U. S. Department of health & human services




НазваниеU. S. Department of health & human services
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call it, that might be posed by each of the issues

that was in that table. And, just to again

recapitulate what we would hope to do, with more or

less success based on available data, is to assess the

level of risk posed by each of those concerns and

issues quantitatively. We would hope to be able to

establish in many cases the probability of a worst

case scenario for each of the issues or concerns, and

then using these data to evaluate the levels of risk

individually and cumulatively, and then finally, based

on this data set, to assess the relative risk of the

product.

Now, as Ive already covered session one,

well start with session two of the meeting that

occurred last week, the session was Wednesday morning,

and the task of the session was to review the

mechanisms of neoplastic development in

carcinogenesis, and to assess the impact of the issues

posed by the use of neoplastic cells as vaccine

substrates.

The basic topic here was the possibility

of the increasing recognition that the neoplastic

process is a multi factor process. It takes a

multiplicity of events, and this has been a very

recent paper in Nature that came out of Doctor

Weinbergs laboratory at MIT, which demonstrated

rather conclusively that at least three to four

separate genetic alterations are required in normal

cells before theyll evolve into a neoplastic cell

which is capable of forming tumors.

And, the idea was to explore this multi 

factor process with the concept of what the

implications of this were for vaccine safety. And,

the consensus that emerged from the panel that

considered the topic after the session, after the

relevant data was presented, basically was that due to

the multi factor processes that produce neoplasia,

neoplastic cell components, which include nucleic

acids and cell proteins that might remain in vaccines,

should pose little or no risk of transferring

neoplastic activity. And the second consensus that we

feel emerged from this discussion was that theres

really no correlation between the degree of

aggressiveness in neoplastic cells and the ability to

transfer neoplastic information to other cells.

Now, I would hasten to point out that

these were  this consensus was based on opinions of

the panel and they readily expressed the fact that

theres not a lot of data out there that sustains some

of these opinions, and therein lies a problem that we

have with trying to make some of the levels of risk

assessment that we would like to make.

The second session, I dont think we

cheated a little bit, we moved the business of viral 

viral and viral cellular interactions into the second

session because this was the most complex, I think, of

the issues that we asked the workshop to address.

These represent a multiplicity of events that occur at

low frequency in cultures where the multiple viruses

are replicating at the same time, and these

interactions include recombination, reassortant,

deletion, repair, pseudo typing and transduction of

cellular DNA or cellular nucleic acids to other types

of cells by way of a virus that may incorporate this

material during this  cycle.

And, since this was a fairly extensive

topic, it occupied two independent sessions of the

meeting, and the consensus that emerged from the panel

that considered this was that these types of

interactions are quite low frequency events, and that

the type of interaction that will occur will, of

course, depend on the virus substrate combination.

Different types of viruses, whether they be a DNA

virus, or an RNA virus, combined with a particular

substrate will determine whether these types of

interactions will occur, and, in fact, at what

frequency at which they may occur.

The third consensus was that novel agents

of unpredictable pathogenicity can arise from these

types of interactions under experimental conditions.

Exactly what type of agent that might arise under

manufacturing conditions, of course, is purely

speculative at this point in time.

And then finally, the panel felt like the

primary cells, in fact, owes, perhaps, a greater risk

than tumor cells for the occurrence of these type of

events, simply because primary cells each batch is

different and each batch would have its own unique

infectious or latent agent that might be involved in

these types of interactions. Therefore, it would be

much more difficult to get a handle on that, and youd

have to try to assess that every time, with each batch

of primary cells, rather than being able to do it once

and have some assurance that you will not see the

introductions of something new by going out and

getting a whole new cell culture system.

And finally, they recognized that

unrecognized and unknown agents, perhaps, represent

the most significant concern that one has to deal with

in this type of situation, and in this regard they

sort of preempted the work of a later panel.

In session four, the task was to review

the issues associated with residual DNA of neoplastic

cells. This has been a perennial problem of tumor

cell substrates, or neoplastic cell substrates, or

cell substrates for a long time, and, in fact, the

issue has been out there and dealt with very

effectively over the years, but each time the

substrate changes some of the dynamics of residual DNA

change and they require us to be back up and take a

look at this situation again.

The consensus of the committee was that

they agreed with panel one, that the risk of

neoplastic activity with residual DNA for neoplastic

cells is minimal to none, that theres really too

little data on the possible infectivity of DNA

containing whole viral genomes to assess the risks

that might be posed by the presence of a latent virus

genome or an infectious pro virus in residual DNA,

were it to be present in sufficient length to encode

for this type of process, and finally, theres no

evidence that human endogenous viral genomes are, in

fact, infectious at this point in time.

We skipped over session five, because that

was the Thursday evening session which I referred to

earlier.

Session six, the task of section six was

to review adventitious agent contamination, and the

consensus that evolved from panel four, who was asked

to discuss this topic, was that vaccines should not

contain infectious agents, period, but adventitious

agents do pose significant challenges to the use of

neoplastic cells as vaccine substrates. Primary

cells, again, represent  they were felt to represent

a greater risk than neoplastic cells. The neoplastic

cells posed risk for the presence of unrecognized

oncogenic agents, such as endogenous retro viruses,

herpes viruses, polyoma viruses and the new class of

circo viruses.

The next consensus item was that needs to

be a rigorous search for retro virus particles, and

especially infectious retro virus in RT positive

neoplastic cells. The presence of RV like particles

were not felt to represent  to be indicative of risk,

but certainly their presence needs to be recognized,

and a variety of detection techniques were discussed,

the complexities were such that I felt it wouldnt be

appropriate to review them right now.

Then finally, and I think quite

significantly, there was a considerable discussion

about the possible presence of abnormal PrP genes, or

the creation or the development of abnormal PrP genes

in human neoplastic cells that needed to be addressed,

although at this point in time theres no data that

says abnormal PrP proteins that could be the product

of such genes would, in fact, represent any threat.

The final session was asked to consider

the development of designer cell substrates for

vaccine manufacture, both the session and the panel,

and the panel was asked to summarize the meeting.

The concept of designer cell substrates is

one that involves using defined genetic elements,

viral, oncogenes, cellular oncogenes, the induction of

telomerase activity, irradiation and various other

types of mutation events to produce a defined

neoplastic event in normal cells. And, once you have

that neoplastic event then that particular cell could

be engineered to have to express various parameters of

genetic activity that might be used to complement

viruses or to simply be used to permit viruses to be

expressed in cell lines that would be difficult to

obtain otherwise.

Under this type of situation, you would

have maximum experimental control over the development

of the cell itself, and this could, perhaps, have

substantial advantages, since the material that you

would start out with would be well known, well

characterized, and in some cases it might have been

used for vaccine production for many years. So, by

introducing this proposal, which is now a very

feasible approach to developing cell substrates, we

hope to get a nice discussion of this process going,

and, in fact, I think we did just that.

The consensus was that there are a wide

variety of ways to effect immortalization of mammalian

cells, and as I alluded to, engineering in this

fashion allows step by step control of the process.

In spite of this, careful consideration 
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