Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients

Abstract

Background and aimsMalignant melanoma is an aggressive tumor sensitive for immunotherapy such as checkpoint blockade antibodies. Still, most patients with late stage disease do not respond, and the side effects can be severe. Stimulation of the CD40 pathway to initiate anti-tumor immunity is a promising alternative. Herein, we demonstrate immune profiling data from melanoma patients treated with an adenovirus-based CD40 ligand gene therapy (AdCD40L).MethodsPeripheral blood mononuclear cells and plasma were collected from malignant melanoma patients (n = 15) enrolled in a phase I/IIa study investigating intratumoral delivery of AdCD40L with or without low dose cyclophosphamide. Cells were analyzed by flow cytometry while plasma samples were analyzed by a multi-array proteomics.ResultsAll patients had an increased Teffector/Tregulatory cell ratio post therapy. Simultaneously, the death receptors TNFR1 and TRAIL-R2 were significantly up-regulated post treatment. Stem cell factor (SCF), E-selectin, and CD6 correlated to enhanced overall survival while a high level of granulocytic myeloid-derived suppressor cells (gMDSCs), IL8, IL10, TGFb1, CCL4, PlGF and Fl3t ligand was highest in patients with short survival.ConclusionsAdCD40L intratumoral injection induced desirable systemic immune effects that correlated to prolonged survival. Further studies using CD40 stimulation in malignant melanoma are warranted. Trial registration The 002:CD40L trial “Phase I/IIa AdCD40L Immunogene Therapy for Malignant Melanoma and Other Solid Tumors” (clinicalTrials.gov identifier: NCT01455259) was registered at September 2011

Evidence of Anti-tumoral Efficacy in an Immune Competent Setting with an iRGD-Modified Hyaluronidase-Armed Oncolytic Adenovirus

“… 16 Accordingly, the virus ICOVIR17K-iRGD might be more effective in clinical studies in which the replication will be more efficient than in the mouse model. Finally, immunovirotherapy may confer benefit to other strategies aimed at inducing anti-tumor immune responses, such as CD40L costimulation, 17 bispecific T cell engagers (BiTEs), 18 incorporation of immunostimulatory genes such as interleukin-12 (IL-12), 19 or checkpoint inhibitors. 20 …”

Concepts for agonistic targeting of CD40 in immuno-oncology

“…29 Part of this phenomenon might not be a direct effect of CD40 signaling, but of secondary upregulation of death receptors on susceptible cell types. 30 However, some clinical effect of the anti-CD40 antibodies lucatumumab and dacetuzumab has been shown against B cell malignancies, which could be attributed to antibody-mediated phagocytosis by macrophages and induction of antibodydependent cytotoxicity (ADCC). 31 Following ligation of CD40, tumor cells show signs of DNA damage, secrete pro-angiogenic factors, like VEGF and IL-8, and generally adopt a state reflecting a senescence-associated secretory phenotype (SASP) due to CD40-induced NFκB activation.…”

“…Additional developments in both the delivery method and the format of CD40L have also shown promise. 30,56,[61][62][63]…”

Local irradiation does not enhance the effect of immunostimulatory AdCD40L gene therapy combined with low dose cyclophosphamide in melanoma patients

“…AdCD40L is a replication-deficient adenovirus carrying the gene for CD40 ligand (CD40L) [ 6 ]. We have previously shown that AdCD40L therapy can be used safely in patients with MM [ 6 ] and that the T cell to T regulatory cell ratio is significantly enhanced post treatment [ 7 ]. The first cohort of patients received four intratumoral injections of AdCD40L and the following cohort received four to eight AdCD40L injections combined with low dose cyclophosphamide conditioning.…”