(P 533) SAFETY AND PRELIMINARY BIOLOGICAL ACTIVITY OF A PHASE II TRIAL OF AUTOLOGOUS DENDRITIC CELLS VACCINATION IN SARCOMAS.

Objective: Immunotherapy has shown controversial and often disappointing results in patients with soft tissue sarcomas. This is probably due to the great variability and heterogeneity between histologies and to the peculiar immunosuppressive intratumoral infiltrate. In this perspective, the use of an autologous dendritic cell vaccine could be able to reverse this resistance. The objective of the phase II RaCaD trial is therefore to evaluate the safety and activity of autologous denditic cell vaccination (DCV) after radical metastasectomy in patients affected by rare tumours, including sarcomas.

Methods: Patients affected by soft tissue sarcoma (STS), neuroendocrine tumors, rare head and neck cancers, undergoing radical metastasectomy are included in the study. All Patients receive adjuvant DCV loaded with autologous tumor homogenate followed by IL-2 daily for five consecutive days starting 48 hours after the vaccination by subcutaneous injection. Treatment cycles are repeated every 28±7 days until disease relapse, unacceptable toxicity, completion of the sixth cycle or withdrawal of the consent by the patient, whichever occurs first. A safety analysis was performed after treatment of the sixth patient. In patients who accepted the related biological study (BioRaV), blood samples were collected pre-surgery, before each vaccine administration and at the end of treatment in order to evaluate the vaccine-induced immune response.

Results: Currently, eight patients have been included in the study, five of whom have STS, one patient with myxofibrosarcoma, one with spermatic cord liposarcoma and three with leiomyosarcoma (1 uterine, 1 retroperitoneal, 1 leg). As reported in Table 1, the DCV followed by IL-2 administration is safe with mild toxicities (highest grade toxicities reported: G2 swelling at inoculation site, asthenia, arthralgias). Currently two patients (myxofibrosarcoma patient and retroperitoneal leiomyosarcoma patient) are free from relapse at 10 and 24 months, respectively. Two patients had a local disease recurrence: the patient affected by inguinal liposarcoma after 28 months and the patient affected by limb leiomyosarcoma with pulmonary metastasis after 10 months. One patient showed multifocal metastatic progression after three months of treatment (uterine leiomyosarcoma).
The variations in peripheral blood immune cell populations between DVC cycles are shown in Figure 1. Moreover, to investigate the immunomodulatory activity of the DCV, the following cytokines were evaluated: IL-1b, IL-12, p70, IL-10, IL-2, IFNg, TNF-a, IL-4, IL-6, VEGF, IL-8, Fibronectin. As shown in figure 2, when patients are grouped according to relapse free survival [RFS], patients with a best RFS (group A) compared to those with the worst RFS (group B), some interesting differences can be highlighted:
1) Patients in group A have higher levels and steadily increasing levels of IL-2 compared to group B.
2) Patients in group A have higher baseline values of VEGF which steadily decreases during treatment than group B.

Conclusion: The first safety analysis demonstrated that autologous dendritic cell vaccine is safe and allowed the trial to continue. For the treatment efficacy evaluation more patients need to be included, nevertheless the serum cytokines evaluation showed promising signs of immune-modulating activity. In particular, all patients in which the IL-2 administrated at each cycle was related to a constantly increased IL-2 serum levels showed a better RFS. Moreover, all the patients in which VEGF levels decreased during the treatment had a better RFS; VEGF is well known immune-suppressor and the ability of DCV to reduce VEGF values could be an indication of its activity.