How Cancer Vaccines Can Educate an Immune Response in Advanced Cancer Patients

Pharmacy Times® interviewed Jeremy Graff, chief scientific officer at IMV, on the development of a unique cancer vaccine delivery system and the results to date of ongoing clinical trials assessing the vaccine delivery system’s efficacy and safety.

Pharmacy Times®: Why is the delivery system for cancer vaccines such an important element of making these vaccines clinically viable?

Jeremy Graff: I think the delivery systems are so important because the way we feed information into the immune system, the way the immune system consumes that information and traffics that information is critically important. The way that, historically, for cancer vaccines anyway, that we fed information into the immune system really has been insufficient. I think that's part and parcel to why, historically, cancer vaccines have not been very effective at generating appropriate immune responses and clinical benefit.

By contrast, the DPX technology delivers information in a way that mirrors the natural flow of antigens. It's picked up almost exclusively by antigen presenting cells. It's trafficked to the lymph nodes, and it's there, as would naturally be the case that the immune response is triggered.

Pharmacy Times®: What is this cancer vaccine delivery system, and what makes it different?

Jeremy Graff: The DPX technology is a unique delivery system, because it really incorporates a variety of different cargo, and it allows us to administer that by a simple subcutaneous injection, effectively once every 2 months, because it's enmeshed in oil; it's not an emulsion, and it's not an aqueous-based formulation—it's really an oil-based solution.

As a consequence, it stays at the site of injection and can only be taken away by the action of the phagocytes of the immune system, again, most notably, the antigen presenting cells, the macrophages, and dendritic cells.

Pharmacy Times®: What are some of the disease targets under investigation for this vaccine delivery system?

Jeremy Graff: For our lead product, maveropepimut-S, we're designing an immune response to the cancer associated protein survivin. Survivin is very commonly up regulated in a wide array of cancers, most notably diffuse large B cell lymphoma, ovarian cancers, and many others. Our clinical history has been richest in the ovarian cancer space, and so we have a phase 2B study that we call AVALON that is ongoing for maveropepimut-S in ovarian cancer patients alongside intermittent low dose cyclophosphamide.

We also have, as our most advanced clinical opportunity, the relapsed refractory diffuse large B cell lymphoma space, and here we're combining our drug maveropepimut-S with pembrolizumab, the checkpoint inhibitor, and low dose intermittent cyclophosphamide.

We have clinical benefit evident in a variety of other cancers as well, and I think most notably, metastatic bladder cancer. We talked about that this past spring at the annual American Association for Cancer Research Conference in April.

Pharmacy Times®: What have clinical trial results shown to date in regard to efficacy and safety?

Jeremy Graff: To date, our clinical history is comprised of more than 300 patients worth of history. What we've seen across multiple indications is deep and prolonged responses by resist, so partial responses, complete responses in long term stable disease. We've seen this in human malignancies like diffuse large B cell lymphoma, we've seen it in metastatic bladder cancer, we've seen it in ovarian cancer, we've seen it in other histologies as well.

The beauty of the therapy given once every 2 months is that it really is very well tolerated. It's a subcutaneous injection, so it can be administered in an outpatient setting, which gives it an advantage. It is, as I said, every 60 days and we alternate thighs. The only safety issue we have is a minimal safety issue grade 1 and 2 injection site reactions, and so by alternating the thighs for each successive dose, we minimize that injection site aggravation.

So it's very well tolerated, and we think, on balance, very effective. It gives opportunities for patients who are otherwise already tortured by the carousel of chemo poisons to actually realize benefit without the downside that we typically associate with cancer therapy.

Pharmacy Times®: Following the quick development of vaccines for COVID-19, why might the development of viable cancer vaccines be a bit more slow-going in comparison, outside of the speed accomplished through FDA’s accelerated approval pathways?

Jeremy Graff: The cancer vaccines are themselves a different type of vaccine than those developed for infectious disease. For infectious disease, we're generally developing what we call prophylactic vaccines. So what we mean by that is these are vaccines designed to educate an immune response so that you can build preexisting immunity before you become afflicted with the pathogen, before you become infected, so that you can eradicate that infection very quickly.

Cancer vaccines, by and large, are different—they’re therapeutic vaccines. They're administered to patients who are already afflicted with the disease. So it operates in a bit of a different way. When we think about cancer vaccines in general. We think about working to inspire or reawaken an immune response to cancer antigens, in many cases because cancer arises from self from our own cells. Cancers are not as well recognized and are therefore not as effectively eradicated by the immune system. So we have that hurdle to overcome.

Then developmentally, we have the hurdle that we often start in advanced cancer patients. We do this for many cancer therapies because that's where we get the best sense for the safety versus efficacy balance that we need. But unfortunately, in our advanced cancer patient populations, they've already been subjected to many, many different therapeutics, chemotherapeutics, radiotherapeutics, some targeted therapeutics, which really can devastate the normal functionality of the immune system. As a consequence, our advanced cancer patients are often left with a less than functional immune response. So trying to educate an immune response in those patients with a cancer vaccine becomes doubly difficult. We're really working upstream against a situation where the patient's immune system is already compromised.

Pharmacy Times®: To date, which disease states have the most promising results that might point to an FDA-approval being more likely on the horizon?

