Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial

Ovarian cancer is the most lethal gynecologic malignancy with an annual incidence of more than 300,000 and a mortality of 200,000 worldwide (1). About 70% of women with ovarian cancer are diagnosed with advanced disease due to a lack of effective screening strategies (2). Moreover, ovarian cancer survival rates have only shown a marginal improvement over the past decades with a 5-year survival of 30%–35% in advanced cases (3).

The initial treatment of ovarian cancer involves surgery and platinum-based chemotherapy. Although the majority of patients respond well to chemotherapy, the risk of recurrence is high, hence requiring additional systemic treatments with various chemotherapeutic agents including paclitaxel, liposomal doxorubicin, or topotecan alone or in combination with an anti-VEGF therapeutic, bevacizumab (4). Unfortunately, patients eventually develop platinum-resistant disease with clinical response rates of only about 10%–15% to any additional therapies (5–7).

Several clinical trials have investigated the efficacy of immunotherapies in ovarian cancer (8–10). In contrast to the significant clinical efficacy in other solid cancers (11–13), single-agent immune checkpoint inhibition blocking programmed cell death protein 1 (pembrolizumab, nivolumab; ref. 8) or programmed death ligand 1 (atezolizumab, avelumab; ref. 9) has demonstrated low overall response rates of around 10% in patients with recurrent ovarian cancer.

Various prior studies have demonstrated that the immune system, and in particular T cells, play an important role in modulating the response to treatment (14, 15). A strong association between higher tumor T-cell infiltration and improved survival (16) provides a strong rationale for the development of T-cell–activating immunotherapy approaches.

Cancer vaccines targeting tumor-associated antigens (TAA) may induce a strong immune response directing CD8⁺ T cells to the tumor microenvironment (TME) and provide long-term immunogenic memory (17). Thus, relevant TAAs with higher expression in tumors compared with the expression in normal tissues can serve as tumor specific targets for immunotherapy.

Survivin is one of the most well-recognized TAAs expressed in various cancers, including ovarian (18, 19), diffuse large B-cell lymphoma (DLBCL; ref. 20), gastrocolic carcinoma (21), breast (22), lung (23), and bladder (24) cancers. In normal adult tissue, survivin expression is mostly undetectable hence making it a candidate for tumor-specific targeting (25). Survivin is a member of the inhibitors of apoptosis protein (IAP) family, which promote tumorigenesis by blocking the activity of caspase-3 and caspase-7, promoting cell survival, proliferation, angiogenesis, and epithelial-to-mesenchymal transition (EMT; refs. 26–28). Several studies have demonstrated that the expression of survivin in ovarian cancer is correlated with advanced stage, increased chemotherapy resistance, and decreased progression-free survival (PFS) and overall survival (OS; refs. 29–32).

Maveropepimut-S (formerly known as DPX-Survivac) is a DPX-based immunotherapy that targets survivin-expressing tumor cells for elimination by educated, cytotoxic T cells. The DPX technology is a lipid-based, nonaqueous delivery platform that can incorporate a range of bioactive molecules to produce targeted, long-lasting immune responses enabled by various formulated components. Maveropepimut-S is the formulation of the DPX platform incorporating five survivin-derived, immunogenic peptides designed to target five common HLA haplotypes in humans, as well as an innate immune stimulant (polydIdC) and a universal T-helper peptide (A16L). In previous clinical studies, maveropepimut-S has been well tolerated, and was shown to induce durable, robust, survivin-specific T-cell responses when combined with intermittent, low-dose cyclophosphamide (33–36). Our previous phase I clinical trial (NCT01416038) confirmed the safety and immunogenicity of maveropepimut-S in patients with advanced ovarian cancer whereby maveropepimut-S, in combination with intermittent low-dose cyclophosphamide, induced a strong, durable, and polyfunctional survivin-specific CD8⁺ T-cell response (36). However, this phase I was a maintenance study not designed to evaluate clinical efficacy. Here we report data from the DeCidE¹ phase II study (NCT02785250) demonstrating clinical efficacy, tolerability, and immunogenicity of this maveropepimut-S treatment regimen in patients with advanced, recurrent ovarian cancer. The single-arm study was designed for analysis using descriptive statistics; an objective response rate (ORR) of 15% or less among evaluable subjects was to be considered comparable with current standard-of-care therapy.

