Immune-Targeted Therapy Continues to Fall Short in Ovarian Cancer

The challenges that have risen in the attempt to implement immune-targeted therapy in ovarian cancer have emphasized prevalent unmet needs that remain for this patient population, according to Kathleen N. Moore, MD, MS, who added that ongoing trials are underway to explore more diverse strategies to combat these difficulties .

“The story is not anywhere near told for immunotherapy in ovarian cancer, but thus far, it is not standard of care and not what I’d be trying to get someone off label just based on current evidence,” Moore said in an interview with OncLive^® following a State of the Science Summit™ (SOSS) on gynecologic cancer, which she chaired.

In the interview, Moore discussed the challenges with utilizing immune-targeted therapy for ovarian cancer, expanded on the impact of the tumor microenvironment on the effectiveness of immune checkpoint inhibitors, and detailed ongoing research with different treatment approaches in ovarian cancer. Moore is the associate director of Clinical Research at the Stephenson Cancer Center and the director of the Oklahoma TSET Phase I Program, as well as a professor in the Section of Gynecologic Oncology, at the University of Oklahoma College of Medicine, in Oklahoma City.

OncLive: What was the goal of your presentation on the role of immune-targeted therapy within ovarian cancer?

Moore: The application of immune therapies in ovarian cancer has been less successful thus far than in other solid tumors where agents like pembrolizumab [Keytruda], nivolumab [Opdivo], and atezolizumab [Tecentriq] have gained many regulatory approvals, either related to single-agent activity or combination activity in a number of lines of different therapies. We haven’t seen that in ovarian cancer despite many clinical trials in different settings across gynecologic cancers, with the exception of cervical cancer where it has been successful and in endometrial [cancer] and biomarker selected [instances]; however, in ovarian cancer, we have been unsuccessful.

My talk was an overview of what we’re trying to target with current immune checkpoint inhibitors within the cancer immunity cycle and was a bit about why we postulate that those agents haven’t been as successful. It probably relates to the tumor microenvironment around the tumor having several incredibly immunosuppressive features that inhibit immune checkpoint inhibitors—[which are administered] either alone or in combination—from having meaningful improvements in outcomes.

It’s not that we’ve given up on those agents, as we certainly still have ongoing clinical trials and occasions where we attempt to use them clinically, but we have moved on a little to try and learn from negative trials, bringing different approaches to immune targeting into the ovarian cancer space.

What are some of the different approaches under exploration in this space?

A variety of different strategies include vaccination, clinical trials that are still ongoing, oncolytic viruses, and adoptive cell therapies, such as CAR T and engineered T-cells—we have examples of those in clinical trials in ovarian cancer with early signals of some efficacy. Those are moving into some larger trials to see if they can be a therapy that helps transform [care] for women with recurrent ovarian cancer.

Examples would include adoptive cell therapies; there’s a number of early phase clinical trials with CAR T-cell [therapy]. There’s one adoptive cell therapy that has moved into a randomized phase 2 trial setting [NCT03132922] and that’s an engineered T cell product that’s targeting the tumor-associated antigen MAGE-A4. This product is HLA restricted, requiring the test of patients’ blood or serum for what HLA subtype they are—we all get 1 HLA subtype from each parent—though, this has nothing to do with the cancer, and it’s just the protein that’s on the T cell that presents whatever foreign protein that we’re trying to target. The drugs have to be designed against a certain HLA, so in this case, we’re looking at HLA-A*0201, and a few others. Then if that’s positive, we screen the tumor for MAGE-A4. If that’s positive, [and] approximately 24% of high-grade series ovarian cancers [are positive], then patients are eligible for this strategy.

Instead of asking a patient’s body to create the immune cells, the T cells, that are going to fight the cancer, [this strategy aims to] find existing T cells in circulating blood and engineer them to kill everything that’s MAGE-A4 expressing. We can then multiply those to several billion and reinfuse those, giving the patient back this army of T cells that for whatever reason our bodies just don’t make. This is a strategy that’s very different than immune checkpoint inhibitors.

Another [different one] is an oncolytic virus strategy with the drug olvimulogene nanivacirepvec [Olvi-Vec] which is a modified oncolytic vaccinia virus that has some mutations that enhance tumor targeting. This is given intraperitoneal for patients whose tumors are resistant to platinum, and for whom platinum could still be an option. These are individualized populations and aren’t all comers, as we’re looking for certain phenotypes.

[Patients on the trial] are given intraperitoneal vaccinia virus with carboplatin-based chemotherapy. This is a very different strategy than we’re used to doing in platinum-resistant ovarian cancer. This is in the phase 3 OnPrime study [NCT05281471] and the phase 1 study to support this was quite promising. We’re going to have to see how this plays out.

[Additionally], a modified interleukin-2 agent [Nemvaleukin alfa] is being developed in the phase 3 clinical trial ARTISTRY-7 [NCT05092360], and a number of other strategies are [also] trying to address the immunosuppressive nature of the ovarian cancer microenvironment in a different way than immune checkpoint inhibitors do, which just haven’t worked.

We’ll see that hopefully some of these will stick and we can move immunotherapy into mainstream [treatment of] this disease. However, for right now, they are still very experimental [therapies].

Why have there been challenges in terms of finding efficacy with these types of agents?

We’re still understanding what went wrong with some of these clinical trials. There’s been some exploratory analysis done from the IMagyn050 trial [NCT03038100], for example, which was a front-line clinical trial of paclitaxel, carboplatin, and bevacizumab [Avastin] with or without the immune checkpoint inhibitor atezolizumab. That combination has been very effective in other tumors, namely lung.

The belief that the mechanisms that lead that [combination] to be successful, which has improved T cell trafficking and decreased regulatory T cell involvement, would translate into the ovarian cancer sector and build upon what’s already an effective regimen of paclitaxel, carboplatin, and bevacizumab was assumed erroneously because it didn’t have the same effect in any way, shape, or form. Thankfully, we didn’t harm anybody, but we didn’t help either.

There’s been some exploratory work that’s been presented and the manuscripts are about to come out from that study, trying to look at what the major mediators of immune resistance were, and maybe what some potential subgroups within ovarian cancer are that might have benefited had we had enough of them on the clinical trial. In very basic terms, we have understood that the microenvironment of ovarian cancer has a number of ways that it escapes immune surveillance, immune priming, inactivation, [and] trafficking the T cells.

We know that we infiltrate T cells into the tumor, but they may be regulatory T cells instead of cytotoxic T cells. It is multifactorial why immune checkpoint inhibitors don’t benefit [this group], so it’s hard to give one simplistic answer to that, other than that the microenvironment is not favorable. These medications by themselves or with chemotherapy have not been as effective as we would have hoped.

What would you like your colleagues to take away from this conversation?

Just because immune checkpoint inhibitors didn’t work or haven’t worked yet, there’s several studies that will be presented. One big phase 3 trial was presented at the International Gynecologic Cancer Society meeting in Seoul Korea. There are still some studies that have finished accruing with different combinations of chemotherapy and bevacizumab with or without different PD-1/ PD-L1 [inhibitors]. We still have some studies to read out and the story is not completely told yet; we’ll see what those show.

The other message is that if those don’t show benefit, there’s a whole second and third generation of newer agents coming that do try to augment the immune response or circumvent it in the case of engineered T cells or CAR T-cell [therapy] where you’re giving the product back. It does drag in endogenous T cells, as well. We’re still coming along with these.