SAN FRANCISCORenal cell carcinoma patients given a
vaccine prepared from their own excised tumors experienced delayed time to
progression (TTP) in a multicenter phase III trial, Christian Doehn, MD, of the
University of Lübeck, Germany, reported at the 99th Annual Meeting of the
American Urological Association (abstract 1646).
Renal cell carcinoma accounts for 85% of all kidney cancers.
Standard therapy for the disease in nonmetastatic stages is usually radical
nephrectomy. However, "there has been, up to now, no adjuvant therapy available
to improve outcomes for those patients," Dr. Doehn said.
For patients with tumors confined to the kidney, relapse
rates approach 50%. For recurring or metastatic disease, the prognosis is
worse. Moreover, current pharmacological treatments for patients with disease
progression all carry substantial potential for severe side effects.
Between January 1997 and August 1998, researchers enrolled
558 patients with stage pT2-3b pN0-3 M0 renal cell tumors who were scheduled
for radical nephrectomy at 55 hospitals throughout Germany. Prior to surgery,
patients were randomized to receive postoperatively six consecutive doses of a
vaccine consisting of cells from their own tumors or standard postoperative
management (watchful waiting). Eligible patients (n = 379) had organ-confined
tumors greater than 2.5 cm or tumors that were regionally advanced but not
The vaccine was prepared separately for each patient from a
sterilized tumor specimen obtained during nephrectomy. Specimens were
transferred to a German company, LipoNova (Hanover), where cell suspensions
from the tumor were prepared and incubated with gamma-interferon and tocopherol
acetate (vitamin E), then washed several times and frozen repeatedly to kill
the cells. The resulting lysate, containing about 5 million tumor cells/mL, was
shipped frozen to the relevant center and stored until use.
Intradermal inoculations with the vaccine began 4 weeks
after surgery and were repeated every 4 weeks thereafter for a total duration
of 6 months. The study’s primary endpoint was time to progression. Patients
were evaluated at 6-month intervals and followed for a minimum of 4 to 5 years.
Five-year progression-free survival for vaccinated subjects was 77.4% vs 67.8%
for controls (P = .0204); progression-free survival rates at 70 months
were 72% and 59.3%, respectively.
At 70 months of follow-up, neither arm had reached median
progression-free survival. The point at which 25% of the vaccinated and control
subjects had progressed was 63.2 months and 42.1 months, respectively. Patients
with larger or higher-grade tumors saw an even greater benefit. Full results of
the study were recently published in The Lancet (363:594-599,
There were only 12 adverse reactions attributable to the
vaccine, and none of them were severe, Dr. Doehn said. Given the poor prognosis
and poor treatment options for patients with progression, he added, any
treatment that succeeds in prolonging progression-free survivalespecially if
its toxicity profile is mild would appear promising.
The vaccine is now undergoing review by the European Medical
Evaluations Agency. To date, Dr. Doehn said, no other late-phase trial testing
a therapeutic vaccine in renal cell cancer has shown substantial clinical
response rates. He noted that a competing vaccine, composed of heat shock
proteins extracted from patients’ tumors, is being administered in an adjuvant
setting in a multicenter phase III trial with even higher patient enrollment.
Results of that trial, sponsored by Antigenics, Inc. (New York City) and
featuring survival as its primary clinical endpoint, are expected early next
Dr. Doehn believes that a therapeutic vaccine is more likely
to be effective in the adjuvant setting. "Many research groups do find evidence
of immunological reactivity," he said. "I think lack of efficacy in trials of
patients with advanced disease is a matter of tumor burden."