Abstract
Platinum-resistant ovarian cancer frequently develops in response to multiple lines of chemotherapy, whereupon the disease becomes relatively intractable and clinical recourse is limited. We document a 58-year-old, advanced-stage, platinum-resistant ovarian cancer patient who previously failed numerous cytotoxic and targeted therapy regimens. She was referred to our gynecologic oncology service with a CA-125 of 3194 U/mL and underwent a modified vaccinia virus coinciding with an IRB approved clinical trial. Following the oncolytic therapy and Cycle 8 chemotherapy, the patient’s CA-125 declined to 440 U/mL; a CT-scan of the abdomen and pelvis revealed a partial response to therapy. The favorable clinical benefit encountered in our case study indicate that the combination of oncolytic viral therapy and chemotherapy should be considered as a therapeutic option for heavily pre-treated ovarian patients who are resistant to traditional approaches to standard of care.
Keywords: ovarian cancer, oncolytic viral therapy, platinum-resistance, clinical response
Introduction
Ovarian cancer is the second most common gynecologic neoplasm in the United States, accounting for 21,410 newly diagnosed cases in 2021 [1]. Standard of care for advanced-stage ovarian cancer encompasses cytoreductive surgery and intravenous platinum/taxane chemotherapy [2]. Initially, most patients respond favorably to their first-line chemotherapy, but ultimately ovarian cancer remains the fifth leading cause of cancer deaths among women [3].
The re-treatment of platinum-based chemotherapy is indicated for recurrent ovarian cancer patients whose platinum-induced clinical response transcended 6 months’ duration [4]. Conversely, for patients with platinum-resistant disease, one may consider single agent topotecan, paclitaxel, bevacizumab and pegylated liposomal doxorubicin or a combination thereof, but response rates are low and overall survival is approximately 12 months [5]. Hence, novel, effective therapies to manage recurrent ovarian cancer are warranted.
Anecdotally, immunotherapy is a viable option for treating ovarian cancer because the disease is highly immunogenic [6]. Moreover, since ovarian cancer is frequently confined to the peritoneal cavity, oncolytic viral therapy is enticing because the treatment is administered loco-regionally [7]. Olvimulogene nanivacirepvec (Olvi-Vec), an anti-cancer vaccine under investigation for the treatment of various malignancies [8], has reportedly been associated with favorable clinical and safety data in the management of recurrent ovarian cancer [9-11]. Herein, we present the history of a heavily pre-treated ovarian cancer patient who exhibited a durable clinical response following treatment with the Olvi-Vec vaccine and chemotherapy.
Case description
A 58-year-old (gravida 2, para 1) female, never-smoker, originally presented to an outside gynecologic oncology service in April 2012 with a large pelvic mass and an elevated CA-125. The patient’s medical history was significant for osteoporosis, chronic pedal edema, gastritis and a pulmonary embolism.
Initially, the patient underwent an extensive exploratory laparotomy with splenectomy, cholecystectomy, total abdominal hysterectomy and bilateral salpingo-oophorectomy in April 2012. Final pathology revealed a stage IIIC, poorly differentiated, serous ovarian adenocarcinoma. Thereafter, she was treated with adjuvant intraperitoneal cisplatin (100 mg/m2) and paclitaxel (60 mg/m2) every three weeks for six cycles.
The patient sustained a clinical response for approximately 18 months, whereupon she exhibited disease progression in the left, distal ureter and left hepatic lobe in September 2014. The patient underwent debulking surgery and completed 6 cycles of carboplatin (AUC 5) and liposomal doxorubicin (30 mg/m2) chemotherapy in April 2015; the patient’s CA-125 was normalized at 11 U/mL.
In November 2015, the patient’s CA-125 increased to 38 U/mL and she commenced with oral cyclophosphamide (150 mg), but the patient relapsed in December 2015, with a CA-125 of 519 U/mL. Subsequently, the patient completed two cycles of niraparib (300 mg/day) but progressed on therapy. In March 2016, she initiated bevacizumab (10 mg/kg) and cyclophosphamide (50 mg) chemotherapy but relapsed after two cycles. The patient completed six cycles of paclitaxel (80 mg/m2) and bevacizumab (10 mg/kg) in December 2016 and her CA-125 declined to 383 U/mL.
