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I) Adjuvant DC vaccinations for MSI-positive CRC patients (n=5)

II) Preventive DC vaccinations for carriers of germline MMR-gene mutation (n=20) withhout manifestation of CRC

DC vaccination

Nicoline Hoogerbrugge-van der Linden, professor

Jolanda IM de Vries, professor

Objectives:

In this Radboud University Nijmegen Medical Centre (RUNMC) initiated study our first objective is to investigate toxicity (safety and feasibility) of vaccination with frameshift-derived neoantigen-loaded DC of CRC patients with an MSI-positive CRC and persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet.

The secondary objectives of the study are:

* to demonstrate that peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population.
* to study the pathological and clinical responses, e.g. disease-free survival, determined according to the standard protocol.

Study design:

This study is a phase I/II open-label study.

Study population:

Two groups of adults will be vaccinated:

Group I) CRC patients, who are known to carry a germline MMR-gene mutation and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status.

Group II) persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet. All participants need to be HLA-A2.1 positive.

Rationale of this study:

Ex vivo generated and tumor-antigen-loaded dendritic cells (DC) are currently used in clinical vaccination protocols in cancer patients. DC vaccines are safe, with minimal side effects. Evaluating more than 200 patients treated the past ten years we found that clinical responses measured in several patients directly coincide with specific cytotoxic T cell responses. The majority of studies investigated the therapeutic effects of DC vaccines in late-stage cancer patients with metastasis. In these (heavily) pretreated patients the immune system is compromised. Based on our observations that a specific immune response is indicative for a good clinical outcome we believe that the full potential of these immunostimulatory cells has to be exploited in high-risk patients with low tumor burden or in a precancerous state.

A good clinical model are carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes, such as patients with Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer or HNPCC). These persons have a lifetime risk of 60-80% for colorectal cancer that has developed within a few years from a precancerous adenoma. The immune system is thought to be of potential great importance as the colorectal cancer in Lynch syndrome is characterized by a strong lymphocyte infiltration, even at the stage of adenomas. In affected cancer lesions, MMR dysfunction results in frameshift mutations at short, repetitive DNA sequences referred to as microsatellites. In coding regions these mutations destroy gene function and have been demonstrated to lead to the production of neopeptides. These neopeptides are: 1) tumor specific, because frameshift mutations only occur in tumor cells and their premalignant progenitors, 2) are very similar between patients, since the same genes are affected by the mismatch repair defect and 3) immunogenic, since cytotoxic T cells (CTL) and helper T cells could be induced in vitro from blood of patients with Lynch syndrome. Similar mechanisms occur in sporadic colon cancer with MMR dysfunction, which represents about 10-15% of all colorectal 2.

Objectives:

In this Radboud University Nijmegen Medical Centre (RUNMC) initiated study our first objective is to investigate toxicity (safety and feasibility) of vaccination with frameshift-derived neoantigen-loaded DC of CRC patients with an MSI-positive CRC and persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet.

The secondary objectives of the study are to demonstrate that peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population. And we want to study the pathological and clinical responses, e.g. disease-free survival, determined according to the standard protocol.

Study design:

This study is a phase I/II open-label study.

Study population:

Two groups of adults will be vaccinated:

Group I) CRC patients, who are known to carry a germline MMR-gene mutation and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status.

Group II) persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet. All participants need to be HLA-A2.1 positive.

Main study endpoints:

The first objective of this study is to toxicity (safety and feasibility) of vaccination with frameshift-derived neoantigen-loaded DC. This will be measured by recording of the adverse events according to the Common Terminology Criteria for Adverse Events version 3.0.

The secondary objectives of the study are to demonstrate that peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population. Immune responses will be assessed as:

* proliferative and humoral response to KLH
* cytokine production of KLH stimulated PBMC
* tumor antigen-specific T cell responses in peripheral blood
* tumor antigen-specific T cell responses in biopsies from DTH
* cytokine production of T cells in biopsies from DTH
* cytotoxicity of T cells in biopsies from DTH
* immunohistochemical characterization of DTH infiltrating lymphocytes

The pathological and clinical responses, e.g. disease-free survival, will be determined according to the standard protocol.

