What is GVAX? How is GVAX being used in myeloma?

What is GVax? How is GVax being used in myeloma? So there are many different types of vaccine approaches in cancer in general and certainly in myeloma. The GVax approach, so in general, the concept of GVax stands for anything that's GM-CSF based. So GM-CSF is an acronym for a protein called granulocyte macrophage colony stimulating factor. Very complicated, GM-CSF or GVax is a lot easier. What was shown, again, experiments done in the 90s, is a concept is that there are tumors that are inherently immunogenic and there are tumors that are inherently non-immunogenic. So for example, the definition of an immunogenic tumor experimentally is that if I take a cancer cell and I irradiate it and I inject it in a mouse and leave it there for two or three weeks, and then I inject the mouse with the live tumor, will that tumor be rejected or not be rejected? If the tumor will be rejected, then that cancer is immunogenic and if it won't be rejected, it's not immunogenic. And so it turns out that if you take all cancers, the vast majority of them are not immunogenic. But if we're going to generate immunotherapy, we have to take the bulk of these tumors which are not immunogenic and make them immunogenic. And so experiments that were done both here at Hopkins as well as at Dana-Farber simultaneously, what they did is they took tumor cells and they put in a whole bunch of immune regulatory proteins. I mean, each cell had just one protein, but there were about 10 or 15 of them. And they asked this question, if we now take these non-immunogenic tumors and we put in these proteins, and again, irradiate the tumor, inject it in the mouse, wait two or three weeks so that the mouse can generate an immune response, and then challenge the mouse with the live tumor, which one will actually work? And it turned out, surprisingly, that the one that worked the best were the tumors that had GMCSF, this protein that I mentioned to you, injected in there. So that sort of opened up the whole field of GVACS. And there were a lot of clinical studies that were done. So GVACS again is any tumor vaccine that uses GMCSF as the adjuvant, as the immune stimulator to generate the response. So the approach in myeloma that we're using with GVACS is a very different approach than has been used with a variety of other tumors. So the first GVACS trials took tumor from the patient. And so the first trials were done in kidney cancer. So patients that had kidney cancer were going to the operating room, the tumor was being removed, it was being minced and separated out into single cells, and then the individual cancer cells were modified to express this protein, GMCSF, and then those cancer cells that had GMCSF in it were irradiated and injected into the patient then and to generate an immune response. But that's very labor intensive, and obviously you have to be there and you can understand the complexities of all of that. And so then the next generation said, well, we're not sure that we actually need what we call autologous tumor, tumor from the patient themselves. What if we use what we call allogeneic tumors? So the concept is that if we take 50 patients with kidney cancer, there are certain proteins that are unique to that individual patient, but the vast majority of the proteins are in common to all patients that have kidney cancer, right? So those are, the term we use are commonly shared antigens. So the vast majority of any tumor, kidney cancer in the case of the first trials, myeloma in the case of what we're interested in, have shared antigens that are commonly shared amongst everybody with myeloma, and then they have unique antigens. And so then there was this big debate in the field that, you know, the best vaccine is going to be the vaccine that generates immunity towards the vast majority of antigens, of proteins. But again, the complexity of getting these cells is significant. So, you know, one approach that we took, as well as a lot of other people, both here and other places said, you know, we recognize that a vaccine made of the patient's own tumor is a lot better than a vaccine made from other people. But we also recognize that the ability to generate that kind of a vaccine is significantly complex and limited. So we're going to say it's much better to give a vaccine that's maybe 60% efficient to 100% of the patients than to give a vaccine that's 100% efficient to 10% of the patients. And so we wanted to take advantage of these commonly shared antigens. And so what we did for myeloma GVACs is we picked two myeloma cell lines that we bought that were chosen because they have unique features that are generally found on high-risk aggressive myeloma. And so the idea was that if we give this vaccine to general myeloma patients, we would potentially see a few things. One is that if a patient already has that cancer, that myeloma that has those high-risk proteins, we could further, you know, increase immune response against those proteins and hopefully be effective. But alternatively, if we take somebody that has low-risk disease, that has never developed, doesn't have those mutations, and we immunize against them, we can prevent them from ultimately going on to develop that. And we did this back in 2005. And at the time, this concept of clonal evolution was not as well developed as it is now. But the concept of clonal evolution was something that has been shown by a variety of groups of people in myeloma that basically, as patients relapse, their myeloma varies. So if we want to call the initial disease clone A, then it goes to B, C, D, E, F, G. And every one of them is acquiring new different genetic hits. And as one can imagine, with subsequent relapses, these cells become much more aggressive. And so the likelihood of mounting an immune response at stage A to proteins that you'll eventually have when you get to stage F is virtually impossible. But if we come in with a vaccine that represents the stage F tumor and give it to patients at stage A, B, or C, we can hopefully prevent them from ever getting to stage F and therefore significantly altering the course of the disease. So that was the first thing that we did is we took cell lines that had these high risk features and we grew them in a way that they could be grown and be given safely to patients. The second thing that we said and did is generated from work that I did as a fellow. And we said, we know that we need GMCSF to generate this vaccine. But we also proved that the GMCSF does not need to be in the cell that we're trying to immunize against. So in other words, in the case of a myeloma vaccine, the GMCSF doesn't have to be made by the myeloma cell. It just has to be made by a cell that's in that environment. And so what I made was I took another cell and we put GMCSF into that cell that we call a bystander cell. So this was a cell that grows in suspension just like myeloma cells and it can grow easily. And we can basically take that cell, this bystander cell and add it to whatever vaccine we want. So theoretically, this bystander cell could be used for anything. It could be used in myeloma, leukemia, lung cancer, prostate cancer, whatever. So that significantly simplified the manufacturing aspect of it. But the second thing that it did, which at the time, again, we didn't know, but ended up being very important, is that like with many biological things, the amount of GMCSF that is required in a vaccine is finite. And we were able to show in mouse models that if we had a vaccine where we gave the bystander cell that had subtherapeutic levels of GMCSF, we were not able to generate an immune response. If we had the therapeutic levels of GMCSF, we were able to generate an immune response. And if we had very high levels of GMCSF, we were not able to generate an immune response. So this was the first example that actually showed, and this ends up being true, I think, with a lot of biological phenomenon, that unlike the way we like to think of in the West where more is better, the more money you have, the happier you are, the reality is that there's probably a sweet spot, right? You can have too much money and you can have not enough money. And the same thing is true with GMCSF. You can have not enough GMCSF and you can have too much GMCSF. So by knowing this, we also know that to make the ideal vaccine, we want the right amount of myeloma cells in there, and we want the right amount of GMCSF. And the only way that we can actually achieve this right balance is by having the source of GMCSF being independent of the source of the myeloma proteins or myeloma cells that are actually there. And so we can alter these ratios to make sure that we're maximizing the amount of myeloma that's there and giving just enough of this GMCSF to generate a therapeutic dose of it, but not too much of it. So that is what we've done with myeloma GVACs. It's made up of three cell lines. Two of them are myeloma cell lines that are not modified. The third line is this GMCSF bystander cell line. And that ratio is put together in a way that we've optimized to be able to hopefully generate the best immune response.