SLIDES & TRANSCRIPTS
Wednesday, February 2, 2000

Report from Working Group D
Michael Caligiuri, MD

DR. CALIGIURI: Just while we are waiting, I can start with a relatively quick summary. I can start with a general statement that our topic was immunotherapy, excluding the antibodies. I think there is an overall consensus in our group that immunotherapy is for the most part in its infancy. Several of the things that we need to really move on aggressively need to still be piloted at single institutions or institutions that choose to cooperate with one another. Because of certain beliefs and disbeliefs, several things are not yet ready for, I think, prime time cooperative group initiation.

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At the top of our agenda was Phase III studies. The thing we agreed on was that we really need to move forward with biotherapies that are currently being tested in several cooperative groups, most notably interleukin-2. CALGB already has an ongoing Phase III study with low-dose IL-2. The CCG has a study that I will call intermediate dose IL-2 where they have had about 500 patients accrued.

Apparently 200 patients have been randomized to interleukin-2, but unfortunately that trial is currently on hold because of toxicity not related to the interleukin-2. There is concern that it may in fact not move forward although that is not clear.

Steve Forman presented some very elegant data from his single institutional Phase II study of intermediate dose IL-2 from the City of Hope. Steve has moved this into the cooperative group for further Phase II piloting. Several of us questioned whether or not this needs further Phase II testing. We couldn't agree on a possible intergroup study or a randomized study that would once and for all, after 15 or 20 years of various IL-2 trials, settle the issue of whether IL-2 is a useful agent in the setting of acute myeloid leukemia. The proposed trial was first remission CR, auto BMT, and then randomize patients to no dose, low-dose IL-2 or this intermediate dose regimen. This is the clinical trial which we feel needs to be done and needs to be done in an intergroup setting and could answer very important questions for us.

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High-dose Phase II trials both institutionally, inter-institutionally and cooperatively and mini-transplants in older patients over the age of 55 in AML is something that is exciting and again, at the top of the list. The leading institutions needed to continue piloting it in AML as one knows there is a lot of pilot data in some of the chronic lymphoid and chronic myeloid diseases. But we do need more pilot data in acute myeloid leukemia.

There was also consensus that it would be useful to develop a mechanism, a Phase II randomized mechanism, for the interested institutions to start to participate in mini-transplants.

Largely there are two concerns. One is that we need many institutions to familiarize themselves with a variety of these modalities because ultimately we are going to take this to a Phase III setting. The other is that there is a serious concern, I guess a historical precedent, that once an institution becomes very comfortable with their own mechanisms and their own modality du jour, they then become very confident that it is the way to pursue things, and then the cooperation in terms of proceeding with randomization begins to get slowed down.

There was a sense that we really need at this point a randomized Phase II and a mechanism to support that, be it the existing cooperative oncology groups or the cooperative BMT group which I guess currently exists on paper, or RFAs that are needed. So, mini-transplants are very high on the list.

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Donor lymphocyte infusion (I guess now we are proceeding down to things that are more experimental) is extremely interesting. Obviously we have the GVL effect, and so we are looking to capitalize on really understanding this.

Any comments I make clinically need to be supported by an equal or greater effort at the basic science level.

Relapsed AML post-allo-BMT is the setting that this should be pursued. It is, as I said, in early development. There is variability in the clinical presentation and so again single institutions need to gain more and more experience in using donor lymphocyte infusions in the setting of AML.

How does one treat relapsed leukemic patients within 6 months post-transplant? What induction regimen can be used prior to donor lymphocyte infusions different from the types of induction regimens that could be used say if someone relapsed a year after transplant?

So, we need larger numbers of patients. We need more experience about how to proceed in this new but exciting field and those interested should be supported. We need to get together two or three institutions that could say, "Look, you know, last year we saw four or five relapsed, post-allo relapsed AMLs, and we would be very interested in participating in this.i Is there a way the NCI can support a small consortium of investigators to gain further experience in this? This is where we need to go.