This multicenter study included eight sites in the United States and Canada. The study was approved by the local Institutional Review Boards (IRB) or Western IRB and all participants provided written informed consent prior to initiating study procedures.

Patients with stage IIc–IV, recurrent, epithelial ovarian, fallopian tube, or peritoneal cancer were eligible for participation in the study; enrollment was open to all histologic subtypes. Subjects with evidence of disease progression, and measurable disease less than 4 cm in any single lesion by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), were eligible. Subjects could not be eligible for an otherwise curative treatment, could have been platinum-sensitive or platinum-resistant to initial platinum-based therapy, and could have had any number of prior lines of therapy. Platinum-resistant and platinum-sensitive are defined as progression after initial chemotherapy between 3 and 6 months (inclusive) or greater than 6 months, respectively. Subjects may have had any number of subsequent lines of chemotherapy. Patients with prior exposure to immunotherapy including immune checkpoint inhibitors were excluded. Participants were required to undergo a pretreatment tumor biopsy.

This was a single-arm, open-label phase II study to evaluate the safety and efficacy of maveropepimut-S with intermittent low-dose cyclophosphamide in a small cohort of patients with recurrent ovarian cancer. Each subject was to receive two initial subcutaneous injections of 0.25 mL maveropepimut-S at study days 7 and 28, followed by up to six 0.1-mL doses administered 8 weeks apart. All doses were delivered subcutaneously to the upper thighs. Injections were delayed in the presence of a grade 2 or greater injection site reaction including ulcerations. Low-dose oral cyclophosphamide, 50 mg twice daily, was self-administered in repeating cycles of 7 days on, 7 days off, beginning at study day 0. Study treatment was continued for up to one year. At the discretion of the treating physician, treatment could be extended beyond one year for patients with clinical benefit from therapy.

Adverse events (AE) were monitored using routine physical examination, vital signs, and routine laboratory assessments. Injection site reactions were evaluated for individual symptoms and measurements recorded when applicable. Findings were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Dose-limiting toxicities (DLT) included most grade 3 or greater adverse reactions occurring between study day 8 and 56. Not included in the definition of DLT were grade 3 injection site reactions or abnormal, nonclinically significant laboratory values, or gastrointestinal events (nausea/vomiting/diarrhea) that quickly resolved.

The status of the disease was assessed by CT or MRI using RECIST v1.1 prior to treatment, between study days 56 and 70, on day 140, and every 8 weeks thereafter. An on-treatment biopsy was performed between day 56 and 70. Subjects who completed the first on-study imaging (day 56–70) were considered evaluable and were included in the analysis of efficacy. Subjects who completed at least two on-treatment blood collections were included in the immunogenicity analysis.

Peripheral blood mononuclear cells (PBMC) were collected pretreatment, prior to each maveropepimut-S dose, and at day 56. CA-125 was determined every 4 weeks. Pre- and on-treatment tumor biopsies (between days 56 and 70) were collected.

The coprimary endpoints of the study were to determine the safety profile of maveropepimut-S and cyclophosphamide and the ORR and disease control rate (DCR) of treatment using RECIST v1.1 criteria. Secondary objectives included both immunogenicity and efficacy assessments. The antigen-specific immune response was measured by IFNγ enzyme-linked immunospot (ELISPOT), and immune cell infiltration of tumors evaluated with multiplex-IHC (mIHC; Akoya Biosciences). Survivin protein expression was assessed by IHC (NeoGenomics); both percentage of positive tumor cells and H score were evaluated. In depth translational methods are available in Supplementary Data (Supplementary Data S1). CA-125 response or progression was determined as described by Rustin and colleagues (37).

Data were collected from March 2019 to June 2021. Participant demographics, baseline characteristics, and safety evaluations were summarized. Efficacy endpoints were analyzed using both the intent-to-treat and the evaluable populations. Exploratory analyses were conducted to assess preliminary response signals in the platinum-sensitive or platinum-resistant populations.

The data generated in this study are available upon request from the corresponding author.

