SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Working Group B: Immunotherapeutic Approaches: Antibodies and Vaccines

Deborah Thomas, M.D.
John Leonard, M.D.

DR. LEONARD: I am, in the interests of time, going to summarize for both of us, but Deb will jump in if I botch things up, which is likely.

So, our group looked at a couple of different questions relating to antibody therapies for lymphoma, and I will cover kind of our thoughts in this regard.

The first was what monoclonal antibodies to study, and we kind of went through a list of a number of different agents that are either in the clinic or in preclinical studies, and there are a number of potential candidates.

I think one of the issues is sorting out which agents are most promising, and should we devote resources to study.

The second big question is, are preclinical studies needed and, if so, what preclinical studies will be most helpful in sorting out the value of an antibody and/or its target.

The third big picture question that we tried to address was how best to utilize antibodies, either as single agents, in combination with chemotherapy and the minimal residual disease situation, or what sorts of scenario would be best to employ these agents.

Then, finally, some of the correlative studies that could be helpful in sorting out all of these issues.

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So, to summarize our thoughts in this regard, we went through and discussed a number of different interesting targets.

In looking through unlabeled antibodies, immunotoxins and radioimmunoconjugates, to a lesser degree, we felt that the three most interesting targets at this point are ASCD20 using Rituximab, given the safety profile, and Rituximab is already in the clinic in a number of B cell disorders.

Campath also was of interest to the group, and it is in trials in minimal residual disease, and we were enthusiastic about pursuing that agent further.

Epratuzumab, which is a humanized anti-CD22 antibody, which has activity in adult follicular lymphomas and diffuse large cell lymphoma, given the nice safety profile of this agent, as well as the wide expression of CD22, the group was interested in pursuing that agent as well at this point.

We talked about some other antibodies and, in particular, a number of different immunotoxins. The issue with immunotoxins include availability, increased toxicity, production issues which relate to availability and purity and such.
In the end of the day, I think that we were a little bit less enthusiastic, particularly in being able to use these in combination. I think they still warrant some promise at this point in time.

TOP

The second question that came up as far as preclinical studies and correlative work relate to the need for data on target expression in ALL.

It became clear that there is a lot of data out there as to what antigens are expressed in the various ALL tumor types, but we have relatively little solid data, it seems, on antigen density and molecules per cell and rates of positivity among patients.

The important question of, does the level of antigen expression correlate with activity, and while high expressing patients may respond to an agent, it is certainly possible that patients or tumors with lower levels of expression but still some expression there could also have clinical responses.

So, we felt that there is a need to get more information in this regard, using relatively standard techniques, given the potential of variation between techniques and institutions, and that this would be useful to have, and perhaps larger centers and cooperative groups could help with this, both to demonstrate the potential feasibility of targets for antibodies, as well as part of clinical trials to correlate expression patterns without common responses to the treatment.

TOP

As a third issue, we talked a little bit about preclinical data. I think the bottom line is that, given the limited evidence of knowing what the dominant mechanism of action is for most antibodies, while they have a number of potential mechanisms, what is the true mechanism of action in the patient?

We really don't know. So, we thought that basically preclinical data is of limited benefit at this point in time.

We didn't feel that using it to decide whether or not to pursue an antibody in the clinic, that that was probably not the best use of preclinical data, but perhaps to get more information on mechanism of action, as well as to help to get some preliminary information on potential combination regimens, whether with other antibodies, chemotherapy or other agents.

Although we would obviously like to see some evidence of some, at least, rationale for using an agent before it is in the clinic, we didn't want to throw things out based on preclinical data.

The other kind of side point was the issue of Fc receptor polymorphisms as correlative studies. Fc receptor polymorphisms have been shown to be, and appear to be, important as markers for improved ADCC in correlation with outcomes to Rituximab in reticular lymphoma, and we felt these studies should also be pursued as part of any studies in ALL employing monoclonal antibodies.

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Finally, the last kind of big question was really, what is the optimal setting for immunotherapy. That question is obviously still out and there are a number of different clinical trial designs that are employed and one could conceive of.

We felt that single agent activity was unlikely in many cases, just because of the proliferation rate of the disease, and it may be disappointing if you just tossed in an antibody at a rapidly progressing disease, giving the time to response to antibodies and so on.

While this is important information to gather, it shouldn't be the make or break decision as to whether or not to pursue an antibody.

There are really two approaches that appear to hold more promise as far as improving outcome. One would be combination therapy such as concurrent with chemotherapy, as is being done, say, with Rituximab and some of the B cell lymphomas, or a sequential strategy that has been used in some settings.

This has the added benefit of being able to use minimal residual disease as a study end point, because you can have patients in after therapy, in remission, monitor effects on minimal residual disease, and be able to potentially use that to note a therapeutic effect, assuming that MRD correlates with outcome, as we have heard today. At that point, I think that summarizes the main issues we covered. Any questions or other points?

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