What work are you leading at Mendus?
We are focused on targeting tumor recurrence by developing therapies that enable the immune system to build up active immunity against residual cancer cells. Active immunity is the only long-lasting form of immunity and therefore has the potential to reduce tumor recurrence and improve long-term survival following first-line treatment.
Our lead product vididencel comprises irradiated leukemic-derived dendritic cells derived from a proprietary cell line, and upon intradermal injection, it is phagocytosed by antigen-presenting cells present in the skin and subsequently triggers broad immune responses against the tumor antigens carried by vididencel. The full spectrum of known and unknown tumor-associated antigens is presented to the immune system, which we’ve shown creates very broad immune responses that are tumor-directed.
"I think that we will start to see a revolution in trying to prevent tumor recurrence, helped by trials that are more elegantly designed and ways of measuring the disease that pick up efficacy signals earlier and more effectively."
What’s driving your focus on tumor recurrence versus other parts of the cancer cycle?
While ICIs like pembrolizumab have been very successful, the industry has been stuck since then on raising the bar for patients. Therefore, we decided to position our product to focus on tumors that are not responding to checkpoint inhibitors, including blood cancers and the solid tumor indication of ovarian cancer.
There is a lot of focus on individual, personalized mutations in cancers, but when you go further back in the history of cancer immunotherapy, there are tons of antigens that have been described in great detail and that are expressed by many different tumors. WT1 is the number-one ranking antigen, but there are many other antigens that have been well-documented to be present in very different tumor types. The leukemic cells we use as the basis of our product may therefore trigger immune responses that are also relevant for other tumors.
Why is tumor recurrence so deadly for patients?
It’s very difficult to get rid of all cancer cells after a primary tumor is established. You can get rid of the bulk of the tumor with methods like surgery, irradiation, and chemotherapy, but the biggest risk is metastasis and residual cells coming back. Once cells come back, they are usually resistant to the earlier lines of therapy. That’s why the major cause of cancer-related deaths is the recurrence, not the primary tumor.
The only truly durable way to control disease is through the immune system, specifically via hematopoietic stem cell transplantation (HSCT, or “bone marrow transplantation”), which still is the only curative approach for blood cancers. However, that approach has typically included risks like graft-versus-host disease. Immune checkpoint inhibitors, which can be effective in solid tumors, are not as effective in blood cancers, so there is a lot of room for improvement in the blood cancer space.
What’ve been the results thus far?
We’ve shown, in AML, a very long survival in a high-risk patient population diagnosed with measurable residual disease, and we’re trying to show the same correlation in ovarian cancer.
In AML, which is our lead indication, patients are treated with high-intensity chemotherapy and then checked for measurable residual disease. MRD is associated with imminent relapse, and once patients relapse, they usually die within five months. In our trial, 14 out of 20 patients that were all MRD-positive at the start of treatment have become long-term survivors, with 13 still alive at 48 months median follow-up. We looked deeper into the immune systems of patients, and found that in the majority of patients, the immune system was still quite good and did build up immune responses, despite their immune systems having taken a hit from the disease and the chemotherapy. All of these patients with good immune responses became long-term survivors, demonstrating proof-of-concept that vididencel acts as active immunotherapy against residual disease.
In high-risk ovarian cancer, which included late-stage disease, there was debulking surgery and chemotherapy, followed by immunotherapy with vididencel to see if we could slow down or even prevent secondary progression of the disease. In the latest readout at 26 months median follow-up, 5 out of 17 or around 30% of the patients treated still had stable disease, including 2 patients beyond 3,5 years of follow-up. No product-related serious side effects were observed, positioning vididencel as a safe immunotherapy that can be combined with other therapeutic modalities, such as checkpoint inhibitors or T cell engagers.
"Sometimes it is enough to just feed it with the information it needs to accomplish immune control over residual disease and allow patients to live longer, healthy lives without the need for continued treatment."
What advances in technology or our understanding of biology are making this moment different for a tumor recurrence-directed therapeutic?
One is that we understand much more about the immune system and disease, specifically that we’re starting to better understand interactions between cancer and the immune system, and the disease itself and its dynamics. Our immunotherapy can prevent recurrence, but only after the initial disease burden has been brought down and you are then able to train the immune system to attack remaining cancer cells with active immunity. We saw that patients with a high level of disease had no benefit, whereas patients with low levels of disease had tremendous benefit.
The other is focusing on recurrence. Typically, we have started at the end of treatment, with highly refractory patients, multiple lines of treatment, trying experimental things and moving forward. That will not work in IO. You need a relatively fresh immune system and be relatively early in the treatment cycle of patients.
People thought it would take forever to show recurrence of disease, but it doesn’t. In a disease like AML, it’s a matter of weeks to months, and you can actually see quite quickly whether you’ve stopped patients from relapsing. Molecular monitoring of disease has become so much more advanced to the point where you can almost see, in real time, effects on disease.
I think that we will start to see a revolution in trying to prevent tumor recurrence, helped by trials that are more elegantly designed and ways of measuring the disease that pick up efficacy signals earlier and more effectively.
What would be your message for other folks working in the IO space?
Sometimes people forget very basic principles, including that we have both active and passive immunity. Active immunity is the only long-lasting form of immunity, but it takes time to build up. It’s different if you inject antibodies, ADCs, CAR Ts, NK cells, etc, because those are, by definition, passive immunity and not of the patient’s own immune system. In the case of cell therapies, you even have to destroy the patient’s own immune system via lymphodepletion, to be able to administer the treatment. You therefore should expect only limited long-term effects.
At the same time, the immune system is an ancient part of life, which has evolved under a lot of evolutionary pressure to protect us from infections and aberrant cells that may cause cancer. Sometimes it is enough to just feed it with the information it needs to accomplish immune control over residual disease and allow patients to live longer, healthy lives without the need for continued treatment. I believe we should not give up on that principle and continue to find new ways to accomplish that ultimate goal.
