Whether they’re in the brain, on the skin, or in the liver, solid tumors are difficult to treat. Because they arise from healthy cells that go haywire, every person’s tumor is different. This tumor heterogeneity means that there is often no “one size fits all” treatment, even for the same types of cancer.
Now, a team of immunologists and neurosurgeons at the biotechnology company Imvax plan to change that.
“We have an immunotherapy that's based on using the patient's own tumor cells as a source of antigen,” said Mark Exley, an immunologist and chief scientific officer at Imvax. While the idea to use a cancer patient’s tumor cells to fight against the tumor is not novel on its own, Exley added, “There are ways in which this is quite radically different, and that explains the substantially better looking clinical data that we've got as well as all the preclinical data we have that looks very positive.”
For example, scientists have isolated patient dendritic cells, exposed them to antigens from the tumor, and reinfused the dendritic cells back into the patient. The challenge with this approach is, “you need to have a lot of [these cells] to reinfuse back into the body because eventually they die,” said Corinne Ying Xuan Chua, a nanomedicine and cancer researcher at Houston Methodist Research Institute who is not associated with Imvax. That approach only leads to minor activation of the immune system against the cancer.
Instead, by triggering a patient’s own tumor cells to release both immunostimulatory molecules and tumor-specific antigens within a biodiffusion chamber temporarily inserted in the patient’s body, the researchers at Imvax turn the uniqueness of the tumor against itself. With positive results in a phase Ib clinical trial in brain cancer, this new immunotherapy may lead to personalized treatments for difficult-to-treat solid cancers.
For Imvax’s cofounder and chief medical officer, David Andrews, the road to this personalized immunotherapy began with glioblastoma, an aggressive type of brain cancer. As an academic and practicing neurosurgeon, Andrews regularly treats patients with glioblastoma and has witnessed the need for better treatments firsthand.
The standard of care for glioblastoma is to remove as much of the brain tumor as possible and then treat the patient with radiation and chemotherapy, but Andrews said, this “is where we've been since 2005.” Even with this treatment regimen, people with glioblastoma only have a 15-month survival prognosis.
Glioblastoma is difficult to treat for several reasons. In addition to being heterogeneous and located behind the blood-brain barrier, glioblastomas actively release factors to suppress the immune system (1).
Andrews and his colleagues at Thomas Jefferson University and later at Imvax reasoned that if they could give the immune system a chance to fight glioblastoma cells that remain after surgery, patients may have better outcomes.
They focused their attention on decades of research on the insulin-like growth factor I receptor (IGF-IR), which cancer cells overexpress to protect themselves from apoptosis (2). Andrews’ and Craig Hooper’s team at Thomas Jefferson University designed an antisense IGF-IR RNA molecule that inhibits glioblastoma tumor’s IGF-IR and triggers tumor cell apoptosis in multiple rodent models (3,4). When they encapsulated both the rat glioblastoma tumor cells and the antisense IGF-IR RNA in a biodiffusion chamber and placed the chamber in the rat’s abdomen for 24 hours, the rats that received the treatment lived three times longer than those that received no treatment, and their tumors never came back (5).
The biodiffusion chamber “has 100 nanometer pores, so it allows out peptides, proteins, exosomes, antigens, and debris in various forms, but not the viable tumor cell,” said Exley. “It also allows out the antigenic stimulus and other components that stimulate the immune response — innate immune stimuli as well as the adaptive immune antigens — at the same time as keeping in some of the immunosuppressive components.”
In recent efforts to understand the mechanisms driving these immune responses to the filled biodiffusion chambers, the Imvax researchers studied them in mouse models. They observed that the tumor cells with the IGF-IR antisense molecule triggered an increased T cell response, a greater interferon gamma response, and a shifting away from immunosuppressive cytokines in the tumor environment. “As well as the antigen specific response, we're also getting a general change in the immune milieu,” said Exley.
Based on the positive preclinical data and a small but promising phase Ia trial, Andrews initiated a phase Ib clinical trial in patients with newly diagnosed glioblastoma. (The Imvax team assumed control of the clinical trial near its conclusion.) When people with glioblastoma arrived at the hospital for their tumor removal surgeries, Andrews and his neurosurgeon colleagues made additional incisions on either side of their abdomens to form small pockets where surgeons would place the filled biodiffusion chambers the next day.
