Adenoviral CD40 Ligand Immunotherapy in 32 Canine Malignant Melanomas–Long-Term Follow Up

Abstract

Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. Gene therapy using adenoviruses encoding the immunostimulatory gene CD40L (AdCD40L) has shown promise in initial clinical trials enrolling human patients with various malignancies including melanoma. We report a study of local AdCD40L treatment in 32 cases of canine melanoma (23 oral, 5 cutaneous, 3 ungual and 1 conjunctival). Eight patients were World Health Organization (WHO) stage I, 9 were stage II, 12 stage III, and 3 stage IV. One to six intratumoral injections of AdCD40L were given every seven days, combined with cytoreductive surgery in 20 cases and only immunotherapy in 12 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response based on result of immunotherapy included 7 complete responses, 5 partial responses, 5 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 285 days (range 20–3435 d). Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is ongoing.

Full-Length Transcriptome: A Reliable Alternative for Single-Cell RNA-Seq Analysis in the Spleen of Teleost Without Reference Genome

“…In order to obtain a more detailed clustering and cell classification of the B cells ( Figures 8C–G ), we used the above mentioned approaches to analyze the B cell population ( Figure 7K ). As a result, the B cell population was further sub-divided into 4 clusters: 1) the cluster with high expression level of CD34 ( 51 ) and hardly expression level of CD20 ( 40 ), CD40 ( 52 , 53 ), IgM ( 54 ), CD27 ( 54 ) and IgD ( 55 ) were identified as early-pre B cell; 2) the cluster with expression of CD20 and CD40 , together with hardly expression of CD34 , IgM , CD27 and IgD were identified as pre B cell; 3) the cluster with expression of CD20 , CD40 and IgM , together with hardly expression level of CD34 , CD27 and IgD were identified as immature B cell; the cluster with the highest expression level of CD20 , CD40 , IgM , CD27 and IgD , together with hardly expression level of CD34 were identified as mature B cell, respectively ( Figures 8C, D ). To verify the reliability of the classification results, we carried out a pseudo-time analysis ( Figure 8E ).…”

“…CMRF35 is a B cell surface protein as well as an immunoregulatory molecule, which has been observed involving in the mucosal immunity of teleost ( 96 ). Then, the B cell population was further sub-divided into 4 clusters: 1) the cluster with high expression level of CD34 ( 51 ) and hardly expression level of CD20 ( 40 ), CD40 ( 52 , 53 ), IgM ( 54 ), CD27 ( 54 ) and IgD ( 55 ) were identified as early-pre B cell; 2) the cluster with high expression level of CD20 and CD40 , together with hardly expression level of CD34 , IgM , CD27 and IgD were identified as pre B cell; 3) the cluster with high expression level of CD20 , CD40 and IgM , together with hardly expression level of CD34 , CD27 and IgD were identified as immature B cell; the cluster with the highest expression level of CD20 , CD40 , IgM , CD27 and IgD , together with hardly expression level of CD34 were identified as mature B cell, respectively. The CD34 molecule is a highly glycosylated type I transmembrane glycoprotein that is selectively expressed on the surface of human and other mammalian pro B cells, and gradually weakens to disappear as the cells mature ( 51 ).…”

“…More and more research results have shown that CD34 molecules play an important role in mediating cell adhesion ( 51 ). CD40 regulates the activation, germinal center formation, antigen presentation and antibody production in B cells ( 52 , 53 ). CD27 is a TNF receptor that stimulates B cells and promotes their differentiation after being activated by the TNF ligand CD70, thereby promoting anti-infection immunity.…”

Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities

“…Direct administration of recombinant CD40L was pursued in non-CNS tumors with a promising safety profile [ 179 ] and is being tested as a fusion protein with SIRPα to initiate checkpoint blockade (ClinicalTrials.gov Identifier: NCT04406623). Gene therapy technology is also being harnessed to deliver CD40L to tumor tissue using engineered Vaccinia virus [ 180 ] and adenoviral vectors [ 181 ] to treat non-CNS tumors. In the context of glioma, the administration of agonistic antibodies against CD40 was tested in preclinical models [ 127 , 182 ].…”

Canine Melanoma Immunology and Immunotherapy: Relevance of Translational Research

“…Equally, agonistic mAbs targeting costimulatory molecules belonging to the tumor necrosis factor receptor superfamily, such as CD27, OX40, and CD40, have shown impressive anti-tumor effects in pre-clinical and clinical studies (52)(53)(54). Interestingly, promising results have been obtained in melanoma-bearing dogs treated with an adenovirus encoding the CD40 ligand (CD40L) (55).…”