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Special Lecture |
The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Dr. Daniel von Hoff, thank you for that marvelous introduction. In the first row at this American Association for Cancer Research meeting today are Dr. and Mrs. Joseph Burchenal. It is a special privilege for me to be honored with this award named after him because he started the medical oncology program at Memorial Sloan-Kettering Cancer Center that I had the honor to chair for 11 years.
I will begin by introducing to you some of my mentors, who taught me the principles and practice of research. I had the privilege of working in the laboratory of Dr. James D. Watson throughout my junior and senior years at Harvard College, from 1956–1958, during the birth of the new field of molecular biology. As a Fulbright Scholar in Scotland, I learned about the complex molecular requirements for defined media that support cell growth in culture from Dr. John Paul. At Harvard Medical School in 1961–1962, I demonstrated but failed to publish antigen (tuberculin)-mediated activation of lymphocyte proliferation under Dr. Bryon Waksman. Dr. Eugene Braunwald, who gave me my first academic position at UCSD,3 taught me the excitement of translational research.
I also wish to acknowledge some of my key collaborators. Our initial experiments producing mAbs against the EGF receptor were designed with Dr. Gordon Sato at UCSD. Other collaborators at UCSD included Drs. Gordon Gill and Hideo Masui. Drs. Tomo Kawamoto and Denry Sato were the two postdoctoral fellows who screened thousands of hybridomas to identify a mAb that could bind to the EGF receptor, block EGF binding, and prevent receptor tyrosine kinase activation.
At Memorial Sloan-Kettering Cancer Center, my major collaborators were Drs. Larry Norton and José Baselga, along with Drs. Rakesh Kumar and Zhen Fan, with whom I continue to explore EGF receptor function at The University of Texas M. D. Anderson Cancer Center.
The clinical investigators who are leading the current clinical trials with anti-EGF receptor mAb include Drs. Waun Ki Hong and Dong Shin at The University of Texas M. D. Anderson Cancer Center, Dr. Harlan Waksal at ImClone Systems, Inc., and many others.
Background
Where were we in the early 1980s, when we began to plan our
investigations on blockade of EGF receptors? This was an exciting
period in the receptor field. Dr. Stanley Cohen reported purification
of the receptor for EGF (1)
. He had previously purified
EGF and identified it as a growth factor (2)
. He was
awarded the Nobel Prize in medicine for these discoveries. The
autocrine hypothesis was published by Drs. Michael Sporn and George
Todaro (3)
, putting forth the startling concept that cells
that secrete TGF-
can autostimulate their own growth by activating
their EGF receptors. Barnes and Sato summarized a decade of research
showing that growth factors accounted for the requirement for serum
when cells are grown in culture (4)
. The activated EGF
receptor and the Rous sarcoma virus transforming factor
src were found to be related proteins that performed
a newly discovered enzymatic function, tyrosine phosphorylation
(5, 6, 7)
. Thus, EGF receptors appeared to be an ideal target
for anticancer therapy.
In 1981, Dr. Gordon Sato and I put forward the hypothesis that a mAb that could block binding of a growth factor to its receptor and thereby prevent activation of receptor function might inhibit cell proliferation. We also postulated that because the growth of cancer cells is unregulated compared with nonmalignant cells, the "dysregulated" cancer cells might be selectively sensitive to death after growth factor deprivation. This was based on reports in the literature that when malignant cells in culture are deprived of an essential nutrient, such as an essential amino acid, they often attempt to continue proliferation and die, whereas normal cells arrest in G1 phase of the cell cycle and survive. It also had been shown that when thyroid cancer cells in culture were deprived of thyroid-stimulating hormone, they died, suggesting a dependence on thyroid-stimulating hormone as a survival factor. Dr. Arthur Pardee (8) had recently defined the restriction point in G1 phase, which we now know is a cell cycle checkpoint, and he pointed out that cancer cells sometimes ignore this signal. In summary, there was evidence that tumor cells were less equipped to handle deprivation of growth-promoting agents than normal cells, and we hoped to capitalize on that difference therapeutically.
In 1983 and 1984, we published a series of studies demonstrating that blockade of human EGF receptors by mAb 225 or mAb 528 produced in our laboratory competitively inhibits the capacity of EGF to activate receptor tyrosine kinase and can inhibit the proliferation of cells bearing EGF receptors, both in culture and in human tumor xenografts in nude mice (9, 10, 11, 12) . Subsequently, these antiproliferative effects in culture and against xenografts have been observed with numerous human tumor cell lines (13) .