“That's the advantage of being able to be done while the patient is in hospital anyway, so then they’re one and done,” said Exley.
Once surgeons removed the tumor cells from the patient, they sent them to Imvax’s manufacturing facility where Imvax scientists treated the tumor cells with the antisense IGF-IR molecule and placed both in multiple biodiffusion chambers. They then irradiated the chambers with a low dose of radiation, which pushes the tumor cells toward immunogenic cell death. In less than 24 hours, the Imvax team then shipped the biodiffusion chambers carrying the patient’s personalized treatment back to the hospital.
Depending on which treatment group the patient had been assigned to, surgeons either placed 10 or 20 biodiffusion chambers into the patient’s abdomen for either 24 or 48 hours. A typical hospital stay for someone with glioblastoma after tumor removal surgery is six days, so even with receiving the Imvax team’s immunotherapy, the patients didn’t have to stay in the hospital any longer than usual.
When Andrews and his colleagues at Thomas Jefferson University assessed these patients six weeks later, they found that patients who had received 20 biodiffusion chambers for 48 hours not only had a strong immune response to the therapy, but they also had longer rates of progression-free survival than the patients in the other treatment groups.
“We went back to the Institutional Review Board and said we want to stop the randomization. It seemed ethical, since there's no difference in safety, that we're just going to finish this with the highest [dose] cohort,” said Andrews. Six weeks after having the biodiffusion chambers removed, the patients received standard-of-care radiation and chemotherapy.
The results of the trial, published in 2021, were incredibly positive (6). “We're now up to 38 months overall survival, and we're maintaining progression-free survival above 17 months. So, that was unexpected,” said Andrews. “As a neurosurgeon in practice for 33 years, I'd never seen [that] before.”
Chua agreed that this approach looks very promising. “You have a local place where you put your processed tumor cells from the patient, and then you expose them directly within that niche to drugs that can perhaps teach the immune system to say, ‘Look, these are the cancer cells. Go out and attack these cancer cells wherever you find them in the body.’ So, this can be helpful not just for glioblastoma; it could be helpful for any other solid tumors.”
Since completing the phase Ib clinical trial, the Imvax researchers have explored exactly that. Working in mice, the team has reported positive results using the personalized biodiffusion chambers to target endometrial, liver, bladder, and ovarian cancers. They have also just begun a phase IIb clinical trial for glioblastoma to assess the effectiveness of their treatment platform. For the phase IIb trial, the Imvax team has optimized the phase Ib trial procedure, and they recently dosed their first patient.
Andrews, Exley, and the entire Imvax team hope that this treatment will lead to a more effective therapy for patients with glioblastoma and other hard-to-treat solid cancers.
Recalling the phase Ib trial results, Andrew said, “What was really thrilling was not only was it safe, but getting these responses was probably the most rewarding experience I've had in neurosurgery.”
Exley agreed: “As an immunologist, to apply immunology and make it work for patients, it's the peak of my career as well.”
References
- Nduom, E.K., Weller, M., and Heimberger, A.B. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol 17, vii9-vii14 (2015).
- Resnicoff, M. et al. The Insulin-like Growth Factor I Receptor Protects Tumor Cells from Apoptosis in Vivo. Cancer Res 55, 2463–2469 (1995).
- Resnicoff, M. et al. Correlation between apoptosis, tumorigenesis, and levels of insulin-like growth factor I receptors. Cancer Res 55, 3739-41 (1995).
- Resnicoff, M. et al. Regression of C6 rat brain tumors by cells expressing an antisense insulin-like growth factor I receptor RNA. J Exp Ther Oncol 1, 385-9 (1996).
- Andrews, D.W. et al. Results of a Pilot Study Involving the Use of an Antisense Oligodeoxynucleotide Directed Against the Insulin-Like Growth Factor Type I Receptor in Malignant Astrocytomas. J Clin Oncol 19, 2189-200 (2001).
- Andrews, D.W. et al. Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma. Clin Cancer Res 27, 1912–1922 (2021).
