate more than $60 billion a year by streamlining and restructuring the way in which they provide services and by reducing administrative costs. And they could free up even more money--an amount impossible to estimate--by better allocating funds among service providers. The authors admit that making those changes won't be easy. The nonprofit world, historically seen as a collection of locally focused charities, has become an enormous sector, but it lacks the managerial processes and incentives that help keep the for-profit world on track. And when the baby boomers start to retire in less than a decade, public budgets will be squeezed even more than they are today. If the nonprofit sector is to help the nation cope with the stresses ahead, it must become more efficient and challenge its traditional concepts of stewardship.