1984 was a very exciting year in the receptor field. Early that year, the EGF receptor and the v-erbB oncoprotein were shown to be similar (14) , and later in the year, three different laboratories showed that the EGF receptor gene and the v-erbB oncogene are homologous (15, 16, 17) . These reports, together with studies showing homology of platelet-derived growth factor ß chain and the sis oncogene product (18 , 19) , created a convergence of two very exciting fields of investigation: growth factor signaling pathways and oncogenes. We had in hand an inhibitory antibody against the product of an oncogene.
In the mid-1980s, a series of studies showed that EGF receptor expression is increased in many types of epithelial tumors and that this typically correlates with a worse prognosis (20, 21, 22, 23, 24, 25) . From these studies and other reports, we estimated that approximately one-third of all human epithelial cancers express high levels of EGF receptors.
In 1986, an antibody produced by Drs. Jeff Drebin, Mark Greene, and Robert Weinberg against the mutated rat HER-2 receptor (closely related to the EGF receptor) was shown to inhibit the growth of xenografts of transfected human cells expressing that receptor (26) . This first antibody against HER-2 did not block the function of the receptor but was able to inhibit cell growth, presumably by down-regulating the receptors. In 1987 and 1989, Dr. Dennis Slamon published his important observation that increased HER-2 expression predicts a worse prognosis in patients with breast cancer (27) , and Genentech, Inc. began preclinical studies with their anti-HER-2 mAb 4D5, which is now known as Herceptin in its humanized form (28) .
In 1991, we performed a Phase I clinical trial with murine mAb 225 in patients with advanced squamous carcinoma of the lung, a malignancy that usually expresses high levels of EGF receptors. This trial clearly demonstrated the safety of administering a mAb against a growth factor receptor in concentrations that were estimated to produce saturation of the targeted receptors. The anti-EGF receptor mAb was labeled with 111In, and scans demonstrated a high uptake in the patients’ tumors and livers (29) .
Having established safety and tumor localization in patients, we were able to secure a hybridoma that produced a human:murine chimera of mAb 225 called C225 through a contract arranged by the National Cancer Institute.
C225 IgG1 is a chimerized mAb that can bind complement. It binds
to EGF receptors with a Kd of 0.2
nM, a tighter affinity than the natural ligand,
and also with greater affinity than the murine antibody from which it
was derived. Mab C225 competes with both EGF and TGF- for binding to
the receptor, inhibits activation of the receptor tyrosine kinase by
growth factor, stimulates receptor internalization, and inhibits the
growth of human tumor xenografts bearing EGF receptors
(30)
. In fact, the activity of chimeric mAb C225 against
well-established human tumor xenografts is better than that of the
murine mAb 225, presumably because of its higher affinity.
The direct mechanism of action of mAb C225 is inhibition of tyrosine
kinase activation. When A431 squamous carcinoma cells are incubated in
culture, autocrine TGF- produced by the cells activates EGF receptor
tyrosine kinase. Addition of mAb 225 to the cultures results in a
concentration-dependent inhibition of receptor tyrosine kinase
activity. This cannot be accounted for by the observed modest reduction
in the amount of EGF receptor protein because of an increase in
receptor internalization and catabolism mediated by the antibody
(9, 10, 11
, 30)
. Thus, mAb C225 is acting as a drug, a
tyrosine kinase inhibitor specific for the EGF receptor.
We have identified six different mechanisms by which C225 may inhibit
tumor cell growth and survival in culture and, more importantly, in
nude mouse xenografts. These mechanisms are listed in Table 1
. I will review some of the experiments
that have elucidated each of these mechanisms.
|
When nontransformed human cells growing in culture are exposed
continuously to saturating concentrations of mAb 225, cell cycle
traversal is arrested in G1 phase. This has been
shown with human foreskin fibroblasts, a colon adenoma cell line, and
MCF10A immortalized mammary cells (10
, 31
, 32)
. The
response of cultured malignant cell lines to mAb 225 varies from a
slowing of the proliferation rate to a complete arrest in the
G1 phase of the cell cycle (33
, 34)
.