In March 2017, the patient exhibited disease progression and was treated with intravenous pembrolizumab (200 mg), but her CA-125 remained elevated at 473 U/mL in November 2017; a CT scan of the abdomen and pelvic demonstrated pelvic lymph node metastases. The patient underwent pelvic radiotherapy (50.4 Gy) and was treated with tamrintamab pamozirin (0.025-0.4 mg/kg every 3 weeks) for 3 cycles until she progressed on therapy in January 2018. The patient was treated again with carboplatin and liposomal doxorubicin chemotherapy but in January 2019, her CA-125 increased to 3194 U/mL.
In February 2019, she was referred to a Phase 2 clinical trial (NCT02759588) involving Olvi-Vec, an oncolytic vaccinia virus. The patient underwent an exploratory laparotomy with lysis of adhesions and placement of an intraperitoneal port-a-cath in preparation for the Olvi-Vec treatment. A CT scan demonstrated measurable disease (Figures 1a-c).
Procedure: A 5-mm laparoscopic incision was made along the left midclavicular line, inferior to the intercostal margin; upon entering the peritoneal cavity, CO2 was used to insufflate the abdomen to 15mmHg. A second 5mm trocar incision was made approximately 6 cm caudally from this incision and another 5mm trocar was inserted for direct visualization. The intraperitoneal catheter was then threaded through the second incision and secured once the trocar was extracted. In 3–7 days thereafter, Olvi-Vec (3×109 pfu over 10 minutes on days 1 and 2) was administered via the intraperitoneal catheter.
Postoperatively, the patient had a fever, which subsided within a week. In April 2019, she began a regimen comprising gemcitabine (800 mg/m2), bevacizumab (15 mg/kg) and carboplatin (AUC 4). The patient was doing well in May 2019 and her CA-125 declined to 1444 U/mL, whereupon a follow-up CT scan of the abdomen and pelvis continued to demonstrate stable disease, according to RECIST criteria [12], However, after cycle 8 in September 2019, the gemcitabine was discontinued due to neutropenia, and she continued with the bevacizumab and carboplatin.
A CT scan of the abdomen and pelvis in December 2019 exhibited a partial response during Cycle 8 (Figures 2a-c), and her CA-125 declined to 447 U/mL. The patient continued to respond to treatment but in March 2020, her CA-125 increased to 2660 U/mL and a CT scan of the abdomen and pelvis corroborated disease progression. The patient expired in June 2020 due to cardiopulmonary complications.
Discussion
Ovarian cancer contributes to nearly 14,000 deaths annually, with an inauspicious overall 5-year survival rate of 48% [3]. Despite relatively high initial response rates to primary induction chemotherapy, patients become increasingly resistant to subsequent therapies and correspondingly, exhibit diminishing progression-free intervals [13]. Hence, more effective ovarian cancer treatments are indicated.
Viral therapy was originally considered as a treatment for malignancies in the early aughts of the 19th century when tumor regression was observed in patients who were immunocompromised [14]. Cancer cells are particularly susceptible to the viral effects, rendering them vulnerable to infections. Accordingly, modified viruses can specifically target neoplastic cells and generate an immune response, while simultaneously preserving the integrity of healthy cells [15].
We review the history of a recurrent ovarian cancer patient who failed successive lines of therapy. The patient underwent Olvi-Vec, an oncolytic vaccinia virus, and chemotherapy; the combination therapy ultimately engendered a partial response to therapy, an effect which persisted for approximately 6 months.
Holloway et al. [9] reported on their clinical trial experience with Olvi-Vec and chemotherapy in a cohort of heavily pre-treated, platinum-resistant or refractory ovarian cancer patients. In their 27 patients, of whom 48% were platinum-resistant, the median overall survival was 15.7 months and 33% of clinical subjects exhibited a survival exceeding 18 months. Additionally, Olvi-Vec has a reasonable safety profile, with adverse reactions comprising rigors, nausea, pyrexia, abdominal pain and emesis [10].
Conclusion
Oncolytic viral therapy potentially confers significant promise in the treatment of intractable malignancies, namely ovarian cancer. In the current report, Olvi-Vec with chemotherapy effectuated a profound therapeutic benefit for our patient, who had persistently relapsed on numerous treatments. Moreover, the preliminary results for Olvi-Vec and chemotherapy in the treatment of platinum- resistant/refractory ovarian cancer are encouraging and will hopefully be corroborated by the aggregate results from the Phase 2 clinical trial.
Conflict of Interest
All authors deny any conflict of interest associated with this manuscript.
