Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer.

PURPOSE: Our previous studies indicated that p53-reactive T cells were associated with clinical benefit in patients with advanced ovarian cancer who were treated with p53-expressing modified vaccinia Ankara (p53MVA) vaccine and gemcitabine chemotherapy. To replace chemotherapy with an approach that will enhance vaccine efficacy and antitumor immunity, we treated patients with p53MVA in combination with PD-1 checkpoint blocker, pembrolizumab. We also attempted to further characterize the activation status of T cells prior to vaccination and during treatment. EXPERIMENTAL DESIGN: Patients received up to three triweekly vaccinations concurrent with pembrolizumab, followed by pembrolizumab monotherapy at 3-week intervals. Correlative studies analyzed peripheral blood T-cell phenotypes and profiles of immune function gene expression. RESULTS: We observed 6/28 (21%) patients with a clinical benefit to therapy, including 3 partial responses (PR) and 3 patients with stable disease (SD) for 6+ months. The median progression-free survival was 1.8 months (95% confidence interval: 1.7-3.8) and median overall survival was 15.1 months (9.4-30.4). Two patients remain progression-free at 28 and 33 months. Of the 18 patients evaluable in correlative studies, 6 were immunologic responders of whom 5 had clinical benefit (3 PR, 2 SD). Immunologic non-responders expressed in pretreatment peripheral blood mononuclear cell samples high levels of mRNA for multiple molecules associated with terminally differentiated T cells. CONCLUSIONS: p53MVA/pembrolizumab immunotherapy showed promising antitumor activity in patients who demonstrated functionally competent peripheral blood T cells. Detection of markers of terminally differentiated T cells before treatment may identify patients unlikely to respond to p53MVA/pembrolizumab. SIGNIFICANCE: The activity of a combination immunotherapy of p53 vaccine and PD-1 checkpoint blockade in patients with platinum-resistant ovarian cancer was evaluated in a phase II trial. Clinical benefit was correlated with the responsive immune status of patients before and during the treatment, defining potential predictive markers for immune therapy.

Impact of Sodium Thiosulfate on Prevention of Nephrotoxicities in HIPEC: An Ancillary Evaluation of Cisplatin-Induced Toxicities in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Complete Pathologic Response to PARP Inhibitor Olaparib in a Patient with Stage IVB Recurrent Endometrioid Endometrial Adenocarcinoma.

Treatment for endometrial cancer is rapidly evolving with the increased use and integration of somatic tumor RNA sequencing in clinical practice. There is a paucity of data regarding PARP inhibition in endometrial cancer given that mutations in homologous recombination genes are rare, and currently no FDA approval exists. A 50-year-old gravida 1 para 1 woman with a diagnosis of stage IVB poorly differentiated endometrioid endometrial adenocarcinoma presented to our comprehensive cancer center. Following surgical staging, she was placed on adjuvant chemotherapy with carboplatin/paclitaxel which was held multiple times due to poor performance status and complications. CT scan of the abdomen and pelvis following cycles 3 of adjuvant chemotherapy showed recurrent progressive disease. She received one cycle of liposomal doxorubicin but discontinued it due to severe cutaneous toxicity. Based on the BRIP1 mutation identified, the patient was placed on compassionate use of Olaparib in January 2020. Imaging during this surveillance period showed a significant decrease in hepatic, peritoneal, and extraperitoneal metastases, and eventually the patient had a clinical complete response in a year. The most recent CT A/P in December 2022 showed no sites of active recurrent or metastatic disease in the abdomen or pelvis. We present a unique case of a patient with recurrent stage IVB poorly differentiated endometrioid endometrial adenocarcinoma with multiple somatic gene mutations including BRIP1, who had a pathologic complete response following compassionate use of Olaparib for 3 years. To our knowledge, this is the first reported case of high grade endometrioid endometrial cancer that has shown a pathologic complete response to a PARP inhibitor.

Feasibility of combining pelvic reconstruction with gynecologic oncology-related surgery.

