Martin Cannon, PhD, professor, microbiology and immunology, the University of Arkansas for Medical Sciences (UAMS), UAMS College of Medicine, discusses the use of dendritic cell vaccines and immune checkpoint inhibitors in ovarian cancer.

In a phase 1 trial (NCT01606241), investigators assessed a Th17-stimulating dendritic cell vaccine in the maintenance setting in patients with stage IIIC or IV ovarian cancer following completion of upfront surgery and chemotherapy, generating encouraging responses. During the phase 1 trial's progress, investigators considered next steps and laid the foundation for a phase 2 trial, which is on the horizon in the same patient population, Cannon says. This phase 2 trial will randomly assign patients in a 2:1 ratio to receive either the dendritic cell vaccination or placebo, he explains. Notably, the focus will be on patients who wouldn't typically receive maintenance PARP inhibitors, Cannon adds. Patients with 

 wild-type or homologous recombination–proficient ovarian cancer have a significant clinical need, as they possess robust DNA repair mechanisms, which make them less likely to benefit from treatment with olaparib (Lynparza) or niraparib (Zejula), Cannon emphasizes. 

Looking to the future, concerns have come up regarding the use of dendritic cell vaccination with immune checkpoint inhibition. Investigators aimed to better understand whether Th17 vaccination could enhance responses to PD-1 inhibition in ovarian cancer mouse models, Cannon expands. Findings indicated that PD-1 inhibition alone had minimal effects on ovarian cancer models, mirroring clinical experiences, Cannon says. Although Th17 vaccination aloneextended survival, the combination of the vaccination and PD-1 inhibition significantly extended survival rates, he notes.

The next logical step is to design a clinical trial involving vaccination in conjunction with pembrolizumab (Keytruda). Investigators have received support from the National Cancer Institute for this potentially upcoming trial, Cannon continues. This research could enhance the clinical efficacy of immune checkpoint inhibitors, he adds. Overall, there are numerous avenues to explore for stimulating T-cell responses and providing support for immune checkpoint inhibition in ovarian cancer, Cannon concludes.

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Martin Cannon, PhD, discusses the use of dendritic cell vaccines and immune checkpoint inhibitors in ovarian cancer.


Dr Cannon on the Use of Dendritic Cell Vaccines in Ovarian Cancer

Martin Cannon, PhD, professor, microbiology and immunology, the University of Arkansas for Medical Sciences (UAMS), UAMS College of Medicine, discusses data seen with immune checkpoint inhibitors in patients with ovarian cancer and why these agents are not as effective in this population as they are in other cancer types.

Findings from a phase 2 trial (UMIN000005714) that were published in the 

 in 2015 showed that patients with platinum-resistant ovarian cancer who received nivolumab (Opdivo) achieved a 15% overall response rate (ORR; 95% CI, 3.2%-37.9%). Among the 3 patients who responded, 2 achieved a complete response, and 1 achieved a partial response. These data did not support the use of immune checkpoint inhibitors in patients with platinum-resistant disease, Cannon explains.

The pivotal phase 2 KEYNOTE-100 trial (NCT02674061), published in 2019 in 

 by Ursula A. Matulonis, MD, of Dana-Farber Cancer Institute, and colleagues, evaluated the efficacy and safety of pembrolizumab (Keytruda) in 2 cohorts of patients with advanced recurrent ovarian cancer. Cohort A consisted of patients who had received 1 to 3 prior lines of treatment with a platinum-free interval or treatment-free interval of 3 to 12 months. Cohort B was comprised of patients who had received between 4 and 6 prior lines of therapy with a platinum-free interval or treatment-free interval of at least 3 months. The ORRs in cohorts A and B, respectively, were 7.4% and 9.9%. These findings indicated that immune checkpoint inhibitors were ineffective in patients with ovarian cancer, Cannon says.

Despite the low response rates seen with immune checkpoint inhibitors in patients with ovarian cancer, these agents are effective in several other cancers, Cannon notes. Importantly, immune checkpoint inhibitors do not target the cancer itself, and instead target T-cell responses, Cannon explains. Therefore, these agents are not effective in patients whose tumors do not have T-cell responses, Cannon emphasizes.

Ovarian cancers may not have enough antitumor T-cell response for immune checkpoint inhibitors to be effective, according to Cannon. These cancers may have low tumor mutational burdens and lack T cell–stimulating antigens, or the tumors may have microenvironments with immune suppression, Cannon says. Ovarian cancers may have T cells, including highly immunosuppressive regulatory T cells. However, these T cells need to be expressed before immune checkpoint inhibitors, such as nivolumab or pembrolizumab, can be effective, Cannon concludes.

Martin Cannon, PhD, discusses data seen with immune checkpoint inhibitors in patients with ovarian cancer and why these agents are not as effective in this population as they are in other cancer types.