As a control, we used our mAb 455 and Dr. Michael Waterfield’s
original anti-EGF receptor mAb R1 (35)
, both of which bind
to the receptor but do not block the binding of EGF or TGF- and do
not inhibit activation of tyrosine kinase. Neither of these control
antibodies inhibited the growth of cultured cells (10
, 32
, 33)
.
We explored the mechanisms for cell cycle arrest in
G1 phase by examining the cyclins and CDKs and
their inhibitors. In cultures of A431 squamous cervical carcinoma
cells, DiFi colon adenocarcinoma cells, and DU145 prostate cancer cells
treated with mAb 225, we found inhibition of CDK2 activity that was not
accompanied by any changes in cyclin or kinase levels but could be
accounted for by a rise in the levels of inhibitor
p27Kip1 bound to CDK (Fig. 1
; Refs. 34
, 36,
and
37
). There was no change in the levels of inhibitor
p21Cip1. Similar changes have been observed in
the MCF10A breast cell line, but with an additional decline in cyclin D
levels (31)
.
|
Apoptosis
In the case of DiFi colon adenocarcinoma cells, cell cycle arrest
at 24 h was followed by programmed cell death at 48 h when
cultures were treated with mAb 225 (33)
. Experiments by Dr. Rakesh
Kumar demonstrated that these cells carry undetectable levels of Bcl-2
(39)
. In antibody-treated cultures, the levels of Bax rose
within 8 h and were sustained until apoptosis occurred
(39)
. Others have reported a rise in Bax in head and neck
cancer cells treated with C225 (40)
. An increase in the
phosphorylated (inactive) form of Bcl-2 in ZR75 breast adenocarcinoma
cells was reported in one study (41)
, whereas another
study reported a decrease in Bcl-2 levels in a head and neck cancer
line in response to C225 (40)
. Recent unpublished
experiments by Dr. Zhen Fan with A431 squamous carcinoma cells showed
C225-induced elevations in caspase-3, -8, and
-9.4
Finally, mAb
225 was also found to sensitize cells to tumor necrosis factor. Thus,
it is evident that a variety of proapoptotic mechanisms are activated
when the EGF receptor signaling pathway is blockaded by mAb 225. EGF
and TGF- appear to function in part as survival factors, inhibiting
the levels of proapoptotic molecules in addition to stimulating cell
proliferation. However, in most cases that we have studied, when cells
in culture are subjected to inhibition of their EGF receptors, the
proapoptotic pathways are not activated to the point of initiating
programmed cell death, and most cells exhibit only slower proliferation
or G1 arrest.
Angiogenesis
As noted, cell growth inhibition by anti-EGF receptor mAb is incomplete for most cultured human tumor cell lines, whereas the effects against xenografts are often more pronounced, especially with human:mouse chimeric mAb C225. A possible explanation for these observations was provided by Dr. Robert Kerbel and Drs. Colin Dinney and Robert Radinsky, who demonstrated antiangiogenesis effects attributable to EGF receptor blockade (38 , 42 , 43) . Cultured bladder cancer cells were shown to secrete high levels of vascular endothelial growth factor, interleukin 8, and basic fibroblast growth factor into the culture medium, and this production of angiogenesis factors was reduced by the addition of mAb C225. When orthotopic xenografts of these bladder cancer cells were excised and examined histologically, 3 weeks of treatment with C225 produced a marked decrease in the presence of new blood vessels as shown by staining with anti-CD31 and a marked reduction in the amounts of vascular endothelial growth factor, interleukin 8, and basic fibroblast growth factor present in the tumor cells as compared with controls (38) . Similar observations were made with xenografted A431 squamous cervical carcinoma cells (42) and a pancreatic carcinoma cell line (43) . Thus, it appears that activity of the EGF receptor signal transduction pathway is required for stimulation of tumor angiogenesis.
Antimetastatic Activity
Studies with xenografts of bladder carcinoma cells were carried out in the orthotopic model developed by Dr. Colin Dinney, in which the cancer cells grow in the bladder wall and metastasize to the lymph nodes and lungs. When tumor-bearing animals were treated with mAb C225 beginning 28 days after tumor implantation, metastases were not observed, compared with the presence of lymph node metastasis in eight of eight untreated control animals and lung metastasis in three of eight controls. Histological staining showed the presence of high levels of matrix metalloproteinase 9 in the tumor cells of control animals and a marked reduction in matrix metalloproteinase 9 in the treated animals (38) .
