By David N. Leff
Freckles may be hazardous to your health.
Not directly, but because the light-brown facial speckling reflects a more specific menace — sunshine. Solar radiation reaching the earth's surface pours down light, heat and an invisible, intangible wavelength ultraviolet (UV) rays.
UV is a prime suspect in perpetrating malignant melanoma, one of the deadliest, fastest-killing and fastest-increasing types of cancer. Arizona, among the sunniest states in the U.S., and Australia, the most sun-drenched land on earth, have relatively high incidence of melanoma in their populations.
In fact, melanoma death rates in the U.S. — 2.5 per 100,000 — vary inversely with latitude. That insidious skin cancer took 6,900 American lives in 1994, according to National Cancer Institute statistics. "An individual living in the U.S.," observed research oncologist Glenn Dranoff, has a one-in-75 lifetime risk of developing melanoma."
Freckling usually happens to people with fair skin, blonde hair and blue eyes, all of which indicate low levels of the pigment melanin, nature's own sunscreen. Melanoma is a malignancy of melanocytes, the skin cells that secrete melanin. The disease usually starts out by strewing wart-like moles or nevi across skin surfaces. Unless promptly diagnosed, and — if positive — surgically removed, these dark malignant growths may metastasize lethally to organs inside the body.
Experimental vaccines abound, aimed at beefing up the victim's humoral and cellular immune cells against the melanotic tumors. Those antibodies and T cells see the malignancy as a foreign pathogen. So far, the practical clinical treatment score is melanoma one, vaccines zero, but the scientists' efforts continue. (See BioWorld Today, March 9, 1998, p. 1.)
Among the latest is a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Oct. 27, 1998. The title of this Phase I clinical trial sums up its strategy and results: "Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor [GM-CSF] generates potent anti-tumor immunity in patients with metastatic melanomas."
Recipe For An 'Immunize-Yourself' Vaccine
Dranoff, whose laboratory is at the Harvard-affiliated Dana-Farber Cancer Institute, in Boston, is the article's senior author. Here is how he and his co-authors proceeded:
"Surgically excised metastatic tumor tissue from 21 terminal melanoma patients was dispersed to single-cell suspensions, and allowed to replicate in culture, at Cell Genesys Inc. [of Foster City, Calif.]," Dranoff told BioWorld Today. "While growing, they were transduced with retroviral particles carrying genes for human GM-CSF. [This is a potent growth factor that energizes the immune system's panoply of pathogen-fighting cytokines and cells.]
"The vaccine cells," he continued, "were then irradiated to prevent their further growth, while retaining their antigenicity, because the virus won't transfer its gene unless the target cells are actively dividing."
To compare low-, medium- and high-dosage effects of their genetically engineered vaccine, the co-authors injected 10 million cells at a time under the skins of their patient cohort at 28-, 14- or 7-day intervals over an 84-day period. "Vaccination sites in all patients," they reported in PNAS, "were characterized histologically by an extensive infiltrate of [immune-defense] dendritic cells, macrophages, eosinophils and T lymphocytes that extended throughout the dermis and into the subcutaneous fat."
To determine whether unleashing this onslaught of immune factors actually had antitumor effects, the researchers compared host reaction to metastatic lesions resected before and after completing the vaccine therapy. The latter biopsies "demonstrated a profound immune response in 11 of 16 patients" from whom tissue was obtainable. These responses occurred in metastatic lesions up to 10 centimeters in diameter. Besides skin and subcutaneous sites, they included internal metastases to lung, spleen and intestine.
Tumors that size need a copious blood supply. Four patients experienced an unexpected antiangiogenic effect from the vaccine, "the targeted destruction of the tumor vasculature, whereby lymphocytes, eosinophils and neutrophils were closely associated with dying tumor blood vessels."
Although a Phase I study tests for dosage and safety rather than efficacy, Dranoff said three patients remain free of disease with follow-up of 36, 36 and 20 months. "Before beginning immunization," he noted, "these patients had developed multiple new metastatic lesions."
"This method of vaccine manufacturing is quite complicated," Dranoff allowed. "On average, it took us about two months to prepare vaccines for each patient. Hence, that's not a procedure that can be scaled up for efficacy testing on large numbers of patients. This first trial was not designed to use a clinic-friendly technique.
"Having seen what we saw," he went on, "the focus of our work became accomplishing the same thing with a vastly simplified vaccine-manufacturing technique. So, since October of last year, we have initiated two new Phase I clinical trials, one again in melanoma, with the same kind of patient group, and another in patients who have metastatic lung cancer. We are enrolling 25 evaluable subjects in each study."
Also New: The Viral Vector
The good news, Dranoff said, is that "in these new, ongoing studies, the vaccine-preparation procedure is whittled down from two months to one day. And what's involved is still dispersing the tumor cells into single-cell suspension.
"Then, we infect these cells overnight with adenovirus [AV], which still brings in the GM-CSF gene. But unlike the retrovirus used in the first study, AV doesn't require cells to be growing. Hence, we don't have to do this prolonged culture. So, the cells can be genetically transfected overnight, then irradiated and frozen down."
This new approach, he said, "allows us to study tumors which are not easy to grow in culture. Melanoma turns out to be very easy, which is one of the reasons we studied it first. But a lot of other tumors, for example, lung, breast, prostate, colon, do not grow well in culture. And the AV vector is potentially amenable to a large number of cancers."
He concluded that vaccination with irradiated autologous melanoma cells engineered to secrete GM-CSF is "a compelling candidate for randomized clinical trials." *