Jeremy Graff: So for us with our DPX technology, and more specifically with our lead DPX product, maveropepimut-S, I think we've gotten data that's very promising in those 3 indications I mentioned before, relapsed refractory diffuse large B cell lymphoma, that data has been driven by our combination with Merck’s pembrolizumab and low dose intermittent cyclophosphamide.

Similarly, with the same combination, we've had really promising data in metastatic bladder cancer patients, patients who had already progressed through checkpoint inhibitor therapy, were given our therapy in combination with pembrolizumab and low dose cyclophosphamide, and we were able to reawaken a very profound immune response and, in some of our patients, that led to a very durable, complete response. That's really remarkable in that setting.

Then lastly, where we have our greatest depth in clinical treatment is the advanced ovarian cancer space, and here it's a bit different. Ovarian cancer has been a tough cancer for immunotherapies to get a toehold in. Ovarian cancer has really been refractory to most of the checkpoint inhibitor therapies. But in our treatment history with advanced ovarian cancer, we really see profound efficacy in terms of long-term partial responses as well as long term stable disease. In that setting, we're only combining maveropepimut-S with low dose intermittent cyclophosphamide. So we're really excited about the broad applicability of maveropepimut-S, as well as its safety profile. Those 2 things give us kind of equal enthusiasm, that we're really providing a groundbreaking therapeutic option for a variety of cancer patients.

Pharmacy Times®: What are your predictions for the future of cancer vaccines and cancer vaccine research?

Jeremy Graff: I think cancer vaccines and cancer vaccine research really benefit greatly from the dawn of immunotherapeutics. Things that we've seen in the past 15 years erupt and really change the course of cancer therapy—what I mean by that are the immune checkpoint inhibitors, primarily we've recognized through the use of those immune checkpoint inhibitors, what types of approaches work best to activate an immune response, a response that’s robust enough response, persistent enough to eradicate disease. I'm excited about cancer vaccines as an approach primarily because I really do think leveraging the power of the immune system to eradicate metastatic disseminated disease is our very best approach. That is, after all, the way our immune system is built.

It will ultimately seek out and destroy cancer cells if we give the appropriate education to the immune system to do that where cancer vaccines failed in the past. I think it's because we didn't know enough about how to leverage the different functionalities of the immune system. Where I'm excited about our technology with DPX and with our lead DPX asset maveropepimut-S is that we are able for the first time in a single formulation, this oil-based solution that we discussed earlier, to add to that therapeutic, not only the specific antigenic instruction that we need in the case of relief product, antigens to the survivin protein, but also components that activate a very specific response from the myeloid cells from the innate immune side of the equation, a really robust immune response to anything, whether it's cancer, or whether it's pathogens, requires both arms of the immune system, and historically, our cancer vaccine approaches, and even many of our early immunotherapeutic approaches have really been very biased to the adaptive arm of the immune system and to T cell-based response.

But T cell-based responses don't really generate robustly and don't persist without the help of the innate immune system without the help of the antigen presenting cells and other myeloid cells that kickstart any immune response. So with our DPX technology in a single formulation, we're able to add those antigens for a T cell response. We're able to add the innate immune activators, very specific innate immune activators, into that program, so that as our product is consumed by antigen presenting cells and macrophages you instigate the maturation of those cells, they're better at presenting those survivin antigens to T cells to activate a more robust T cell response.

Prior cancer vaccines, really just administer the antigens without the costimulatory instruction that we think we really need to drive a robust response. Now that we're seeing defined clinical benefit, and we're seeing it in more than one therapeutic opportunity. By that I mean, in ovarian cancer in a malignancy, like DLBCL, and bladder cancer and some others, I'm fairly confident that we have an opportunity here to break open the cancer vaccine space in a way that we've not seen in the past. And largely that's on the backs of our ability to understand and leverage what we need to do to drive an immune response that's robust and persistent, that we need to activate both arms of the immune system to make this a reality. And I think we're on the cusp of being able to do that.

So I would imagine cancer vaccine research in the future looks to incorporate these multiple, multiple components like we can and like we do in DPX. I would also imagine that those cancer vaccines now look to incorporate antigens to many different potential cancer associated proteins, or neoantigens. So we're going to see and DPX allows for this itself, that we can combine a surviving group of antigens with antigens to a mutant RAS protein and p53. Two things that represent other genetic anomalies like translocations that are unique to those cancer cells so that we're not only fighting the battle to instigate an immune response to a protein that that maybe through development we've, we've gotten an intolerance to, but we're able to instigate a robust immune response to the new proteins that erupt on the backside of the epigenetic and genetic chaos that many cancers display.

So I'm excited for the cancer vaccine space because there is an incredible amount of potential here now that we can start to unlock the keys to a robust and persistent immune response. If we look forward, even to the prior question, about infectious disease vaccines versus cancer vaccines, and more broadly, prophylactic versus therapeutic vaccines—it's not difficult to imagine a day in the near future where we're prophylactically able to give folks a vaccine against cancers that they might be particularly susceptible to based upon their unique genetics. So patients that have particular genetic syndromes, we could vaccinate in a prophylactic way to ensure that as their precancerous and cancerous lesions erupt because of their genetics, they get eliminated immediately by an already existent immune response. So I think there's an enormous potential in this field.