INTRODUCTION AND HYPOTHESIS: At our institution, every patient seen by the gynecologic oncology service is screened for pelvic floor dysfunction. This study was aimed at determining if a combined surgical approach by gynecologic oncology and urogynecology services at our institution was feasible and safe for this patient population. METHODS: We performed a retrospective review of patients undergoing combined surgery by gynecologic oncology and urogynecology services at our institution from 2013 to 2021. Perioperative variables, postoperative adverse events, and long-term outcomes were assessed, and descriptive statistics were performed. RESULTS: From 20 December 2013 to 29 January 2021, a total of 102 patients underwent concurrent surgical repair of pelvic organ prolapse and/or stress urinary incontinence. Seventy-three patients (71.6%) had normal/benign pathologic conditions, and 29 (28.4%) had premalignant/malignant pathologic conditions. Ten patients (9.8%) had a postoperative complication, including reoperation for exposed midurethral sling (4.9%), urinary retention requiring midurethral sling release (2.9%), reoperation for hemoperitoneum (1.0%), and anemia requiring blood transfusion (1.0%). Nine complications occurred in patients with benign/normal pathologic conditions (12.3%), and one complication occurred in patients with pre-malignant/malignant pathologic conditions (3.4%). CONCLUSIONS: In our single-institution experience, concurrent gynecologic oncology and pelvic floor reconstructive surgery were safe and feasible in combination with no reported major morbidity events.

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design.

Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods: This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7-25 mg/m2) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results: The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions: This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

Hyperthermic Intraperitoneal Chemotherapy-Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) confers a survival benefit in epithelial ovarian cancer (EOC) and in preclinical models. However, the molecular changes induced by HIPEC have not been corroborated in humans. PATIENTS AND METHODS: A feasibility trial evaluated clinical and safety outcomes of HIPEC with cisplatin during optimal cytoreductive surgery (CRS) in patients with EOC diagnosed with stage III, IV, or recurrent EOC. Pre- and post-HIPEC biopsies were comprehensively profiled with genomic and transcriptomic sequencing to identify mutational and RNAseq signatures correlating with response; the tumor microenvironment was profiled to identify potential immune biomarkers; and transcriptional signatures of tumors and normal samples before and after HIPEC were compared to investigate HIPEC-induced acute transcriptional changes. RESULTS: Thirty-five patients had HIPEC at the time of optimal CRS; all patients had optimal CRS. The median progression-free survival (PFS) was 24.7 months for primary patients and 22.4 for recurrent patients. There were no grade 4 or 5 adverse events. Anemia was the most common grade 3 adverse event (43%). Hierarchical cluster analyses identified distinct transcriptomic signatures of good versus poor responders to HIPEC correlating with a PFS of 29.9 versus 7.3 months, respectively. Among good responders, significant HIPEC-induced molecular changes included immune pathway upregulation and DNA repair pathway downregulation. Within cancer islands, % programmed cell death protein 1 expression in CD8+ T cells significantly increased after HIPEC. An exceptional responder (PFS 58 months) demonstrated the highest programmed cell death protein 1 increase. Heat shock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors. CONCLUSION: Distinct transcriptomic signatures identify responders to HIPEC, and preclinical model findings are confirmed for the first time in a human cohort.

PIPAC for the Treatment of Gynecologic and Gastrointestinal Peritoneal Metastases: Technical and Logistic Considerations of a Phase 1 Trial.

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

Pterostilbene in Cancer Therapy.

Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of red sandalwood. As recently reported by our group, PT was shown to be effective in the treatment of melanoma. Counterintuitively, PT is not effective (cytotoxic) against melanoma in vitro, and only under in vivo conditions does PT display its anticancer activity. This study elucidated that PT can be effective against melanoma through the inhibition of adrenocorticotropic hormone production in the brain of a mouse, which weakens the Nrf2-dependent antioxidant defenses of melanoma and also pancreatic cancers. This results in both the inhibition of tumor growth and sensitization of the tumor to oxidative stress. Moreover, PT can promote cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 content, a known stabilizer of lysosomal membranes. In addition, the safety of PT administered i.v. has been evaluated in mice. PT was found to be pharmacologically safe because it showed no organ-specific or systemic toxicity (including tissue histopathologic examination and regular hematology and clinical chemistry data) even when administered i.v. at a high dose (30 mg/kg per day × 23 days). Moreover, new pharmacological advances are being developed to increase its bioavailability and, thereby, its bioefficacy. Therefore, although applications of PT in cancer therapy are just beginning to be explored, it represents a potential (and effective) adjuvant/sensitizing therapy which may improve the results of various oncotherapies. The aim of this review is to present and discuss the results that in our opinion best support the usefulness of PT in cancer therapy, making special emphasis on the in vivo evidence.

Prolapse repair after anterior exenteration.

