Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients.
The immunosuppressive environment of advanced tumors is a primary obstacle to the efficacy of immunostimulatory and vaccine approaches. Here, we report an approach to arm an oncolytic virus with CD40 ligand (CD40L) to stimulate beneficial immunologic responses in patients. A double-targeted chimeric adenovirus controlled by the hTERT promoter and expressing CD40L (CGTG-401) was constructed and nine patients with progressing advanced solid tumors refractory to standard therapies were treated intratumorally. No serious adverse events resulting in patient hospitalization occurred. Moderate or no increases in neutralizing antibodies were seen, suggesting effective Th1 immunologic effects. An assessment of the blood levels of virus indicated 17.5% of the samples (n = 40) were positive at a low level early after treatment, but not thereafter. In contrast, high levels of virus, CD40L, and RANTES were documented locally at the tumor. Peripheral blood mononuclear cells were analyzed by IFN-γ ELISPOT analysis and induction of both survivin-specific and adenovirus-specific T cells was seen. Antitumor T-cell responses were even more pronounced when assessed by intracellular cytokine staining after stimulation with tumor type-specific peptide pools. Of the evaluable patients, 83% displayed disease control at 3 months and in both cases in which treatment was continued the effect was sustained for at least 8 months. Injected and noninjected lesions responded identically. Together, these findings support further clinical evaluation of CGTG-401.
Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.
Sari
S
Pesonen
Iulia
I
Diaconu
Lotta
L
Kangasniemi
Tuuli
T
Ranki
Anna
A
Kanerva
Saila K
SK
Pesonen
Ulrike
U
Gerdemann
Ann M
AM
Leen
Kalevi
K
Kairemo
Minna
M
Oksanen
Elina
E
Haavisto
Sirkka-Liisa
SL
Holm
Aila
A
Karioja-Kallio
Satu
S
Kauppinen
Kaarina P L
KP
Partanen
Leena
L
Laasonen
Tima
T
Joensuu
Tuomo
T
Alanko
Vincenzo
V
Cerullo
Akseli
A
Hemminki
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000328:Adult; D000914:Antibodies, Viral / Q000032:analysis; D023201:CD40 Ligand / Q000032:analysis / Q000235:genetics*; D018946:Chemokine CCL5 / Q000032:analysis; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D049268:Positron-Emission Tomography; D019098:Telomerase / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology; D014057:Tomography, X-Ray Computed; D014771:Virion / Q000302:isolation & purification
D000914:Antibodies, Viral; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D023201:CD40 Ligand; D007371:Interferon-gamma; C509186:TERT protein, human; D019098:Telomerase