Possible Contribution of Immune Mechanisms
To evaluate the possible role of the immune system in the antitumor effects of mAb 225 against human tumor xenografts, we explored the efficacy of a F(ab')2 fragment of the antibody, which lacks the Fc portion that mediates immune mechanisms. The disarmed F(ab')2 225 fragment was able to inhibit tumor cell growth in xenografts, but not quite as effectively as complete mAb 225 (44) . These results demonstrate that mAb 225 against the EGF receptor can mediate antitumor activity in the absence of immune function but do not rule out a possible contributing immunological effect.
Additional studies with mAb C225 in culture were carried out by Dr. Ralph Reisfeld. He demonstrated the capacity of this antibody to elicit antibody-dependent cellular cytotoxicity against a cultured human melanoma cell line, using human peripheral blood mononuclear cells as the effectors (45) .
Potentiation of Chemotherapy and Radiation Therapy: Preclinical and Clinical Studies
Our studies demonstrating synergystic antitumor activity when C225
is combined with chemotherapy were stimulated by two reports in the
literature. The original observation came from the laboratory of Dr.
Michael Sela (46)
. Cisplatin in combination with another
anti-EGF receptor mAb showed augmented activity against a human tumor
xenograft. A similar observation was made soon afterward using
cisplatin in combination with a mAb against HER-2 (47)
. We
decided to aggressively pursue these observations. In a series of
studies, we were able to demonstrate synergystic antitumor activity
against well-established human tumor xenografts of both adenocarcinoma
and squamous carcinoma cell lines when murine mAb 225 treatment was
combined with the maximum tolerated doses of either doxorubicin or
cisplatin (48
, 49)
. Treatment either with drug alone or
with antibody alone merely reduced tumor growth or had little effect,
whereas combined therapy eradicated the well-established xenografts
(Fig. 2)
. A third study showed
synergystic, curative antitumor activity when mAb 225 treatment was
combined with paclitaxel, this time with suboptimal doses of the
chemotherapeutic agent (50)
. Another study by Dr.
Fortunato Ciardiello et al. (51)
showed
synergystic antitumor activity of mAb C225 when given in combination
with topotecan against a colon adenocarcinoma xenograft. These data
demonstrate that blockade of EGF receptors by mAb 225 or mAb C225 can
potentiate the antitumor activities of a variety of chemotherapeutic
agents that have different mechanisms of action.
|
The mechanism for this synergism is under study. Preliminary data
suggest that repair of drug-induced damage may be hampered by
inhibition of the EGF receptor signaling pathway. We favor the
possibility that in the presence of cellular damage from chemotherapy,
EGF or TGF- becomes a survival factor rather than a growth factor,
tipping the balance toward drug-induced apoptosis. This is consistent
with the role of growth factors as survival factors in cultures of
hematopoietic cells and in cultured epithelial tumor cells driven to
proliferate by expression of an oncogene (52
, 53)
. On the
basis of our experimental results, we moved forward with clinical
trials of C225.
We also collaborated with Genentech, Inc. in studies of the anti-HER2 mAb Herceptin. I had the privilege of collaborating with Drs. José Baselga and Larry Norton in the first clinical trial that provided positive proof of concept that an antibody against a growth factor receptor could produce antitumor effects in human patients (54) . This trial involved 43 women with advanced breast cancer who received weekly injections of Herceptin. There were four partial responses and one complete response in a patient who continues to receive Herceptin 6 years later. A parallel trial by Dr. Dennis Slamon showed a 25% response rate in patients with advanced and heavily pretreated breast cancer who received Herceptin plus cisplatin (55) .
In parallel with our laboratory studies of C225 plus chemotherapy, we performed preclinical experiments with Herceptin, supplied by Genentech, Inc. We found that when Herceptin treatment was combined with either doxorubicin or paclitaxel, there was synergystic antitumor activity against BT474 human breast adenocarcinoma cell xenografts (56) . The effects were more pronounced with paclitaxel. These observations provided the preclinical data that supported Genentech’s Phase III multicenter clinical trial led by Dr. Dennis Slamon, which combined Herceptin with either doxorubicin/cyclophosphamide or paclitaxel in patients with advanced breast cancer (57) . The positive results from this pivotal trial, especially with paclitaxel, led to Food and Drug Administration approval of Herceptin for use in the treatment of breast cancer.
