Antiglioma immunological memory in response to conditional cytotoxic/immune-stimulatory gene therapy: humoral and cellular immunity lead to tumor regression.
OBJECTIVE
Glioblastoma multiforme is a deadly primary brain cancer. Because the tumor kills due to recurrences, we tested the hypothesis that a new treatment would lead to immunological memory in a rat model of recurrent glioblastoma multiforme.


METHODS
We developed a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltration of immune cells into the tumor microenvironment, and an Ad expressing herpes simplex virus-1-thymidine kinase (TK), which kills proliferating tumor cells in the presence of ganciclovir.


RESULTS
This treatment induced immunological memory that led to rejection of a second glioblastoma multiforme implanted in the contralateral hemisphere and of an extracranial glioblastoma multiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme-specific T cells and displayed specific delayed-type hypersensitivity. Using depleting antibodies, we showed that rejection of the second tumor was dependent on CD8(+) T cells. Circulating anti-glioma antibodies were observed when glioblastoma multiforme cells were implanted intradermally in naïve rats or in long-term survivors. However, rats bearing intracranial glioblastoma multiforme only exhibited circulating antitumoral antibodies upon treatment with Ad-Flt3L + Ad-TK. This combined treatment induced tumor regression and release of the chromatin-binding protein high mobility group box 1 in two further intracranial glioblastoma multiforme models, that is, Fisher rats bearing intracranial 9L and F98 glioblastoma multiforme cells.


CONCLUSIONS
Treatment with Ad-Flt3L + Ad-TK triggered systemic anti-glioblastoma multiforme cellular and humoral immune responses, and anti-glioblastoma multiforme immunological memory. Release of the chromatin-binding protein high mobility group box 1 could be used as a noninvasive biomarker of therapeutic efficacy for glioblastoma multiforme. The robust treatment efficacy lends further support to its implementation in a phase I clinical trial.
Ghulam Muhammad
A K M
AK
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90048, USA.
Candolfi
Marianela
M
King
Gwendalyn D
GD
Yagiz
Kader
K
Foulad
David
D
Mineharu
Yohei
Y
Kroeger
Kurt M
KM
Treuer
Katherine A
KA
Nichols
W Stephen
WS
Sanderson
Nicholas S
NS
Yang
Jieping
J
Khayznikov
Maksim
M
Van Rooijen
Nico
N
Lowenstein
Pedro R
PR
Castro
Maria G
MG
D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D041722:Genes, Transgenic, Suicide / Q000235:genetics / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D056724:Immunity, Humoral / Q000235:genetics*; D007156:Immunologic Memory / Q000235:genetics*; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D051381:Rats; D012074:Remission Induction / Q000379:methods; D013937:Thymidine Kinase / Q000235:genetics; D047368:Tumor Burden
D008565:Membrane Proteins; C084881:flt3 ligand protein; D013937:Thymidine Kinase