Martin Cannon, PhD, delves into ongoing research on the use of dendritic cell vaccines to generate Th17 responses in patients with ovarian cancer and details how this could address a need for select patients with ovarian cancer.
Although immune checkpoint inhibitors have demonstrated limited efficacy in the treatment of patients with ovarian cancer, the use of dendritic cell vaccines to stimulate T-cell responses could enhance the viability of immunotherapy in this patient population, according to Martin Cannon, PhD.
“If you want to get good results with immune checkpoint inhibitors, you have to [stimulate a] T-cell response. If you can simulate a T-cell response, it's going to improve the prospects for clinical responses for immune checkpoint inhibitors in patients [with ovarian cancer],” Cannon said in an interview with OncLive® following a State of the Science Summit™ on gynecologic oncology.
In the interview, Cannon, a professor of microbiology and immunology at the University of Arkansas for Medical Sciences (UAMS), UAMS College of Medicine in Little Rock, delved into ongoing research on the use of dendritic cell vaccines to generate Th17 responses in patients with ovarian cancer and detailed how this could address a need for select patients with ovarian cancer.
Cannon: Cancer vaccines come in a variety of different forms. There may be hundreds of different ways of going at this, but they have one thing in common: to try to stimulate a T-cell response to tumor antigens associated with whatever malignancy they’re targeting. We opted for dendritic cell vaccination, which isn't everybody's favorite choice, as it is perceived as difficult, expensive, and idiosyncratic as opposed to something off the shelf, such as the COVID-19 vaccines. Constructs like that have been used in cancer, too.
However, the advantage with dendritic cell vaccines is that you can educate dendritic cells to stimulate particular types of immune responses. In ovarian cancer, that might be important because earlier studies on the pathology of ovarian cancer have shown that regulatory T cells are strongly associated with reduced overall survival, whereas Th17 cells are associated with prolonged survival.
Our simple idea was to see if we [elicit] a Th17 response. This has two potential advantages. First, we’re simulating a T-cell response to ovarian tumor antigens. Second, we might be able to subvert immune suppression in the microenvironment. It might effectively kill two birds with one stone.
We figured out how to create a Th17-stimulating dendritic cell vaccine, and it did what it was supposed to do. We took that to the clinic and did a phase 1 trial [NCT01606241] in patients with stage IIIC or IV ovarian cancer in the maintenance setting after completion of up-front surgery and chemotherapy. Typically, in ovarian cancer, you have a window where, traditionally, you wait. You wouldn't treat any further unless [a patient] showed recurrence. However, that has changed a bit because we now have maintenance PARP inhibitors that are widely used in that setting for [patients with] ovarian cancer.
We did the phase 1 clinical trial and returned recurrence-free survival [RFS] rates [where some] patients had no evidence of disease at all at 5 years and counting. We published that in 2020, and 3 years on, it hasn’t changed. Those patients who were free of disease are still free of disease. That was encouraging, and as a phase 1 trial, it was a good start. We also found it stimulated Th17 T-cell responses and folate receptor–alpha antibody responses, and those antibody responses correlated with RFS.
Are there any next steps currently planned for the investigation of Th17-stimulating dendritic cell vaccines?
When [that phase 1] trial was running, we were thinking about what we could do next. Certainly, we'll do a phase 2 trial in the same setting of 78 patients who will be randomly assigned 2:1 to get dendritic cell vaccination vs placebo. We will specifically look at patients who would not be put on [maintenance] PARP inhibitors. There is still a strong clinical need for these patients who are BRCA wild-type, or homologous recombination competent. They have constant DNA repair mechanisms, and they will be less likely to benefit from olaparib [Lynparza] or niraparib [Zejula].
The other thing that we were thinking about is that while we can stimulate T-cell responses in patients with ovarian cancer and it seems clinically as though this might help a decent proportion of them, can we combine [a dendritic cell vaccine] with immune checkpoint inhibitors? Not without a T-cell response. We went back to the mice at this point and we asked: does Th17 dendritic cell vaccination improve responses to anti–PD-1 in a mouse model of ovarian cancer?
We found that, and the anti–PD-1 alone did essentially nothing, which reflects the clinical experience. The Th17 vaccination [alone] did prolong survival. Then when we put the two together, it worked brilliantly. It pushed survival out, and we're quite pleased with that. The next obvious thing is to design a clinical trial with the vaccination in combination with pembrolizumab [Keytruda]. We just got that support from the National Cancer Institute to do that. We're starting in , and that will be fairly small, phase 2 trial. This [may be an] opportunity to improve clinical efficacy of immune checkpoint inhibitors.
This is just our own idiosyncratic take on it; we've been [evaluating] dendritic cell vaccines for a long time. There are any number of other ways to potentially stimulate T-cell responses and provide support for immune checkpoint inhibition in cancer. We could turn around what is currently a fairly bleak situation for some patients.
There have been a number of studies indicating that there is an immune component to the efficacy of PARP inhibitors. There have been quite a few combination trials of immune checkpoint inhibitors and PARP inhibitors, though many hasn't quite lived up to promise.
Despite this, the recent [phase 3 DUO-O trial (NCT03737643)] using an anti–PD-L1 [durvalumab (Imfinzi)], a PARP inhibitor [olaparib], and bevacizumab [Avastin] looks encouraging. There is certainly an opportunity for the combination strategies, including PARP and checkpoint inhibitors. Building on [these strategies] is our primary motivation.
Notably, we've done some work with breast cancer and produced these experiences experimentally with ovarian cancer. This is another clinical setting where checkpoints are important. We tried combining the two [approaches], and sure enough, it came out there too. Therefore, this could apply to several other disease settings, such as endometrial cancers. Recent results with pembrolizumab [plus carboplatin and paclitaxel] in an endometrial cancer study [the phase 3 NRG-GY018 trial (NCT03914612)] published in the New England Journal of Medicine showed strong data in those patients because deficiencies during mismatch repair [MMR] now have a substantially improved survival.
Those with MMR deficiencies are more immunogenic. In other words, you've got to have a T-cell response for pembrolizumab to work. However, on the flip side of that, are those with MMR deficiency less immunogenic? They're the ones that need help. Overall, there are a number of areas where this looks like it might be a very favorable strategy.
Block MS, Dietz AB, Gustafson MP, et al. Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients. Nat Comm. 11, 5173 (2020). doi.org/10.1038/s41467-020-18962-z