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A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.

Mice bearing either of the two rapidly growing mouse leukemias, L1210 or P388, or the slow-growing B16 melanoma responded to i.p. injections of Macromomycin B (NSC 170105) with significant increases in life-span. The maximal increases in life-span obtained in these experiments were 37% for L1210, 68% for P388, and 120% for B16. In addition, there were 7 of 30 cures for varying doses of Macromomycin in the B16 melanoma. Activity of over 50% increase in life-span in B16 was obtained with a daily i.p. injection on Days 1 to 9 of 16 to 40 mg/kg. Animals that had received s.c. implanted Lewis lung tumors responded to either single or repeated injections (8 to 16 mg/kg) given at the site of tumor implant by a marked reduction in growth of the primary tumor, increased life-span, and some cures. The same doses were without effect when administered i.p. The reported activity of Macromomycin against L1210, P388 leukemias, B16 melanoma, and Lewis lung carcinoma make it a good candidate for development for clinical trial against human solid tumors. A new method of evaluating activity against solid tumors, "responder analysis," is also presented.