Med Oncol. & Tumor Pharmacother. Vol 10 No. 1/2 pp. 53-59, 1993 0736--0118/90 $3.00 + .00 STRATEGIES FOR CYTOKINE UTILISATION IN TUMOR THERAPY FRANCESCO DI PIERRO, 1 FEDERICA CAVALLO, 1 FEDERICA PERICLE, 1 SABRINA BERTINI, I, MIRELLA GIOVARELLI 1 and GUIDO FORNI 2. lInstitute of Microbiology, and ~CNR Center for Immunogenetics and Histocompatibility, University of Turin, Turin, Italy (First submitted 16 November 1992; accepted after revision 6 December 1992) The state of the art with regard to the employment of various cytokine-based tumor immunotherapy strategies and their mechanisms of action are critically reviewed. As matters now stand, adoptive transfer of LAK cells or tumor inf'dtrating lymphocytes together with high doses of IL-2 constitutes the only immunologic way to hinder tumor growth in advanced stages of cancer. On the other hand, many experimental data show that the local presence of cytokines, either injected repeatedly at tumor site or released by cytokine-gene engineered tumor cells, arouses immunogenicity in apparently nonimmunogenic spontaneous tumors. By strengthening the notion that most tumors are potentially immunogenic, these f'mdings offer substantial evidence to stres~ the potential use ofcytoklnes as a component of new tumor vaccines. Key Words: Cytokines, Tumor vaccine, IL-2, LAK cells, NK cells, Transfcetion, Gene therapy. SPONTANEOUS TUMORS ARE DEFECTIVE IMNIUNOGENS Expression of mutated proteins or peptides on their mem- brane is a common step in the process whereby cells become neoplastic. Cells thus transformed are potentially recognizable by the immune system, which can hinder their growth and spread.~ Much recent evidence is contrary to the conclusion, primarily drawn from Hewitt's experi- ments, 2 that spontaneous tumors are not antigenic. In both experimental animals and in man, specific immune re- sponses have been elicited against spontaneous tumors previously considered to be devoid of tumor associated antigens (TAA). Characterization of antigen molecules expressed by spontaneous tumors in both mice and man indicates that 'nonantigenic' tumors should be regarded as 'defective immunogens'. L3 The choice lies between two yardsticks. If antigenicity is regarded as the expression of TAA that could be the target of both specific and nonspe- cific immune reactivity, most spontaneous tumors are probably antigenic, whereas if immunogenicity is the abil- ity to generate an immune response, the overwhelming majority of spontaneous tumors display marginal if any immunogenicity. 4 This radically different explanation of the failure of tumors to elicit an immune response is also of practical *To whom correspondence should be addressed: CNR-Center of Immu- nogenetics and Histocompatibility, Via Santena 19, 10126 Turin, Italy 53 importance as a rationale for the use of immunologic strategies to hinder tumor growth. If spontaneous tumors were not antigenic, employment of artificially induced and highly immunogenic tumors as experimental models would nearly always be devoid of clinical relevance. WHY SHOULD SPONTANEOUS TUMORS BE DEFECTIVE IMMUNOGENS ? The importance of immune mechanisms in surveillance against initial tumors, and hampering their growth and metastasis has been disputed. 5'6 What we can say, at all events, is that since such mechanisms are both natural and capable of adaptation, any tumor that reaches a clinical status must have been (and still be) able to sneak through their net, however tight its meshes. This ability to elude or circumvent an immune response, or even proceed without provoking any response at all, is the hallmark of tu- morigenic transformed cells. Any signal they may present to the immune system is both ignored by its natural mecha- nisms and not sufficient to bring about their adaptation. WHY ARE TUMORS DEFECTIVE IMMUNOGENS ? Lack of immunogenicity may result from a combina- tion of several distinct features: a gap in the T-lymphocyte repertoire; poor presentation of TAA peptide fragments by