BiovaxID: An Interview with Dr. Eduardo M. Sotomayor (Part 4 of a series)

For this next installment in my ongoing series,"BiovaxID: On the Trail of the Lymphoma Vaccine," I interviewed one of the world's leading authorities on lymphoma, Dr. Eduardo M. Sotomayor.

Dr. Sotomayor serves as Chair of the Department of Malignant Hematology and holds the Susan and John Sykes Endowed Chair in Hematologic Malignancies at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.

In addition to numerous awards and research grants, Dr. Sotomayor is a member of the Lymphoma Research Foundation's Mantle Cell Lymphoma Consortium, and he was most recently named to Biovest's Scientific Advisory Board.

Dr. Sotomayor served as one of the principal investigators in the Phase III clinical trial evaluating BiovaxID in the consolidation setting against follicular lymphoma and co-authored the ensuing paper in the Journal of Clinical Oncology ¹.

We discussed BiovaxID, the response to the vaccine by regulatory agencies in Europe and the US, as well as a similar lymphoma vaccine under development at Moffitt, and the mystery that is mantle cell lymphoma, among other things.

The Interview

Ross Bonander: Were you surprised when the FDA requested a second Phase III trial for BiovaxID?

Sotomayor: Yes. But you have to look at the history of this vaccine. The trial began in 2000. That was really before the widespread use of rituximab. Most of the patients in the trial received PACE chemotherapy. After ritiximab became common practice we had to modify the trial to allow patients to be treated with chemotherapy that included rituximab.

So one of the questions the FDA had was, 'This trial began before rituximab, how can you apply trial results to the current practice?'

[NB: I had never heard of the PACE regimen before. PACE is doxorubicin (Adriamycin®), cyclophosphamide, etopiside and prednisone]

RB: Will participants in the second trial be pre-treated with R-CHOP?

We haven't decided that. Already things have changed. For patients with FL we now have bendamustine and rituximab, CHOP plus rituximab, so I imagine it will probably be something like 'chemotherapy plus rituximab' followed by the vaccine.

RB: Rituximab depletes a person's B-cells. How is it that BiovaxID can be effective in a patient who is immunosuppressed on account of rituximab?

That was the big question that everybody was concerned about. Then there came the study by Larry Kwak in 2005 [2] that showed that you can deplete the B-cells and still get a very good T-cell mediated response. The B-cells aren't needed to produce antibodies. As long as the T-cells are there, they can do the job. This has since been proven by several other groups.

RB: Compared to rituximab, which has a laundry list of potential side effects, the BiovaxID safety profile is amazing.

This is true for all vaccines in development. The worst you might get is a skin reaction.

RB: You mean all vaccines, or all therapeutic vaccines?

Therapeutic. There is only one currently approved by the FDA—Provenge, by Dendreon for prostate cancer. It is different from BiovaxID in terms of composition, but the underlying hypothesis and mechanism is the same: With all therapeutic vaccines you are trying to activate the immune system.

RB: And that's sort of a main problem in cancer, that the immune system doesn't recognize a cancer cell as something to attack?

Well several studies show that the immune system does respond but the response isn't strong enough. Or that the tumor cell puts up firewalls or fences. If you look for a T-cell response in a cancer patient, it is there—it's just paralyzed. It's what we call tolerance. What we are trying to do with vaccines is to wake up the T cells.

RB: To train them the way they're trained by any other vaccine.

That's right.

RB: The market approval process for BiovaxID is moving much more smoothly in Canada and Europe than in the US.

They're all very independent. They may look to each other, but they act very independently. For instance when we went to Europe, the EMA [the European equivalent of the FDA] was extremely impressed with the hematological response [from BiovaxID]. They were also very intrigued by the [Phase II] mantle cell lymphoma data, but the problem is that that was a small study.

The FDA was very excited about the data for BiovaxID against follicular lymphoma and mantle cell lymphoma as well, but, again, they all act very independently.

RB: Is there a phase III trial in the works for BiovaxID against mantle cell lymphoma?

Well, our group here at Moffitt is very excited about this, we have many mantle cell lymphoma patients but the problem is the funding. Ideally, the FDA would have granted Biovest conditional approval for BiovaxID, which would have attracted investors, which helps to pay for the trial. It's sort of a catch-22: do this clinical trial and we'll approve it,' but without that conditional approval where do you get the funding?

At Moffitt we have our own lymphoma vaccine as well. Not BiovaxID but very, very similar.

RB: I don't understand mantle cell lymphoma. I remember just a couple years ago it was called an indolent lymphoma. Now it's aggressive.

Initially, mantle cell lymphoma was believed to be indolent. But then it was found that most mantle cell lymphoma patients had aggressive disease that needed to be treated. So now we know that it is very heterogeneous. A percentage of patients will present with very aggressive disease, and following initial treatment and remission, will need a [stem cell] transplant. Meanwhile 20 percent of mantle cell lymphoma patients have indolent disease.

RB: Are there any sort of biomarkers to tell you who's who?

That's what we are looking for. Everybody's looking for biomarkers. We see a lot of mantle cell lymphoma patients and what we do is, if the patient is coming in with a little amount of disease, feeling well, then we just follow those patients. Our data shows that if the patient does not receive treatment within one year after diagnosis and is still doing well, it's very likely an indolent lymphoma.

