Leptomeningeal carcinomatosis occurs in 5% to 20% of all cancer patien
ts (9,18,22). Among the adult population, most cases of leptomeningeal
carcinomatosis are due to breast or lung carcinomas. Over recent year
s the incidence of leptomeningeal carcinomatosis has been reported to
increase, perhaps since cancer patients survive longer with improved s
ystemic therapy (1,4,5,10,15,17,18,22,28). Patients with leptomeningea
l carcinomatosis have an exceedingly poor prognosis. Whem maximal ther
apy is tolerated (intrathecal methotrexate and whole-brain irradiation
), mean survival is limited to six to seven months (7,18,30) and fewer
than 15% of the patients are alive at one year (26). Leptoimeningel i
nvolvment is not necessarily a premorbid phenomenon, and in two-thirds
of cases, it occures when systemic disease is stable or in complete r
emission (7,30). In an attempt to improve this grim prognosis of patie
nts with leptomeningeal carcinomatosis, we have developed a novel appr
oach for the treatment of meningeal carcinomatosis. This approach make
s use of recombinant DNA technology to transfer a sensitivity gene int
o the malignant cells seeding the leptomeninges. This is achieved by d
irect intrathecal injection of cells that actively produce a retrovira
l vector carrying the herpes simplex thymidine kinase gene (HSV-Tk1) w
hich sensitizes the cells to the antiviral drug ganciclovir. The intra
thecally injected producer cells and vector particles can circulate in
the CSF and infect cells which are actively synthesizing DNA. In the
subarachnoid space, such cells are predominantly tumor cells. The HSV-
Tk1 gene is incorporated into the genome of tumor cells and results in
expression of the protein encoded by the gene. The enzymatic interact
ion between HSV-Tk1 and ganciclovir leads to the production of toxic t
riphosphates of ganciclovir that interfere with DNA synthesis and resu
lt in the death of the tumor cells. Since the thymidine kinase enzyme,
which is normally present in mammalian cells, has very low affinity f
or ganciclovir, systemic toxicity related to this mechanism is not exp
ected. This type of in vivo gene transfer has several unique features.
First, these retroviral vectors will only integrate into and express
their genes in cells which are actively synthesizing DNA. Therefore, n
on-proliferating normal brain and spinal cord tissue should not acquir
e the HSV-Tk1 gene and will remain insensitive to ganciclovir. Second,
all the transduced tumor cells (and retroviral vector producer cells)
will be killed by ganciclovir treatment, reducing the risk of inserti
onal mutagenesis. Third, in this setting, delivery of the producer cel
ls and viral vectors will be facilitated by the normally circulating C
SF which bathes the whole surface of the central nervous system (CNS).
This clinical trial will evaluate the safety of this approach, assess
the dynamics of retroviral vectors in the subarachnoid space, and eva
luate the potential antitumor efficacy of the approach. Patients in Gr
oup A will receive an intraventricular injection at a dose of 1 x 10(9
) vector producer cells, followed by ganciclovir treatment seven days
later for two weeks. Patients in Group B will receive intraventricular
and intrathecal injections at a dose of 1 x 10(9) vector producer cel
ls each (total dose of 2 x 10(9) HSV-Tk1 cells), followed by ganciclov
ir treatment seven days later for two weeks. Group C patients will rec
eive intraventricular and intrathecal injections at a dose of 2 x 10(9
) vector producer cells each (total of 4 x 10(9) HSV-Tk1 cells), follo
wed by ganciclovir treatment seven days later for two weeks. Group D p
atients will receive intraventricular and intrathecal injecions at a d
ose of 2 x 10(9) vector producer cells each, followed three days later
by repeat intraventricular and intrathecal injections at the same dos
e (total dose of 8 x 10(9) HSV-Tk1 cells), followed by 14 days of ganc
iclovir beginning on Day 7. CSF samples will be analyzed for vector ti
ters at multiple time points, and if no toxicity is encountered, 12 pa
tients will be treated in Group E of the study with the same parameter
s as Group D (or any previous group if a maximum tolerated dose below
that in Group D is identified). Indications of antitumor efficacy will
include monitoring of clinical symptoms, craniospinal MRT evaluation,
and CSF analysis for cytology and tumor markers.