Dendritic Cell Vaccination in Patients With Lynch Syndrome or Colorectal Cancer With MSI

Data will be shared in an upcoming publication.

Patients will be followed for toxicity, autoimmunity and immunological response during the study and 2 and 6 months thereafter at the outpatient clinic. Subsequently, follow up will be performed as for standard practice.

Toxicity will be assessed using the Clinical Toxicity Criteria NCI CTC version 3.0.

Pathological evaluation: Biopsies of carcinomas and or adenomas will be taken. One will be snap frozen and stored at -80 and one will be fixed in buffered formalin, for maximum of 24 hours and processed using microwave enhanced procedures. The composition of the tissue will be evaluated using standard histology supplemented with immunohistochemistry for subsets of inflammatory cells. The amount of and composition of the inflammation will be quantified using automated and semi automated quantitative methods. Based on initial results mRNA studies on cytokines and or chemokines will be performed and in addition immunohistochemistry for receptors for these molecules.

Progression-free survival is defined as the time from registration to the first recurrence of disease. Overall survival is defined as the time from registration to death. The status of disease is determined at regular intervals by taking the patients's history, physical examination, and colonoscopy. If signs or symptoms suggest disease recurrence at any site, the appropriate tests should be performed to confirm or exclude this.

Radboud University Medical Center

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Cisplatin

mature DC injected intradermally and intravenously loaded with mRNA encoding tumor-associated antigens gp100 and tyrosinase

mature DC injected intradermally and intravenously loaded with mRNA encoding tumor-associated antigens gp100 and tyrosinase. each DC vaccine will be preceded by cisplatin infusion: 50 mg/m2, 1-2h before DC injection.

DC vaccination with cisplatinum

Winette van der Graaf, professor

This is an exploratory study and the primary objective is the immunogenicity and feasibility of combined chemotherapy-DC vaccination. The secondary objectives are the toxicity and clinical efficacy. This study will provide important data on the immunological efficacy of DC immunochemotherapy.

1. Rationale Investigators have explored immunotherapy and have now vaccinated well over 200 stage III and IV melanoma patients in the Netherlands with monocyte-derived dendritic cell (DC) vaccines and proved that DC therapy is safe with minimal side effects.

   Cytotoxic chemotherapy and radiotherapy have long been viewed as strategies that directly impact the viability of the tumor cell, and that the immune system contributed little to their efficacy. The commonly held opinion was that chemotherapy and immunotherapy could not be combined because of the myelo-suppressive effect of most chemotherapeutic agents. However, it becomes increasingly obvious that chemotherapy also possess the capacity to trigger tumor antigen release and danger signals in a manner that provokes engagement of innate and adaptive immunity that may be capitalized upon.

   Small proof-of-concept clinical trials in cancer patients indicate that the efficacy of anti-cancer vaccines may indeed be enhanced by chemotherapy \[2\]. Also preliminary observations indicate that chemotherapeutic agents, in particular platinum compounds (cisplatin, carboplatin and oxaliplatin) are immunogenic and may contribute to reverse tumor cell induced immunosuppression/immune deviation.

   Investigators hypothesize that DC vaccination, when combined with other more conventional anti-tumor treatments such as chemotherapy, that eradicate large numbers of cancer cells, may allow the T cells to clear the remaining cancer cells and to provide immunological memory to prevent relapse.
2. Objectives This is an exploratory study and the primary objective is the immunogenicity and feasibility of combined chemotherapy-DC vaccination. The secondary objectives are the toxicity and clinical efficacy. This study will provide important data on the immunological efficacy of DC immunochemotherapy.
3. Study design This study is an open label randomized phase II study.
4. Study population Our study population consists of melanoma patients, with expression of melanoma associated tumor antigens gp100 and tyrosinase. Melanoma patients with regional lymph node metastasis in whom a radical lymph node dissection is performed within 2 months of inclusion in this study (further referred to as stage III) and melanoma patients with measurable distant metastases (further referred to as stage IV) will be included.
5. Main study endpoints The primary objective of the study is to investigate the immunogenicity and feasibility of combined chemotherapy-DC vaccination. The secondary objective is to investigate the toxicity and clinical responses (only in stage IV) upon DC immunochemotherapy.

