Gene therapy against cancer usually begins by trying toget the immune system's T cells to do their thing _ orthings.

For one thing, human cytotoxic T lymphocytes cansometimes recognize a tumor cell, and destroy it. Foranother, T cells can cunningly infiltrate a tumor and do itin.

For a T cell to get revved up to such an anti-cancer pitch,once it has spotted the tumor by the antigen unfurled onits surface, it needs help. That is, it needs a cytokine,especially one called interleukin-2 (IL-2), to stimulate Tcell replication, and activate its cell-killing activity.

For more than a decade, research oncologists havewrestled with IL-2, trying to beef it up in their attacks oncancer. Basically, they've removed chunks of a patient'stumor, minced up the malignant cells, mixed them withrecombinant IL-2, and shot the package back systemicallyinto the recipient .

Results of this ex vivo approach have been mildlyencouraging, but mixed. A few patients have enjoyedrewarding remissions of varying duration, though at thecost of horrendous side effects, from leaking bloodvessels, edema and anemia to chills, fever, nausea andlow blood pressure. But by and large, the tumors haveprevailed over the IL-2 therapies.

Now, a team at McMaster University in Hamilton,Ontario, headed by gene therapist Frank Graham, hasgone from recombinant IL-2 externally injected togenerating the cytokine inside the patient's own body,where it can attack the living cancer from within.

So far, his "patients" are all transgenic mice, speciallyengineered to mimic humans with breast cancer, and tocall up their own immune system cytokines.

Graham's paper in today's Proceedings of the NationalAcademy of Sciences (PNAS) bears the title:"Intratumoral injection of an adenovirus expressinginterleukin-2 induces regression and immunity in amurine breast cancer model."

To date, Graham told BioWorld Today, "about 50 percentof the tumors in our treated animals regressed totally, andhave never recurred. Now we're well over one year fromthe time the first mice were treated with our adenovirusvector, and they're heading into ripe old murine age,tumor-free."

The transgenic mice used by the McMaster team alldevelop spontaneous adenocarcinomas of all mammaryepithelium by eight to 10 weeks of age. They resemblethe hard tumors of human breast cancer, and willmetastasize to the lungs. These tumors express a specificantigen under the control of mouse mammary nucleotidesequences.

Graham's first author, doctoral candidate ChristinaAddison, with material and tactical assistance from co-author Robert Ralston of Chiron Corp., of Emeryville,Calif., constructed an adenovirus vector packing the genefor IL-2.

They injected that vector directly into the tumors of non-transgenic mice, bearing malignancies transplanted fromthe transgenic ones.

In the first of three experiments, Addison and her teamdivided a cohort of mice into one active and two controlgroups. The first nine animals got a shot of vector into afull-blown, and growing, tumor on one flank. The secondreceived a mock injection, containing only theadenovirus, without an IL-2 gene. Into the tumor of thethird went a simple dose of saline.

Of the nine who received the active gene-therapytreatment, eight underwent complete regression. Theninth, Graham surmises, "may have sustained leakage ofthe vector package from within the injected tumor mass."

Twelve weeks after their tumors disappeared, eight of thenine regressors got an injection of 1 million fresh andvirulent tumor cells into the opposite flank. So didcontrols, with mock vectors or saline. All 10 of the latterduly developed tumors between 15 and 21 days.

Nothing untoward happened to the eight originalsurvivors, who continue to do well.

"We interpret these results," Graham observed, "to be thestimulation of an immune response against the tumor,which eliminates the cancerous cells, and protects theanimal against subsequent injection at another site. Theimportant point," he added, "is that unless the mouse'simmune system is given a kind of jump-start byexpression of IL-2 within the tumor cells, the immuneresponse is absent or ineffective."

"Unlike cancer therapies that use cytotoxic genes or drugsto mediate tumor cell killing," the PNAS paperconcluded, "this form of immunotherapy may generateimmune responses that would lead to protection fromdistal secondary tumor development or metastases. Thisimmunity is extremely important for the treatment ofcancers such as breast cancer and melanoma where thepatient usually succumbs to the metastatic spread of thedisease."

The McMaster team, Graham said, "is now workingtogether with two clinicians at Toronto hospitals toinitiate Phase I clinical trials for breast cancer andmelanoma. We hope to be able to start them toward theend of this year." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.