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In a carbon ion treatment the nuclear fragmentation of both target and beam projectiles impacts on the dose released on the tumor and on the surrounding healthy tissues. Carbon ion fragmentation occurring inside the patient body has to be studied in order to take into account this contribution. These data are also important for the development of the range monitoring techniques with charged particles. The production of charged fragments generated by carbon ion beams of 115–353 MeV/u kinetic energy impinging on carbon, oxygen, and hydrogen targets has been measured at the CNAO particle therapy center (Pavia, Italy). The use of thin targets of graphite (C), PMMA (C2O5H8) and polyvinyl-toluene [plastic scintillator (PS), ${\text{C}}_{b}{\text{H}}_{a}$ ] allowed to measure fragments production cross sections, exploiting a time-of-flight (ToF) technique. PS detectors have been used to perform the ToF measurements, while LYSO crystals have been used for the deposited energy measurement and to perform particle identification. Cross sections have been measured at 90° and 60° with respect to the beam direction. The measured proton, deuteron, and triton differential production cross sections on C, O, and H, obtained exploiting the target subtraction strategy, are presented here as a function of the fragment kinetic energy.

Cancer vaccines are intended to promote a long-lasting memory response against tumors.Rationale for cancer vaccines is based on two observations: a) many tumors express antigens (TA), which are recognized by specific cytotoxic T lymphocytes; b) these lymphocytes may protect the host against tumor growth in vivo.So far, cancer vaccines have been developed using soluble TA and, more recently, TA presented by dendritic cells (DC), the most powerful antigen presenting cells (APC). DCs play a key role in the process leading to antigen recognition and lymphocyte activation. Despite a deeper understanding of these processes, clinical efficacy of cancer vaccines is still hampered by the heterogeneity of the studies performed so far, and by the largely unknown mechanisms through which tumors escape immunosurveillance.Current DC-based cancer vaccines require the preparation of DCs from patient blood monocytes, as well as DC-loading with TA. Both whole tumor and TA peptides are used as source of TA. Similar schedules have been implemented in many clinical trials on melanoma, kidney and prostate cancer, with partial responses ranging from 7% to 30%. The study population was made up of non-respondent patients to any other therapy; the DC vaccination showed an extremely low toxicity.22 patients with metastatic melanoma received a DC vaccine in Forlì (Italy) since August 2001. Good correlation between immunologic response, clinical response and overall survival was found. A clinical trial on pulsed APC administration to patients with recurring prostate cancer is ready to be started in Torino (Italy), pending the Ministerial approval from a local cell factory.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-α2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-α 25 × 106U Day 1 + ip carboplatin 400 mg/m2Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3–4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P= 0.000) and flu-like syndrome (P= 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1–72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-α does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Abstract:  Adoptive tumour infiltrating lymphocytes (TIL) in combination with a modulated dosage of interleukin-2 (IL-2) can be used with acceptable toxicity in the treatment of immunogenic tumours. Following an experience of reinfusion in advanced melanoma, colorectal and renal cancer patients, treatment was given to disease-free patients after metastasectomy. The high risk of relapse and favourable ratio between reinfused TIL and possible microscopic residual disease determined this choice of adjuvant treatment. A group of 12 patients with advanced disease (7 melanoma, 4 colorectal carcinoma, 1 kidney carcinoma) were treated with TIL (median 5.8×1010 cells) and IL-2 (West’s schedule) modulated towards a lower dosage (from 12 to 6 MIU/day) in order to maintain an acceptable level of toxicity. As treatment was well tolerated, it was offered to another 22 patients in an adjuvant setting after metastasectomy (11 melanoma, 10 colorectal carcinoma, 1 renal cancer), the median dose of TIL reinfused being 4.95×1010 cells. No objective response was observed in advanced patients: all patients progressed after a median of 1.5 months (0–8 months) and median survival was 8 months (3–22+ months). Thirteen patients from the second group are still disease-free after a median of 23+ months (9+–47+ months). The remaining 9 patients relapsed after a median of 5 months (3–18 months). Toxicity was moderate as clinical and hepatic/renal function parameters were used to assess the need for dose reductions. Consequently, there was great diversity in IL-2 dosages administered. In particular, there seemed to be a difference in IL-2 doses administered between disease-free cases and those who progressed (17.5 MIU/day versus 7 MIU/day in melanoma patients; 11.2 MIU/day versus 7.1 MIU/day in colorectal cancer patients). By contrast, no differences were observed between number of TIL reinfused and clinical response. Phenotypical characteristics of reinfused TIL were similar to those reported in the literature: 97% were CD3 and 92% were CD8. Aspecific cytolytic activity was evaluated on 12 cases whereas, in 2 melanoma cases, autologous tumour tissue was available for the specific cytotoxicity test. Perforin levels in TIL measured at the end of culture were generally high or very high. Cytokine levels were measured on the supernatant at the end of culture, with an estreme variability in results. Finally, ζ chain and p56lck were histologically assessed on the resected tissue from which TIL were cultivated. There were virtually none of the former and a complete absence of the latter, which concurs with data reported in the literature. The same immunocytochemical analysis was carried out on TIL at the end of culture. This time an almost complete restoration of both functions was seen, especially in melanoma patients, who are still free from disease. The study is on-going and it has been decided to focus on disease-free patients after metastasectomy in order to increase the number and possibility of clinical and histological correlations.