Platin-based Chemotherapeutics to Enhance Dendritic Cell Vaccine Efficacy in Melanoma Patients

Immunochemotherapy: Do Platin-based Chemotherapeutics Enhance Dendritic Cell Vaccine Efficacy in Melanoma Patients?

Urinary Tract, Sexual Organs, and Pregnancy Conditions

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Urogenital Neoplasms

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Ovarian Cancer

Ovarian Epithelial Cancer

DC vaccination with 1 x 10(6th) tumor lysate or WT1 and MUC1 peptide and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals(6 weeks)

DC vaccination with 1 x 10(6th) tumor lysate or tumor peptides and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals; (6 weeks)

Tina Porubsky, RN

Cheryl Czerlanis, MD

Ronald Potkul, MD

Amir Elmishad, MD

Patrick Stiff, MD

The purpose of this study is to determine if a dendritic cell vaccine made with autologous tumor lysate or for patients who are HLA-A2 with peptides of MUC1 and WT1 therapy will produce remissions in patients with advanced ovarian cancer. This research is being done because we want to find new therapies for treatment of relapsed or refractory (resistant to ordinary treatment) ovarian cancer. The use of vaccine therapy is research.

A new experimental approach for treating refractory or relapsed ovarian cancer involves using the patients own immune system to kill the cancer cells. These immune cells are called monocytes and are harvested from blood. The process of Leukapheresis collects the monocytes called Dendritic Cells. This is usually a 3 hour process done in the comfort of a hospital bed in the apheresis lab, similar to giving blood for donation. Approximately 300cc's are collected during this process, the equivalent of about 10 ounces of blood. Once these dendritic cells are collected - a special laboratory grows and processes them into a vaccine using a patient's own tumor cells or for those with a specific HLA type (HLA-A2) with tumor peptides. This preparation is then given back to the patient hopefully to stimulate the immune system to kill cancer cells. This type of treatment is considered biological research.

Patients with advanced ovarian carcinoma who have failed initial curative chemotherapy attempts will be evaluated at the time of relapse for tumor debulking surgery prior to the initiation of salvage chemotherapy. If appropriate, samples will be collected for tumor lysate preparation for vaccination as per the existing Loyola protocol. Lysates may also be produced by the collection of malignant effusions as performed for palliation of symptoms. Patients will then receive palliative chemotherapy to a maximum tumor cytoreduction. Patients from whom sufficient tumor cells have been collected for DC-based vaccine production will undergo a leukapheresis for DC cell production. Once completed, these patients will receive a DC vaccination with 1 x 106 tumor lysate and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals; or for those who are HLA-A2 restricted with pharmaceutical grade MUC1 and WT1 tumor peptides.

Ovarian Dendritic Cell Vaccine Trial

Defining the Role of CD4+CD25+ Immunoregulatory T-cells in the Treatment of Patients With Advanced Ovarian Cancer Who Receive Dendritic Cell Based Vaccine Therapies

Loyola University

Professor of Medicine, Director, Cardinal Bernardin Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dendritic Cell Vaccination in Patients With Lynch Syndrome or Colorectal Cancer With MSI	NCT01885702	Colorectal Canc...	DC vaccination	18 Years - 75 Years	Radboud University Medical Center
Platin-based Chemotherapeutics to Enhance Dendritic Cell Vaccine Efficacy in Melanoma Patients	NCT02285413	Melanoma	DC vaccination DC vaccination ...	18 Years - 70 Years	Radboud University Medical Center
Ovarian Dendritic Cell Vaccine Trial	NCT00703105	Ovarian Cancer	DC vaccination	18 Years -	Loyola University

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