Dr Cannon on Suboptimal Efficacy Findings With Immunotherapy in Ovarian Cancer

Martin Cannon, PhD, professor, Department of Microbiology, University of Arkansas for Medical Sciences College of Medicine, discusses potential reasons that contribute to the lack of success with immune checkpoint inhibitors in ovarian cancer, highlighting areas to focus upon to improve these responses to immunotherapy approaches in the future.

immune checkpoint inhibitors have produced encouraging therapeutic responses in patients who have presented with a wide spectrum of tumor types, Cannon begins. However, the agents use in ovarian cancer has proven far less effective, he says.

When attempting to understand why immunotherapy has not yielded high responses in ovarian cancer, it is first vital to recognize that immune checkpoint inhibitors target T-cell responses rather than the tumor itself, Cannon states. Consequently, the utilization of immune checkpoint inhibitors becomes ineffective in the absence of an initial intrinsic T-cell response to the tumor, he explains. This lack of substantial T-cell activation could be present in ovarian cancer, and may be attributed to factors such as a low tumor mutational burden or a low number of T-cell stimulating antigens, Cannon says, leading to limited immunogenicity. Immune suppression in the tumor microenvironment may also occur due to the presence of regulatory T-cells, he adds. These features decrease the efficacy of immune checkpoint inhibitors, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), necessitating upfront intervention prior to their use, Cannon notes.

To improve the functionality of these drugs, it is important to address the initiation of anti-tumor T-cell immunity as well as local immune suppression, Cannon continues. An optimal approach, therefore, involves stimulating anti-tumor T-cell immunity and concurrently mitigating immunosuppression within the tumor microenvironment, he suggests.

If anti-tumor T-cell responses can be proactively enhanced, meaningful responses to immune checkpoint inhibitors in ovarian cancer may become attainable, Cannon says. This comprehensive strategy offers a promising direction for improving the landscape of ovarian cancer treatment, Cannon concludes.

Martin Cannon, PhD, discusses explanations for the lack of success with immune checkpoint inhibitors in ovarian cancer, and how to potentially improve responses to immunotherapy approaches in this tumor type.
 

Dr Cannon on Improving Responses With Immunotherapy in Ovarian Cancer

Martin Cannon, PhD, professor, Department of Microbiology and Immunology, University of Arkansas for Medical Sciences (UAMS) College of Medicine, discusses the phase 1 investigation of the Th17 dendritic cell vaccine in ovarian cancer, and how it could potentially improve suboptimal responses when treated with immunotherapy alone in this population.

A correlation between Th17 cell infiltration and prolonged overall survival in patients with ovarian cancer patients was identified in previous research, prompting interest in harnessing Th17 cells. Accordingly, a Th17-stimulating dendritic cell vaccine was developed to potentially improve immune responses and clinical outcomes in this space, Cannon begins. 

The immunogenicity and safety of the Th17-stimulating dendritic cell vaccine in patients with stage IIIC–IV ovarian cancer was evaluated in a single-arm, open-label, phase 1 clinical trial (NCT02111941), Cannon details. Patients received the dendritic cell vaccine in the maintenance setting following the completion of upfront surgery and chemotherapy, he says. Primary end points of the phase 1 trial include safety and tolerability, with recurrence-free survival (RFS) and immunogenicity as secondary end points. Of the 19 patients enrolled on the study, 18 were evaluable.

Cannon notes that when the study was designed, strategies in the maintenance setting involved the cessation of treatment for 12 to 18 months, while the patient was monitored for recurrence, at which point treatment would resume. However, the approvals for, and increasing use of, PARP inhibitors in the maintenance setting has since changed this approach, he adds.

Initial results from the study were reported in 2020, and demonstrated that vaccination with Th17-inducing folate-receptor alpha (FRα)–loaded dendritic cells was safe, generated antigen-specific immunity, and was associated with increased remission, Cannon reports. A comparison of T-cell frequency before and after vaccination showed that the vaccine successfully stimulated Th1, Th17, and antibody responses to FRα in most patients with ovarian cancer.

Moreover, Th1 and FRα antibody responses were associated with high RFS, Cannon says. The median RFS with the vaccine was 12.1 months, and the median overall survival (OS) was not reached. At a median follow-up of 49.2 months, the recurrence-free survival rate was 38.9% in at-risk, efficacy evaluable patients. Regarding safety, the vaccine was well tolerated and produced transient, low-grade adverse effects (AE) primarily caused by injection site reactions.

Martin Cannon, PhD, discusses the phase 1 investigation of the Th17 dendritic cell vaccine in ovarian cancer, and how it could potentially improve suboptimal responses when treated with immunotherapy alone in this population.

Martin Cannon, PhD

Articles

Dr Cannon on the Use of Dendritic Cell Vaccines in Ovarian Cancer

Dr Cannon on Suboptimal Efficacy Findings With Immunotherapy in Ovarian Cancer

Dr Cannon on Improving Responses With Immunotherapy in Ovarian Cancer

Dr Cannon on the Investigation of the Th17 Dendritic Cell Vaccine in Ovarian Cancer