Adenovirus-Interferon-g (TG1042) Demonstates Clinical Activity in Relapsing Primary Cutaneous Lymphoma (PCL): A Phase I/II Multicentric Trial.

PCL has been successfully treated with interferons (IFNs), which can offset the Th2 dominance associated with PCL. Intratumoral (IT) injection of TG1042 (a non-replicating recombinant adenovirus with a human IFN-γ cDNA insert) allows high local levels of IFN-γ without severe toxicity induced by systemic delivery. We undertook a multicentric, phase I/II, open-label, trial of repeated, IT injection of TG1042 in patients with advanced primary T cell (CTCL) and multilesional B cell (CBCL) cutaneous lymphoma. The designated lesions were injected on day 1, 8 and 15 with no injection in the fourth week (1 cycle) and thereafter up to 4 cycles. Immunohistochemistry and qPCR were performed on injected lesions biopsied at baseline and after each cycle. In the phase I step, undertaken on a monocentric basis, 9 patients were enrolled in 3 successive cohorts at the doses of 3×10⁹ viral particles (vp), 3×10¹⁰ and 3×10¹¹ vp injected in only one lesion and 9 additonal patients were treated at the doses of 3×10¹¹ vp divided in up to 3 lesions. In the phase II step, 18 additional patients have been planned to be treated on a multicentric basis at 3×10¹¹ vp injected in up to 3 lesions. To date, the 36 planned patients (30 CTCL and 6 CBCL) have been enrolled and received a total of 280 injections, 26 patients have completed the treatment. Treatment is well tolerated with only 3 grade III toxicity. Injection site reaction and flue like syndrom are the most commonly observed adverse events. Local clinical response has been observed in 13 (7 complete responses) out of 27 evaluable patients. Disappearance of non-injected lesions was also observed and led to 12 overall responses (6 complete responses) out of 26 evaluable patients. Histology demonstrates pronounced differences in infiltrate patterns following treatment, with signs of vasculitis and increased numbers of eosinophils, neutrophils, CD8 and TIA-1+ve cells. CD4/CD8 ratio decreased in most tumors. Transgene-IFN-γ mRNA was detectable in injected lesions. Gene expression analysis of biopsies and PBMC shows up-regulation of IFN-γ and various immune response-associated genes. Final clinical and immunological data will be presented. In conclusion, these data show that the administration of TG1042 is well tolerated and results in clinical responses associated with in situ immunological changes. These encouraging results demonstrate a potential significant benefit of TG1042 for the treatment of primary cutaneous lymphoma.