In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 2019-2019
Abstract:
2019 Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. The absence of functional dendritic cells from the brain precludes anti-brain tumor immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to the brain (Ad-Flt3L) to induce an effective anti-tumor immune response. This strategy induced an efficacious, cytotoxic CD8 and CD4 T-dependent immune response in many animal models of glioma. This immune response also generated anti-tumor memory, and the capacity for neoantigen recognition. Methods: The trial was approved by FDA and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 i.u., and increasing to 1x10^11 i.u. of each vector. Dose escalation proceeded by increasing the vector dose through a total of 6 combinations administered to 6 cohorts of 3 patients each. Two cycles of 14 days each of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1-3 post surgery for 14 days, and Cycle 2 on Week 8-12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Results: Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. At this time the MTD has not been reached. There were approx. 248 AEs, and 26 SAEs; these have not been linked to treatment. At this time the MTD has not been reached. A secondary outcome is overall survival. Preliminary analysis of partial data may suggest that the combined viral vector therapy may provide a clinically significant survival. Conclusions: Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2019.37.15_suppl.2019
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2019
detail.hit.zdb_id:
2005181-5
Bookmarklink