By David N. Leff

Cervical cancer and cancer of the anus have three things in common: Both are sexually transmitted diseases. The human papilloma virus (HPV) causes both of them. And the two malignancies share the same type of squamo-columnar cells that mark the junction between two areas of epithelium.

It's this boundary region in the vaginal cervix that pathologists performing Pap smears gently scrape to harvest cast-off epithelial cells, which they scope for signs of future cervical cancer. "Women are supposed to have Pap smears on a regular basis," observed immunologist Marvin Siegel. "It's an initial diagnosis, which looks at the cytology of the cells you get out, which tells you if you have to look further." Siegel is executive vice president of research and development at StressGen Biotechnologies Inc. in Collegeville, Pa.

It may take as long as seven years for an initially abnormal cervix to evolve into full-blown cancer. This precancerous cervical intraepithelial neoplasia (CIN) comes in three degrees of advancement toward malignancy - CIN I, CIN II and CIN III.

"There are three grades of current treatment" Siegel explained: "CIN I calls for watchful waiting, because a significant number of its patients do regress. CIN II does not regress, and CIN III is the immediate precursor of invasive cancer."

Just a year ago, StressGen started a multicenter Phase I clinical trial of a novel, and highly specific anticancer compound - HspE7 - in women diagnosed with CIN II and III. "We're two patients shy," Siegel told BioWorld Today, "of finishing our total enrollment of 30 participants."

This recombinant candidate therapeutic, he explained, "consists of a heat shock protein from the genome of Mycobacteria fused to an immunogenic oncogene, E7, on Papilloma virus type 16, which perpetrates cervical and anal cancer.

Mice Blaze Trail To Clinic

"We have acquired a lot of preclinical data," Siegel added, "showing we could rid experimental animals of already-existing tumors that were transformed because of the E7 oncogene. It was preclinical data that led us to suggest that we should go to the clinic." (See BioWorld Today, April 21, 1998, p. 1.)

The latest preclinical findings on which StressGen bases its clinical trial program appeared on Jan. 17, 2000, in the twice-monthly Journal of Experimental Medicine, under the title: "In vivo cytotoxic T lymphocyte elicitation by mycobacterial heat shock protein 70 [molecular weight] fusion proteins maps to a discrete domain and is CD4⁺ T cell independent." Its senior author is cell biologist Richard Young, a member of the Whitehead Institute for Biomedical Research in Cambridge, Mass.

When he and his co-authors vaccinated knockout mice, deprived of immune defenses, with the fusion protein, the animals were able to mount a cellular [T-cell] immune response. "If this recombinant vaccine behaves the same way in humans," Young predicted, "these findings will have profound implications for developing safe vaccines to immunize similarly immunocompromised humans, such as AIDS patients."

Young sits on StressGen's board of directors and scientific advisory board, and collaborates with Siegel and the firm's scientists.

"What Rick has shown," Siegel pointed out, "is that these heat shock protein fusions will generate CTLs [cytotoxic T lymphocytes], which will recognize cells carrying the E7 oncogene, and destroy them. Young and his co-authors have shown in this particular paper," he added, "that this antigen presentation, and development of CTLs, is independent of helper T cells, known as CD4s."

"Until now," Young pointed out, "researchers had thought that CTLs could only be activated when CD4 T cells were present. But immunocompromised AIDS patients lack these critical CD4 cells."

StressGen has three more clinical trials of its HspE7 fusion protein pending: a recently completed Phase I, an ongoing Phase II and - over the horizon - a Phase III study.

"This second Phase I trial," Siegel recounted, "enrolled 24 healthy human volunteers, men and women, for dose escalation and safety. We also drew blood before and after treatment to look for some immune parameters. There were no significant adverse events. We got HIV-negative men as well as women," he explained, "because we were going into an additional disease - anal intraepithelial neoplasia (AIN).

"Our Phase II AIN trial opened this fall. It is a double-blind, placebo-controlled efficacy study of the fusion protein, with biopsy on appropriate schedules, looking for regression of anal lesion. We are scheduled to have an interim analysis blinded to us, but obviously not to a third party, sometime around the end of the second quarter of this year."

Phase II Clinical Trial Presages Phase III

"This Phase II trial," Siegel pointed out, "is powered enough in theory to give us statistics. So we designed it as if it were pivotal. Whether or not the FDA will accept this as sufficient is hard to say. We believe we will have additional work to do."

Siegel made the point that "AIN - anal dysplasia - is the exact corollary of CIN, the cervical neoplasm. A lot of epidemiology and virology suggests that much of the anal dysplasia goes on to become anal cancer, just as the cervical dysplasia did in the years prior to Pap tests. Then it ran about 35 cases per 100,000 women. Now of course with routine Pap screening, the incidence of CIN progressing to cervical cancer is very low in North America and Europe. In the non-industrialized world it's the third leading killer of women.

"As for anal dysplasia," he went on, "there's been no treatment, and very few physicians actually Pap-smear anuses. The incidence of AIN seems to be the same as what CIN was prior to Pap smears. And the incidence of anal cancer is probably in the neighborhood of 3,000 to 4,000 people a year. AIN is a disease both of men and women, as one could expect from sexual practices."