Between March 12, 2019, and October 28, 2019, 22 subjects were enrolled in the phase II part of the DeCidE¹ trial (Fig. 1). The median age was 58 (range, 38–78) years. The majority of subjects were White (63.6%), followed by Asian (18.2%) and race unknown (18.2%). All subjects enrolled had an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 at time of study entry and had high-grade ovarian cancer. All subjects but one had stage III or IV disease at diagnosis and all but one had tumors of serous subtype (all high-grade serous) with median lines of prior therapy of 3 (range, 1–6). Seven of 22 (31.8%) subjects had received prior bevacizumab and 13 of 22 (59.1%) had received prior therapy with a PARP inhibitor. The majority of patients (13/22; 59.1%) were platinum-resistant or refractory to their most recent platinum-based therapy. Sixteen (16/22; 72.7%) subjects were germline breast cancer gene (gBRCA) wild-type (WT), 4 of 22 (18.2%) had a gBRCA1 mutation, and 1 of 22 (4.5%) a gBRCA2 mutation. One subject out of 22 (4.5%) was BRCA status unknown. Survivin expression was detected in the tumor of all 19 evaluable patients. Three subjects did not remain on study; one was ineligible and the other two experienced clinical progression prior to receiving a second dose of maveropepimut-S. These three subjects were therefore considered unevaluable in the per protocol population. Details of subject characteristics can be found in Table 1.

Among the 19 evaluable subjects, four had a partial response (PR) for an ORR of 21.1%; (90% CI, 7.5%–41.9%). A total of 21 patients met the study eligibility criteria and were included in the modified intent-to-treat (mITT) population; an ORR of 19.0% (4/21; 90% CI, 6.8%–38.4%) was observed in this mITT population.

Table 2 summarizes the best response by RECIST v1.1 criteria in the evaluable population overall and based on platinum resistance status. Two PRs were observed in 8 subjects (25.0%) with platinum-sensitive disease and two of 11 subjects (18.2%) with platinum-resistant disease. The DCR for the evaluable population was 50.0% for platinum-sensitive and 72.7% for platinum-resistant disease with an overall DCR of 63.2% (90% CI, 41.8%–81.3%). The overall DCR for the mITT population was 57.1% (12/21; 90% CI, 37.2%–75.5%). Four patients with stable disease (SD) by RECIST v1.1 maintained clinical benefit for 24.9, 11.8, 6.7, and 6.4 months, respectively. Three out of these four subjects were resistant to platinum.

Overall, 10 of 19 subjects (52.6.%) experienced a reduction in the sum of their target lesions (Fig. 2A). In the platinum-sensitive subjects, 3 of 8 (37.5%) were on the trial for more than 12 months. Among the patients with platinum-resistant disease, 4 of 11 (36.4%) remained on treatment for more than 6 months, and one (9.1%) patient for more than 12 months (Fig. 2B). One of the platinum-sensitive subjects continued with optional maveropepimut-S dosing beyond the 1-year study, remaining on trial for more than 24 months. Median time on trial for evaluable subjects was 4.4 months (range, 2.1–24.9). The median number of maveropepimut-S treatments received by evaluable subjects was 3 (range, 1–13). Responses and benefit were observed in both PARP inhibitor– as well as bevacizumab-exposed subjects.

Overall, 22 subjects received at least one dose of cyclophosphamide and 21 (95.5%) received at least one dose of maveropepimut-S. The average number of maveropepimut-S injections received was 3.5 (range, 0–13). Nineteen (86.4%) of the subjects reported one or more treatment-related adverse events (TRAE). Figure 3 summarizes the reported TRAEs. The majority of TRAEs were grade 1 or 2 events (83/95 unique events, 87.4%). Eight subjects (36.4%) reported one or more grade 3 TRAEs and no subjects experienced a grade 4 or higher TRAE. The grade 3 TRAEs included injection site induration (1), injection site ulcer (5), myositis (1), fatigue (2), anemia (2), and pyrexia (1). The most common TRAEs were injection site reactions, namely induration (15/22 subjects, 68.2%), erythema (9, 40.9%), ulcer, and pruritus (5 each, 22.7%; Fig. 3A). The most common systemic events were fatigue (11, 50.0%) and nausea (5, 22.7%; Fig. 3B).

Maveropepimut-S–induced survivin-specific T-cell responses were assessed in longitudinally collected PBMC samples using complementary in vitro MHC-tetramer (Fig. 4A) and ex vivo IFNγ ELISPOT assays. Induction of survivin-specific CD8⁺ T-cell responses upon maveropepimut-S treatment was detected in 14 of 16 (87%) assessable subjects using in vitro MHC-tetramer assay (Fig. 4B). Four subjects demonstrated long-lasting, sustained antigen-specific CD8⁺ T-cell responses on-treatment as far as up to study day 386 (Fig. 4A).

