Autologous Dendritic Cells Metronomic Cyclophosphamide and Checkpoint Blockade in Children With Relapsed HGG

  • STATUS
    Recruiting
  • End date
    Apr 30, 2024
  • participants needed
    25
  • sponsor
    Wuerzburg University Hospital
Updated on 26 January 2021

Summary

This phase I/II trials evaluates the feasibility, safety and efficacy of an individualized cancer vaccine, based on autologous, tumor-lysate loaded dendritic cells in children and adolescents with relapsed high-grade gliomas. In addition, regulatory T cells are depleted by a short cycle of metronomic cyclophosphamide upfront of the vaccine in order to facilitate induction of immune responses.

Therapeutic DC vaccines are followed by four cycles of Nivo/Ipi double checkpoint blockade and a Nivolumab monotherapy maintenance in order to optimize the induced T-cell response.

Description

Relapsed high-grade gliomas (in the following addressed as high-grade gliomas = HGG) in children and adolescents represent a very bad prognosis group for which a recommended standard salvage therapy is currently not available.

Combination of Dendritic Cell (DC) vaccination, metronomic cyclophosphamide, and checkpoint blockade will be investigated in the present trial as a new treatment strategy for these patients: metronomic cyclophosphamide has been shown to significantly reduce numbers of regulatory T cells (Treg) without inducing general leukopenia. DCs might induce tumour-directed immune responses thereby facilitating long-term remissions. Efficacy of primed T-cell responses by the vaccine will potentially be enhanced by the application of checkpoint inhibitors Nivolumab (antiPD-L1) and Ipilimumab (antiCTLA4) in the post-vaccine phase and during maintenance.

Cyclophosphamide is an established drug used as an anti-cancer or immunosuppressive substance since decades, with extensive experience when used in low, non-myeloablative dosages. DCs represent an innovative new strategy in cellular immunotherapy. DCs in cancer patients have been used in a number of smaller studies, and in some of these trials, promising results could be obtained. Several studies showed a trend towards a prolonged overall survival with a few long-term survivors which is otherwise extremely rare in this high-risk population. Results seemed to be more favourable in pediatric than in adult patients. Checkpoint inhibitors (antiPD-L1 and/or antiCTLA4) have been shown to exhibit synergistic effects with vaccines in preclinical models, and prelimnary data of several early stage trials have shown promising results. Therefore, our study aims to improve the efficacy of a DC-based therapeutic vaccine by optimizing the conditions upfront of the vaccine (Treg depletion) and improving T-cell responses by checkpoint blockade after the vaccine in the effector phase.

In conclusion, this study will exploit the optimal efficacy of a therapeutic vaccine in children and adolescents with relapsed HGG.

Details
Condition Childhood Glioblastoma
Treatment depletion of regulatory T cells, reoperation, reoperation, cancer vaccine, cancer vaccine, checkpoint blockade
Clinical Study IdentifierNCT03879512
SponsorWuerzburg University Hospital
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 3 yrs and 21 yrs?
Gender: Male or Female
Do you have Childhood Glioblastoma?
Do you have any of these conditions: Do you have Childhood Glioblastoma??
Diagnosis of relapsed high-grade malignant glioma confirmed by central neuropathological and neuroradiological review (last magnetic resonance imaging diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma World Health Organization (WHO III), anaplastic oligodendroglioma (WHO III), anaplastic oligoastrocytoma (WHO III), anaplastic pilocytic astrocytoma (WHO III), anaplastic ganglioglioma (WHO III), anaplastic pleomorphic xanthoastrocytoma (analogous to WHO III), giant cell glioblastoma (WHO IV), and gliosarcoma (WHO IV) relapsed after first-line therapy
Patients aged 3 years and older but under 21 years at time of relapse diagnosis
Written informed consent of the patient (mandatory from 14 years of age) or the parents (mandatory till 18 years of age)
Prospect of resection of relapse tumour by neurosurgery (total, subtotal or partial)

Exclusion Criteria

Known hypersensitivity or contraindication to cyclophosphamide
Known hypersensitivity or contraindications to Nivolumab or Ipilimumab
Other malignancies, either simultaneous or within the last 2 years
Active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
Pregnancy and / or lactation
Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly or surgical sterile)
Current or recent (within 4 weeks prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial
Severe concomitant diseases (e.g. immune deficiency syndrome)
Severe psychological disease or neurological damage without possibility to communicate
Clinical signs of intracranial pressure
Intracerebral hemorrhage, gliomatosis
No severe blood count abnormalities: leukocytes < 2.000/l, Hb <10 g/dl, thrombocytes < 100.000/l
No severe liver enzyme elevation (> 2-3x fold of normal)
Ongoing reirradiation or chemotherapy (within the last 4 weeks) (irradiation of formerly non-involved fields is allowed, but not part of this study)
Estimated life expectancy of less than 2 months
Preexisting severe cardiac disease
Presence of unresectable spinal metastases
Karnofsky index < 50%
Active infection within the last 2 weeks
Previous infection with Human Immunodeficiency, Hepatitis C, Human T-Lymphocyte 1/2, Hepatitis B Virus, Lues, protozoan parasites, or other chronic bacterial infections
With regard to prevention of variant Creutzfeldt-Jakob disease the following patients have to be excluded
Patients receiving systemic immunosuppressive or immunoactivating substances
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