Intratumoral CD40 stimulating therapy in patients with advanced cancer

Sammanfattning: CD40-CD40L interaction activates DCs to become highly efficient APCs and skews the adaptive immune response towards a Th I phenotype driving cytotoxic T cells, M1 macrophages and natural killer cells. Furthermore, engagement of CD40L to CD40 positive cancer cells can have direct anti-proliferative effects, induce apoptosis and increase expression of MHC and other co-stimulatory molecules, thereby enhancing cancer cell recognition. Hence, activating the CD40-CD40L pathway may lead to several potential anti-tumoral effects. In this thesis we evaluated activation of the CD40-CD40L pathway in patients with solid cancer by investigating three medicinal products administered mainly through intratumoral injection: ADC1013 - an agonistic CD40 antibody, AdCD40L - a replication deficient adenovirus carrying the gene for CD40L and LOAd703 - an oncolytic adenovirus carrying two immunostimulatory genes: TMZ-CD40L and 4-1BBL. In paper I, ADC-1013 was investigated in patients with metastatic cancer (n=23) in a phase I trial. ADC-1013 was injected intratumorally (n=18) or intravenously (n=5). AdCD40L was investigated in  a phase I/II study reported in paper II and III, respectively. In one cohort (paper II), patients with metastatic malignant melanoma (n=9) were treated with four weekly intratumoral injections with AdCD40L preceded by radiotherapy (single fraction 8 Gy) of the metastasis to subsequently be injected. Concomitant low dose cyclophosphamide was administered before the first and fourth intratumoral injection. In another cohort (paper III), patients with metastatic non melanoma solid cancer (n=6) were treated with the same schedule except from radiotherapy. Paper III also reports the results of the first-ever patient treated with AdCD40L. In paper IV, the preliminary results of phase I of a phase I/II study investigating LOAd703 administered intratumorally at a two-week interval are presented. LOAd703 was given as an add-on to standard-of-care chemotherapy, or with gemcitabine conditioning in patients having received established treatments. Patients (n=9) had locally advanced or metastatic pancreatic cancer, metastatic ovarian cancer or colorectal cancer. We conclude that treatment with all three medicinal products was safe and tolerable. For ADC-1013, the therapeutic ratio seemed to be more favorable for intratumoral injections into superficial metastases compared to deep metastases. We demonstrated that AdCD40L can be combined with radiotherapy without increasing toxicity although radiotherapy did not enhance treatment efficacy. Further, LOAd703 was safe to combine with chemotherapy. Although the number of patients treated in each trial was limited, and almost all patients were considered refractory to standard treatment at inclusion, some patients seemed to benefit from treatment which is encouraging.