We are learning more and more about this disease all the time. The patients we have treated with the [Moffitt] vaccine, they have aggressive disease. And they are still alive. Again, our vaccine is a little different from BiovaxID but the results are very similar.

RB: That kind of success is what you've also seen with BiovaxID, is that right?

Yes, with BiovaxID in mantle cell lymphoma patients, after an 11 year follow-up 90 percent are still alive, seen now in two independent studies—one with BiovaxID and one with the [Moffitt] vaccine. Now, after receiving the vaccine the disease does come back, so we watch these patients and re-treat them when needed. But overall, for reasons we don't completely understand yet, these patients are living longer.

These are the results that regulators in both Europe and the US are excited about. So if you asked me 'Does the vaccine work?' the answer is yes, the vaccine works.

But if you ask a biostatistician, 'Does the vaccine work?' he would say well according to the available data the answer would be yes, but the available data doesn't represent enough people yet to say definitely yes. Biologically it makes sense, but when it comes to regulators like the FDA, they look at all the biostatistics.

RB: Recently I wrote about the FDA's cancer drug approval record, which is all over the map regarding clinical trial design and end points, but constant in terms of meeting an unmet need. Where does BiovaxID fit in that context?

Well so, what consolidation treatments do we have, we have rituximab maintenance every three months but there are side effects associated with that. But there was clinical trial data introduced at ASH last year [the annual meeting of the American Society of Hematology] that indicated rituximab maintenance was no better than observation. So there is a window there for other consolidation treatments. BiovaxID is certainly one of them, especially with the relative absence of side effects. The question the FDA was asking was, in the BiovaxID phase III trial you have them receiving chemotherapy then the vaccine, if they receive chemotherapy and rituximab, how do you know the vaccine is going to improve the response?

RB: But patients on rituximab maintenance are immunosuppressed, they have to receive an infusion every few months for two years and there may be complications there, they can't be vaccinated against the flu--

They are susceptible to infections, yes. And in about one percent of those patients they can develop a serious neurological disorder called progressive multifocal leukoencephalopathy (PML) that mimics Alzheimer's and generally ends in death.

[NB: PML is a brain virus that most people carry but that rarely ever causes any problems, except in patients with weakened immune systems.]

RB: Tumor lysis syndrome is also a possible side effect of rituximab, correct? If rituximab causes the cancer cells to die and their contents spill into the bloodstream, why doesn't the same thing happen in a therapeutic vaccine? What is a T-cell doing to kill a cell that rituximab isn't?

Well, no, the reason we don't see tumor lysis syndrome in these vaccines is because when we use a vaccine, the patient's tumor has already been [largely] eliminated. They will have had a complete response to induction therapy and there is no evidence of disease, but likely some microscopic evidence somewhere in the body. That is where the vaccine comes in.

RB: So if a patient had a bulky mass—

If there's a bulky mass there, the vaccine won't work. No vaccine will work against that. If you have a patient with a lot of disease, you need to use chemotherapy and radiation to reduce the tumor burden. Then you can use the vaccine. When you have a lot of disease and you kill those cells rapidly, then you see tumor lysis syndrome.

The potential problems of rituximab maintenance though, like requiring infusions and lengthy doctor visits and other side effects, compared to a simple, quick vaccine shot every couple months, these things seem to me that these are quality of life issues. Does the FDA not acknowledge this benefit?

They do. They understand that. The sticking point for them remains what we talked about at the beginning—can the data on BiovaxID be applied to patients receiving rituximab. It all comes back to that.

RB: If the first phase III trial for BiovaxID against follicular lymphoma took several years from beginning to end, it seems like another phase III trial would take just as long—I mean they have to recruit et cetera—meaning FDA approval is several years away.

Not necessarily, especially if it is conducted against mantle cell lymphoma. But also remember, ten years ago the technology to create this vaccine was comparatively primitive. It's much, much improved upon, much faster, so that aspect will not take remotely as long. Additionally, ten years ago, there were not many people interested in these vaccines. Now, there is a lot of interest, meaning it is likely many more patients will be interested in participating.

RB: Where does something like BiovaxID fit in among the many therapeutic cancer vaccines said to be in the pipeline?

Follicular lymphoma and mantle cell lymphoma, those are going to be the big markets for approval. But then once a vaccine is approved, as a lymphoma doctor if I have a patient with another type of lymphoma I would try to get approval to try the vaccine in that patient. That's what we did with rituximab; it was initially approved only for follicular lymphoma, but we were trying it against any subtype—mantle cell, chronic lymphocytic lymphoma—and the same would probably hold for an approved lymphoma vaccine. Doctors will seek approval to use it on a case by case basis. You still need the collective data of a trial for broader approval, but the groundwork is there to justify it.

END NOTES

1. Schuster SJ et al. Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma. J Clin Oncol 29:2787-2794.
2. Neelapu SS, Kwak LW et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005 Sep;11(9):986-91.

BiovaxID: On the Trail of the Lymphoma Vaccine

Follow the links below to read the rest of this series:

• Part One
• Part Two
• Part Three