NEOadjuvant Dendritic Cell Vaccination for Ovarian Cancer

Study Overview
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Brief Summary
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This goal of this single arm, single center, exploratory phase I/II clinical trial is to learn more about the immunological efficacy, safety and feasibility of an autologous tumor lysate-loaded autologous XP-DC (cDC1)-based vaccine in patients with ovarian cancer.

Detailed Description
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Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Despite intensified treatment, 5-year overall survival rates only improved modestly over the last 20 years and remain low at around 30% for patients with advanced disease in the Netherlands. To this day, results from trials with the checkpoint inhibitors, that have revolutionized treatment in other cancer types, have been disappointing in EOC. Therefore, novel effective therapies are long awaited. Recently, naturally circulating blood -derived dendritic cells (nDC) were shown to be potent in inducing cytotoxic immune responses and tumor regression in cancer patients. An even more specialized DC subset, referred to as cDC1 (conventional Dendritic Cells type 1) or XP-DC (specialized cross presenting DC) have shown their superiority in preclinical models. They are better at inducing cytotoxic T-cell responses against tumors after uptake of necrotic tumor cell material, a phenomenon called cross-presentation. This capability in cross-presentation makes XP-DC an ideal DC type in combination with tumor lysate-loading to induce immune responses against the scarce neoantigens present in EOC tumors. The objective of this exploratory trial is to investigate the immunological efficacy as well as safety and feasibility of tumor-lysate loaded XP-DC in EOC patients undergoing (neo-)adjuvant chemotherapy. To this end 10 patients with stage III ovarian cancer will be included and offered a combined approach with DC vaccination in addition to standard-of-care chemotherapy and surgery. Extensive monitoring of the immune system throughout the course of the trial will be performed.

Official Title
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Induction of Neo-Antigen Specific Cytotoxic T Cells by Autologous Tumor Lysate-loaded Specialized Cross-Presenting Dendritic Cells in Epithelial Ovarian Cancer Patients Treated With Neoadjuvant Chemotherapy, the NEODOC Study

Conditions
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Epithelial Ovarian Cancer, Ovarian Carcinoma

Intervention / Treatment
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* Biological: XP-DC vaccinations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women over 18 years old with histologically confirmed primary epithelial ovarian cancer. Not amenable by primary debulking surgery and in need of neoadjuvant chemotherapy and interval debulking High-grade serous histology FIGO stage IIIc or FIGO stage IIIb with extensive abdominal spread WHO/ECOG performance status 0-1 Neutrophils >1.5x 109/L lymphocytes >0.8x 109/L, platelets >100x 109/L, hemoglobin >5,6 mmol/L (9.0 g/dl), estimated glomerular filtration rate > 45 ml/min/1.73m2, AST/ALT <3 x ULN, serum bilirubin <1.5 x ULN (exception: Gilbert's syndrome is permitted) Expected adequacy of follow-up Postmenopausal or evidence of non-childbearing status or for women of childbearing potential: negative urine or serum pregnancy test, within 28 days of study treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as 1) Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments or 2) surgical sterilisation (bilateral oophorectomy or hysterectomy). Informed consent Exclusion Criteria: Recurrent ovarian cancer Histologies other than high grade serous ovarian cancer such as, but not restricted to, endometrioid, low-grade serous, mucinous, clear cell or carcinosarcoma Unable and/or unwilling to undergo standard chemotherapy and interval debulking surgery FIGO stage I-IIb, stage IIIa, stage IV History of any second malignancy, with the exception of adequately treated basal cell carcinoma Any serious clinical condition that may interfere with the safe administration of DC vaccinations Heart failure (NYHA class III/IV) Any uncontrolled co-morbidity, e.g. psychiatric or social conditions interfering which participation Unable to undergo a tumor biopsy Pregnancy or insufficient anti-conception if reproduction is still possible Active infection of Hepatitis B, C, HIV and syphilis Serious other active infections Known allergy to shell fish Auto immune disease (exception: vitiligo is permitted) History of organ allografts Chronic treatment with systemic immunosuppressive drugs (i.e. more than 10 mg prednisolone equivalent)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XP-DC vaccinations<br>Patients in this arm will receive XP-DC vaccination in addition to standard-of-care treatment. | Biological: XP-DC vaccinations<br>* Autologous cross-presenting dendritic cells loaded with autologous tumor lysate and KLH<br>* Other names: cdc1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with an immunological response to XP-DC vaccination | Immunologically responding patients are defined as: T cells isolated from vaccine challenged sites (DTH biopsies) that can be expanded and 1) express T cell receptors specific for the vaccine and 2) show effector functions measured by IFN-gamma secretion or cytolytic activity against tumor antigen expressing target cells. Immunologically non-responding patients are defined as: No T cells, or T cells isolated from DTH biopsies that cannot be expanded, or T cells that can be expanded but do not recognize tumor antigens, or can recognize tumor antigens but do not display T effector functions i.e. lysis of tumor cell targets or release of IFN-α. | At DTH skin test after the second vaccination (approximately study week 10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by incidence of treatment-related adverse events | Toxicity will be assessed according to CTCAE version 4.03. | Throughout the treatment phase until 1 year of follow-up | 
| Feasibility of tumor lysate-loaded XP-DC vaccinations in patients with stage III EOC | Feasibility assessment will be based on reporting of: the number of patients from whom a successful apheresis product can be obtained the number of patients from whom (both quantitatively and qualitatively) sufficient tumor lysate can be obtained the number of patients for whom a DC product can be manufactured that meets the prespecified criteria the number of patients that has received the planned number of vaccinations. | Throughout the treatment phase until the last planned vaccination (approximately study week 23) | 
| Recurrence free survival (RFS) after 12 months |  | 1 year | 
| Number of patients with complete pathological response |  | At time of debulking surgery (approximately study week 11) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, dendritic cell vaccination, ovarian cancer