This report presents our experience in performing prolapse repair after anterior exenteration. The patient had a history of invasive bladder cancer and underwent a robotically assisted laparoscopic anterior exenteration with extended bilateral pelvic lymph node dissection and creation of an Indiana pouch continent diversion. Her pelvic organ prolapse progressed over time despite multiple pessary fittings. She eventually decided to proceed with pelvic reconstructive surgery 6 years after her cancer surgery. She underwent a successful vaginal native tissue reconstruction with uterosacral ligament suspension, posterior repair and reconstruction of the anterior compartment. The patient has been followed for 16 months without recurrent prolapse. Vaginal native tissue pelvic reconstruction is feasible in a patient with a history of pelvic exenteration.

Novel Chimeric Poxvirus CF17 Improves Survival in a Murine Model of Intraperitoneal Ovarian Cancer Metastasis.

Despite improvements in surgical techniques and chemotherapy, ovarian cancer remains the most lethal gynecologic cancer. Thus, there is an urgent need for more effective therapeutics, particularly for chemo-resistant peritoneal ovarian cancer metastases. Oncolytic virotherapy represents an innovative treatment paradigm; however, for oncolytic viruses tested from the last generation of genetically engineered viruses, the therapeutic benefits have been modest. To overcome these limitations, we generated a chimeric poxvirus, CF17, through the chimerization of nine species of orthopoxviruses. Compared with its parental viruses, CF17 has demonstrated superior oncolytic characteristics. Here, we report the oncolytic potential of CF17 in ovarian cancer. Replication of CF17 and its resulting cytotoxicity were observed at multiplicities of infection (MOIs) as low as 0.001 in human and mouse cancer cell lines in vitro. Furthermore, CF17 exerted potent antitumor effects in a syngeneic mouse model of ovarian cancer at doses as low as 6 × 106 plaque-forming units. Together, these data merit further investigation of the potential use of this novel chimeric poxvirus as an effective treatment for aggressive intraperitoneal ovarian cancer.

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer.

More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.

Neural Stem Cells Improve the Delivery of Oncolytic Chimeric Orthopoxvirus in a Metastatic Ovarian Cancer Model.

Oncolytic virotherapy represents a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance, which reduces viral delivery to the tumor. Patient-derived mesenchymal stem cells that home to tumors have been used as viral delivery tools, but variability associated with autologous cell isolations limits the clinical applicability of this approach. We previously developed an allogeneic, clonal neural stem cell (NSC) line (HB1.F3.CD21) that can be used to deliver viral cargo. Here, we demonstrate that this NSC line can improve the delivery of a thymidine kinase gene-deficient conditionally replication-competent orthopoxvirus, CF33, in a preclinical cisplatin-resistant peritoneal ovarian metastases model. Overall, our findings provide the basis for using off-the-shelf allogeneic cell-based delivery platforms for oncolytic viruses, thus providing a more efficient delivery alternative compared with the free virus administration approach.

Erratum: Enhanced Delivery of Oncolytic Adenovirus by Neural Stem Cells for Treatment of Metastatic Ovarian Cancer.

[This corrects the article DOI: 10.1016/j.omto.2018.12.003.].

NSCs are permissive to oncolytic Myxoma virus and provide a delivery method for targeted ovarian cancer therapy.

Despite the development of many anticancer agents over the past 20 years, ovarian cancer remains the most lethal gynecologic malignancy. Due to a lack of effective screening, the majority of patients with ovarian cancer are diagnosed at an advanced stage, and only ~20% of patients are cured. Thus, in addition to improved screening methods, there is an urgent need for novel anticancer agents that are effective against late-stage, metastatic disease. Oncolytic virotherapy is a promising approach; unfortunately, systemic delivery of viruses to tumors remains a major challenge. In this regard, neural stem/progenitor cells (NSCs) with well-established tumor-homing properties may serve as an effective delivery platform for oncolytic viruses. In this study, we tested the efficacy of myxoma virus (MYXV), a rabbit-specific poxvirus that has demonstrated efficacy against a variety of tumors, using human and mouse ovarian cancer cell lines. We showed that MYXV effectively lysed ovarian cancer cells in vitro, reducing their viability. We also demonstrated that MYXV can infect human NSCs, specifically the clonal HB1.F3.CD21 NSC line. Taken together, these results suggest that NSC-mediated delivery of MYXV may be a promising strategy for achieving more selectively targeted anti-tumor efficacy.