Meanwhile, clinical trials with C225 have been pursued aggressively by
ImClone Systems, Inc., which licensed mAb C225 from the University of
California. Table 2
summarizes a series
of nine Phase I and I/II trials that involved treatment of 184 patients
with advanced epithelial malignancies (58)
. Two percent of
patients had anaphylaxis, responding to epinephrine, an incidence
commonly observed in treatment with humanized or chimeric mAbs. Nine
percent of patients developed grade 3 or greater dermatological
toxicity consisting of a folliculitis resembling acne, primarily on the
face and trunk, which resolved when treatment was completed. There were
no other significant organ toxicities. Only 2 of 55 patients tested
demonstrated the presence of a serum antibody against C225, and a low
neutralizing titer was reached in only 1 of these 2 patients
(58)
.
|
Two Phase Ib/IIa trials in advanced head and neck cancer were presented in abstract form at the American Society of Clinical Oncology Meeting in 1999. The first involved combined treatment with weekly C225 plus with 60 Gy of local radiotherapy given as 2 Gy/day over 6 weeks (59) . The antibody dose was 100 mg/m2 weekly in the three initial patients, and this dose was increased to reach a 400–500 mg/m2 loading dose followed by 200–250 mg/m2 weekly in the final four patients. The response rate was 100%, and 13 of 15 patients achieved a complete remission as evidenced by endoscopy and computed tomography scan. The expected complete plus partial response rate to radiation alone is 50–60%, based on the literature.
The second trial involved treatment with 100 mg/m2 cisplatin monthly plus C225 weekly, escalated in groups of three or four patients (60) . Nine of 12 patients were evaluated for a clinical response. There was one complete response (confirmed by biopsy), and there were five partial responses, for a response rate of 67%, and only one patient had disease progression during therapy. Of special significance was the fact that three of the responders, including the complete responder, had received cisplatin in combination with other therapy prior to the study.
Phase III randomized multicenter trials are under way, assessing the efficacy of mAb C225 with either cisplatin or radiotherapy for treatment of advanced head and neck cancer. Other trials are exploring mAb C225 with gemcitabine for treatment of pancreatic cancer and mAb C225 with irinotecan for treatment of metastatic colorectal adenocarcinoma.
Clinical trials have been initiated by a number of pharmaceutical companies using other low molecular weight inhibitors of the EGF receptor that act intracellularly on the kinase portion of the receptor. Inhibitors of other downstream targets in the signal transduction pathway activated by EGF receptors are also being developed, and an inhibitor of farnesyl transferase that may block ras activation is in early trials.
This review and others (13) have summarized much of the preclinical data and the results of clinical trials that demonstrate the potential efficacy of therapy with human:chimeric mAb C225, which blocks the activation of EGF receptors. Herceptin mAb against HER-2 is now approved for clinical use. This research has involved scientists in academia, the pharmaceutical industry, and the National Cancer Institute, and our own contributions involve the work of many collaborators. It is highly likely that blockade of growth factor-mediated signal transduction pathways, in combination with chemotherapy or radiotherapy, will enhance our ability to inhibit and, in some cases, eradicate many of the common epithelial human malignancies (61) .
ACKNOWLEDGMENTS
I thank Kay Biescar for excellent secretarial support in producing the manuscript.
FOOTNOTES
1 Presented at the 90th Annual
Meeting, American Association for Cancer Research, April 10–14, 1999,
Philadelphia, Pennsylvania. The research on anti-EGF receptor mAbs in
J. M.’s laboratory has been supported by grants from the National
Cancer Institute since 1982. J. M. has a financial interest and holds
a Board of Directors position in ImClone Systems, Inc., the company
that is carrying out the clinical trials with C225. 
2 To whom requests for reprints should be
addressed, at The University of Texas M. D. Anderson Cancer Center,
Box 091, 1515 Holcombe Boulevard, Houston, TX 77030.
3 The abbreviations used are: UCSD, University of
California San Diego; mAb, monoclonal antibody; EGF, epidermal growth
factor; TGF, transforming growth factor; CDK, cyclin-dependent
kinase.
4 Z. Fan, unpublished observations.
5 L. Milas et al., unpublished
observations.
Received 12/29/99; accepted 12/31/99.
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), mAb (1 mg/mouse) twice weekly for 4 weeks (
), or both
therapeutic agents (
). Arrows, the timing of
administration of treatment. The data are expressed as mean tumor
size ± SE (seven mice/group). In B, the mice were
observed for 6 months for survival (from Ref.