These observations were confirmed by the ex vivo IFNγ ELISPOT assay demonstrating a statistically significant increase in antigen-specific IFNγ responses from baseline to the best observed ELISPOT responses in longitudinal collected on-treatment samples (P = 0.0009, Wilcoxon signed-rank test; Fig. 4C). Moreover, the magnitude of best on-treatment antigen-specific IFNγ responses (Fig. 4D) as well as the proportion of subjects with an overall positive ELISPOT response was highest in the patients with clinical response (PR; Fig. 4E).

Immune cell infiltration of tumors was evaluated with multiplex immunofluorescence (mIF; Akoya Biosciences). For each slide, fluorescence brightfield whole slide scans (WSS) were acquired at 10× using the Vectra image capture system. Up to five nonoverlapping image fields for each slide were captured using the Vectra system at 20× magnification and processed using inForm software. Results indicated subjects with tumor regression show a trend toward higher baseline and on-treatment infiltration of immune cells both in the percentage of cells and density compared with subjects without tumor regression. When assessing on-treatment samples, on average, subjects with tumor regression showed increased infiltration of lymphocytes, including cytotoxic T cells (CD3⁺ and CD8⁺), memory T cells (CD45RO⁺), and B cells (CD20). A representative mIF figure showing a 3.5-fold increase in cytotoxic T cells, 1.9-fold increase in memory T cells and 1.1-fold increase in B-cell percentage in the on-treatment sample is shown in Fig. 5.

This is the first report that describes the clinical efficacy of a novel T-cell stimulating therapy for the treatment of recurrent ovarian cancer. Treatment of patients with recurrent platinum-sensitive and resistant ovarian cancer using maveropepimut-S and intermittent, low-dose cyclophosphamide resulted in ORR and DCR of 21.1% and 63.2%, respectively. Clinical responses were observed in patients with platinum-sensitive (ORR 25.0%) and platinum-resistant disease (18.2%). In addition, clinical responses were observed in patients with up to six prior lines of therapy, prior exposure to PARP inhibitors and/or bevacizumab, and regardless of BRCA mutation status. The treatment of maveropepimut-S and cyclophosphamide showed promising clinical benefits in patients with recurrent ovarian cancer. The response rates in this study are higher than expected in patients with recurrent ovarian cancer following multiple lines of chemotherapy. Further clinical studies will investigate whether maveropepimut-S/cyclophosphamide treatment improves the standard-of-care in this patient population.

Historically, therapeutic cancer vaccines have been widely studied in the past decades in numerous clinical trials and numerous indications. Unfortunately, these prior cancer vaccine efforts have largely disappointed in eliciting clinical benefit (reviewed in Chow 2020; ref. 38). Among the cancer vaccines assessed in phase II studies, protein or peptide antigen targeting P53 (39), WT1 (40), SART2 and ART4 (41) had reported best responses as SD only. Despite a well-known suppression effect on regulatory T cell (Treg) function as a chemotherapeutic agent (42), adding cyclophosphamide to cancer vaccine regimens has only demonstrated SD responses without any better clinical outcome (42) over single-agent therapy. Immunologic responses were often noted in these cancer vaccine trials (43) with modest clinical benefit. Personalized vaccines using autologous dendritic cells (DC) pulsed with oxidized autologous whole-tumor cell lysate have been shown to elicit broad antitumor immunity (44). Gemogenovatucel-T (Vigil), an autologous tumor cell vaccine manufactured to reduce expression of the immune-suppressive TGF-β1 and TGF-β2, has demonstrated clinical benefit when used in first-line maintenance for patients with homologous recombination proficient ovarian cancer (45).

In the DeCidE¹ study, maveropepimut-S has shown clinical responses, including PR and SD, regardless of platinum-resistant status. Considering the limited response to other therapies (36), these results support further investigation of maveropepimut-S/cyclophosphamide in platinum-resistant patients.

The benefits of the maveropepimut-S/cyclophosphamide treatment are not confined to patients who achieve a measurable response by RECIST v1.1. Patients often derive clinical benefit from stabilization of the disease while maintaining a good quality of life (46). In our trial, four subjects with SD by RECIST v1.1 maintained clinical benefit for 24.9, 11.8, 6.7, and 6.4 months, respectively. In addition, the therapy was well-tolerated without any significant safety concerns, an observation similar to that in previous maveropepimut-S treatment cohorts (36).