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More basic research on understanding the GVL effect, that is to say, more research on understanding what are the target antigens that are being recognized? When do we see this having an effect? What is the nature of the immunogenicity when we do see this working? And, what is the nature of anergy, induction of tolerance, and resistance to apoptosis and when we don't see this working?

All of these things need to be pursued in our individual laboratories or for clinical investigators with your basic science colleagues.

One of the things we all recognize; we keep saying over and over again, is AML is a heterogeneous group of diseases. It is very likely that all of these mechanisms or some of these mechanisms are important in AML subgroups. It is already clear that certain translocations do in fact alter one's immunogenicity. I think that we have taken a healthy skepticism about approaching this globally, and we need to be looking at various subsets of AMLs for how they set up their decoys and how others are immunogenic.

Animal model work. We all know John Dick has some very elegant SCID human mouse models. It would be very nice if this could be used and set up in several institutions, obviously to exploit some of these questions. Once we determine how cells are resistant, say, to apoptosis, we need to then look at interventions that would alter that resistance. And then, we need to determine if altering that resistance to apoptosis actually translates into an effective cytolytic response. Clearly one wants to do that in something like the SCID-hu model before one considers moving into the clinical trial. There is some interest on combining some of the DLI with biologics, again, trying to overcome resistance to apoptosis and induction of anergy.

So, for example, interleukin-2 is known to reverse the anergic state and different cytokines and other biologics can be combined with this.

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The engineered cellular therapies are very early in development but again extremely exciting. The T cell work we heard about from Stan Riddell and other work such as pulsed dendritic cells, that is dendritic cells pulsed with peptides and then differentiating AML blasts which themselves may serve as antigen-presenting cells, are exciting early observations. They need to be followed up in single institutions.

The T cell story has been very useful for validating the relevance of target antigens. That is to say, one can pursue discovery and recognition, but obviously one can develop clones and put them into patients and actually measure biologic responses in vivo. We can then begin to understand what are the key targets in vivo and what is going on is very exciting. So, we need more basic work, more investigators interested in pursuing this, and obviously the funding mechanism to do this.

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Getting away from the cellular and more into the vaccination approaches, again there is a variety of antigens which people are pursuing quite aggressively at institutions that look very promising. Within several years, these should be ready for more of a cooperative group setting.

Those include the minor antigens that we have heard about, differentiation, things like WT1, gene fusions like AML-1 ETO, oncogenes such as ras, overexpressed associated antigens, proteases that we heard about, for example. All of these are interesting, are being pursued in the peptide or protein fashion with or without dendritic cells.

Most of the data are early. There is limited evidence of clinical response yet. So, as we will see in the next slide, we will have to work a little bit more on understanding the mechanisms. Those of you who were in the immunotherapy group heard about Glen Dranoff's trial, actually just starting, where he has got adenoviral vectors that express GM-CSF successfully into AML blasts. He irradiates those AML blasts and then is pursuing a vaccination strategy with those. So, there is a lot of excitement and enthusiasm about pursuing this approach.

In terms of funding mechanisms that might be useful, there is a lot of interest in seeing support for vaccination strategies in hematologic malignancy in general, correlated with a real pursuit of understanding how these vaccines may or may not work.

How do we enhance vaccination? I think few of us are seeing in cancer in general outstanding responses to the current preparations. So, we need to work more on how to enhance this process, elucidating what the relevant antigens are and understanding the process of immune reconstitution following first remission CR, allo and autotransplant in order to know when best to try to exploit various immune parameters.

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I will end with the impediments. It is really establishing among the investigators criteria for surrogate marker endpoints in order to facilitate completion of these trials. Can we as a group of investigators really decide on a series of surrogate markers that we will all accept?

I think I will end there.

Are there questions or comments?

DR. LARSON: Thanks, Mike.

Are there questions or comments either for Michael or for any of the other presenters?

Any final comments from members of the Committee?

Otherwise, I think we will draw this symposium to a close. It has been a very full day and one-half. I hope it has been fun for you, and we look forward to seeing you again at another meeting.

(Thereupon, at 11:25 a.m., the meeting was adjourned.)

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