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The article reconstructs the current status and development prospects of CAR-T therapies. It further explores the legitimacy of some production and administration paths of these therapies by national networks of hospital centers equipped with cellular workshops, according to an "in-house" model. Specific attention is paid to CAR-T produced in the context of clinical trials and according to the so-called "hospital exception", disciplined in Italy by a ministerial decree adopted in 2015 aiming at guaranteeing sustainability and accessibility of these innovative advanced therapies.

Adoptive immunotherapy trials with tumor infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) were carried out in the treatment of advanced melanoma with a 34% of overall responses (OR). However, theoretically it should be of greater benefit as adjuvant therapy, especially in high-risk stages (stage III and resected stage IV). In a pilot study, 22 patients (aged 23-72 years) with stage III-IV melanoma who underwent radical metastasectomy were reinfused with TIL cultivated and expanded in vitro with IL-2 from surgically removed metastases. IL-2 (starting dose 12 x 10(6) IU/m2) was co-administered as a continuous infusion according to West's scheme. A total of 8/22 (36.3%) patients were disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall survival (OS) in the remaining 14 patients were 44% and 37% and 52% and 45% at 2 and 3 years, respectively. The CNS was the only site of disease recurrence in 57% of patients who relapsed. DF patients received a higher median dose of IL-2 than those who progressed (total dose 110 x 10(6) vs 86 x 10(6) IU/m2, respectively). The progressive reduction in IL-2 dosage allowed all patients to complete treatment without permanent grade 4 toxicity. The effects of tumor immunosuppression in lymphocytes inside the tumor (TCR z and e chains, p56lck, FAS and FAS-ligand) confirmed that the potential function of TIL, immunodepressed at the time of metastasectomy, was significantly restored after in vitro, culture with IL-2. Adjuvant adoptive immunotherapy with TIL and IL-2 seems to improve DFS and OS, in comparison with literature data. Further studies are required to determine its role in the adjuvant treatment of patients with high-risk melanoma.

Local adoptive immunotherapy employed on a selected population using IL2-activated immune cells (A-LAK cells) and IL2 resulted in complete growth inhibition of a human squamous cell carcinoma of the head and neck implanted three to seven days previously and growing in nude mice. Although the in vitro cytotoxicity of A-LAK cells against the carcinoma cells was not higher than that of the whole population (LAK cells), the in vivo antitumor efficacy was from 4 to 9 times higher for A-LAK cells, as confirmed by the total number of injected cells needed for a complete growth inhibition. In addition, local A-LAK cell administration was characterized by early peritumoral erythema and swelling, not observed during LAK-cell therapy, which disappeared at the end of therapy. Histology of the tumors, during and at the end of therapy, showed an initial granulocytic and plasma cellular infiltration followed by mononuclear infiltration of the stroma of the tumor. The tumors showed a terminal-like differentiation with an increase of the keratinic layer and decrease of basal epithelial cells. These effects were proportional to the number of A-LAK cells injected. With the highest number of A-LAK cells, a complete epithelial disorganization was observed and 4 weeks from therapy termination the tumors were reduced to keratinic areas surrounded by connective tissue. These observations suggest the possibility of a A-LAK cell-dependent process of accelerated tumor differentiation and keratinization leading to tumor regression in nude mice.

Innovative approaches to cancer treatment have been made possible today by genetic engineering and hybridoma technologies. In this paper, attention is focused on the use of anti-idiotypic monoclonal antibodies such as internal tumor-associated antigens. These MoAbs may be able to overcome the immunosuppression in cancer patients by stimulating "silent" clones, or by allowing T cell help to become active, thus enhancing the overall immune response which the nominal antigen is unable to do. Preliminary experiences of active specific immunotherapy with monoclonal antiidiotypic antibodies in cancer patients are reported.