The mechanism of action of maveropepimut-S relies on its ability to generate de novo survivin-specific, cytotoxic T cells, as demonstrated in several other clinical trials (36, 47). In the DeCidE¹ trial, we have shown that maveropepimut-S generates survivin-specific T-cell responses in the blood and promotes clonal expansion and diversity of survivin-specific T cells in the tumor (33, 48). Our current data suggest that the magnitude of the systemic, survivin-specific T-cell response by IFNγ might be associated with the observed clinical benefit. In addition, the TME might be an important modulator of response to maveropepimut-S/cyclophosphamide. In our current analysis of the TME in target lesions prior to maveropepimut-S/cyclophosphamide treatment, we find higher baseline levels of T- and B-cell infiltration in patients with a better response to maveropepimut-S/cyclophosphamide (49). In contrast, in patients who lack clinical response to maveropepimut-S/cyclophosphamide, we found baseline upregulation of pathways in the TME that are known to suppress antitumor T-cell responses (e.g., the β-catenin pathway). Further exploration of the TME might lead to the identification of biomarkers or predictors of response that could improve the selection of patients with predicted benefit to maveropepimut-S/cyclophosphamide.

Our clinical trial has several limitations, including a small sample size and a heterogenous patient population. The next phase of development of maveropepimut-S/cyclophosphamide will need to focus on a more homogenous cohort of patients with recurrent ovarian cancer, e.g., patients with platinum-resistant disease only.

The combination treatment of maveropepimut-S and cyclophosphamide was well-tolerated and showed promising clinical benefit in patients with recurrent ovarian cancer regardless of platinum sensitivity. Our data support further investigation of an expanded cohort in patients with recurrent ovarian cancer.

O. Dorigo reports grants and personal fees from IMV during the conduct of the study; grants from Bioclipse, EMD Serono, Novartis, AstraZeneca, Millenium Pharma, and Clovis Oncology; and personal fees from PSI CRO Deutschland GmbH, Eisai, PACT, Agenus, Epsila Bio, R-Pharm U.S., and Clovis Oncology outside the submitted work. A.M. Oza reports PI and Steering Committees with AstraZeneca, GSK, and Clovis, as well as Advisory Boards with AstraZeneca and Morphosys. S.A. Ghamande reports grants from IMV during the conduct of the study, as well as personal fees from GSK and Eisai outside the submitted work. L.D. MacDonald reports other support from IMV Inc. during the conduct of the study and has a patent for PCT/IB2019/059899 pending. H. Torrey reports other support from IMV Inc. during the conduct of the study. V. Kaliaperumal reports other support from IMV Inc. during the conduct of the study. H.A. Hirsch reports personal fees from CRISPR Therapeutics outside the submitted work. Y.M. Bramhecha reports other support from IMV Inc. during the conduct of the study. S. Fiset reports other support from IMV Inc. during the conduct of the study and has a patent for PCT/IB2019/059899 pending. No disclosures were reported by the other authors.

O. Dorigo: Conceptualization, formal analysis, supervision, investigation, writing–original draft, writing–review, and editing. A.M. Oza: Conceptualization, investigation, writing–review, and editing. T. Pejovic: Investigation, writing–review, and editing. P. Ghatage: Investigation, writing–review, and editing. S. Ghamande: Investigation, writing–review, and editing. D. Provencher: Investigation, writing–review, and editing. L.D. MacDonald: Conceptualization, data curation, formal analysis, methodology, writing–original draft, project administration, writing–review, and editing. H. Torrey: Data curation, validation, methodology, writing–review, and editing. V. Kaliaperumal: Data curation, validation, methodology, writing–review, and editing. W. Ebrahimizadeh: Data curation, formal analysis, validation, methodology, writing–original draft, writing–review, and editing. H.A. Hirsch: Formal analysis, validation, methodology, project administration, writing–review, and editing. Y. Bramhecha: Data curation, formal analysis, methodology, writing–original draft, project administration, writing–review, and editing. J. Villella: Conceptualization, investigation, writing–review, and editing. S. Fiset: Conceptualization, resources, data curation, formal analysis, supervision, writing–original draft, project administration, writing–review, and editing.

This work was funded by IMV Inc. We thank the patients and their families for their participation in this study, as well as the study teams at each of the study sites. We thank Kathya Daigle, MSc, and Barry Kennedy, PhD, for their technical contribution to this study.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.