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Bruce G. Redman, D.O.,
Clinical Associate Professor
Department of Internal Medicine
Vernon Sondak, M.D.,
Associate Professor, Department of Surgery
It is currently estimated that the risk of developing melanoma
is one in 75, and if current trends continue this risk will
continue to rise (1). While surgery remains the mainstay of
curative treatment in early-stage disease, large numbers of
patients continue to progress to a more advanced stage of
disease. Standard chemotherapy options, whether single agent
dacarbazine or combination therapy, have had little impact
on the natural history of advanced disease. Dacarbazine, when
administered as a single agent, produces response rates of
15 to 20% of short duration (2). Multiple randomized trials
have failed to show a benefit of adding additional agents
to dacarbazine (3,4). Newer treatment modalities are obviously
needed if we are to impact on this potentially lethal disease.
Immunotherapeutic approaches are one area of intense research
at the University of Michigan Comprehensive Cancer Center.
Immunobiology of Melanoma
Why should immunotherapeutic approaches to the treatment
of melanoma be expected to have any impact on this disease?
There are several lines of evidence that support such an approach.
Patients with melanoma have been found to have circulating
T cells that are specific against their own melanoma cells
(5). These specific T cells have also been isolated from metastatic
melanoma tumor nodules referred to as tumor infiltrating lymphocytes
(TIL). The tumor-specific T cells also have been found to
recognize specific antigens, including some unique to cells
of melanocytic differentiation and some specific to a broad
range of tumor cells (tumor specific antigens) (Table
1). This evidence has been used to hypothesize that there
is some form of an immune response against melanoma occurring
in these patients.
If there is an ongoing immune response in patients with
melanoma, why hasn't the disease been eradicated in these
individuals? There are several hypotheses that have been generated
based on clinical findings. Melanoma cells may be able to
avoid immune detection by loss of the major histocompat-ibility
complex (MHC) or accessory molecules (e.g. B7, ICAM-1), which
are required for an appropriate T cell response. Melanoma
cells may express tumor antigens but at low levels insufficient
to expand an adequate immune response for tumor eradication.
Finally tumor cells have been found to secrete various soluble
factors (e.g. TGF-b, interleukin-10, Fas ligand), which are
potentially immune suppressive. All these possible mechanisms
are operational to some extent, resulting in the inability
of an immune response to eradicate melanoma.
Immunotherapeutic Approaches
The immunotherapeutic approaches to melanoma can be categorized
into; 1) administration of cytokines to expand or enhance
an immune response, 2) adoptive transfer of autologous lymphocytes
that have been manipulated in vitro, 3) vaccination of patients
against antigens associated with melanoma and finally 4) combinations
of the above.
The cytokine interleukin-2 (IL-2) has been evaluated
as a single agent in the treatment of metastatic melanoma.
When administered in the FDA approved high dose bolus regimen
of 600,000-720,000 IU/kg every 8 hours for 14 doses 16% of
patients respond (6% complete response) (6). The majority
of the CRs to high dose IL-2 have lasted beyond 4.5 years.
IL-2 has also been evaluated in combination regimens with
interferon-alpha and multi-agent chemotherapy (biochemotherapy).
Reports from several single institution trials have reported
response rates with biochemotherapy of 55-60% (10-20% CR)
(7,8). A small randomized trial from the NCI surgery branch
evaluating chemotherapy vs. biochemotherapy failed to show
an advantage for biochemotherapy when survival was used as
the endpoint (9). Hopefully an ongoing large intergroup trial
randomizing patients with metastatic melanoma between a combination
chemotherapy regimen of cisplatin, dacarbazine and vinblastine
vs. the same chemotherapy with IL-2 and interferon-alpha will
clarify the issue of whether adding immunotherapy to chemotherapy
is better then chemotherapy alone. Evaluations of other cytokine
and cytokine combinations including the combination of flt3-ligand
and interferon (Table
2 ) at our institution remains an area of active research.
The adoptive immunotherapy of melanoma is an area of
active investigation either alone or with added cytokines.
The source of lymphocytes and the in vitro manipulation utilized
differ from trial to trial. TIL with systemic IL-2 has been
evaluated in the treatment of metastatic melanoma. Though
response rates have been encouraging, treatment is complicated
by a need for autologous tumor (which sometimes does not provide
adequate numbers of TIL) and the time required to grow out
adequate TIL (resulting in disease progression in patients).
Other investigators are evaluating alternative sources of
lymphocytes for in vitro manipulation and adoptive transfer.
Potential sources of lymphocytes include tumor draining lymph
nodes, in situ manipulated tumor nodules and peripheral blood
lymphocytes.
At the University of Michigan we have pursued several
approaches to adoptive therapy of melanoma (Table
2 ). One approach has been to "infect" a tumor
nodule with the gene for the HLA-B7 MHC protein in patients
who are HLA-B7 negative. The rationale behind this approach
is that expression of a foreign MHC protein will induce an
immune response, which will lead to recognition of melanoma
antigens that are expressed at low levels. In prior trials
utilizing this approach, several injected tumor nodules have
regressed, the regressions being associated with an intense
inflammatory response. We have expanded on this initial work
by harvesting an injected tumor nodule and expanding the infiltrating
lymphocytes in vitro with IL-2. These expanded lymphocytes
are then adoptively transferred back to the patient with systemic
IL-2. Another adoptive immunotherapy approach we are evaluating
involves taking peripheral blood lymphocytes from patients
who are HLA-A2 positive and in vitro inserting the gene for
a T cell receptor (TCR) specific for the MART-1 melanoma antigen.
These lymphocytes, which now express the specific TCR for
MART-1, are adoptively transferred back to the patient.
Vaccine-based strategies also are being evaluated in
the treatment of melanoma. In the past, vaccines were made
of whole cells or crude cell extracts either alone or with
an immune adjuvant. With the recognition and purification
of melanoma antigens (Table 1) and new knowledge about professional
antigen presenting cells (APC), vaccination strategies are
once again an area of active clinical research. One type of
APC that has generated the most clinical interest is the dendritic
cell (DC). The DC is unique in that it has the ability to
present antigen and stimulate a naive T cell response from
both CD4 (helper cells) and CD8 (cytotoxic) T cells (10).
A naive T cell response is a T cell responding to an antigen
which it has not been exposed to previously and therefore
has no memory for the eliciting antigen. As an APC the DC
expresses both MHC Class I and II, as well as multiple accessory
molecules required for the appropriate stimulation of an effective
T cell response.
We are evaluating two such approaches to the vaccination
of patients with melanoma. In the first we are administering
DC that have been obtained from a patient by leukapheresis
and pulsed with melanoma associated antigens gp100 and tyrosinase
in vitro. This trial is evaluating this approach in patients
who are HLA-A2 positive and who have Stage IIA and IIB resected
melanoma (primary tumor >1.5 mm and negative lymph nodes).
We are also evaluating DC based vaccination strategies in
patients with metastatic melanoma. In this trial we are utilizing
DC pulsed with autologous melanoma. The use of autologous
tumor avoids one of the problems of utilizing defined peptide
antigens in that all melanoma cells in an individual patient
may not express the peptide(s) that are being used as part
of the vaccine. These autologous tumor-pulsed DC are then
administered back to the patient either alone or with IL-2.
The Cutaneous Oncology Program and the Tumor Immunology
Program of the University of Michigan Comprehensive Cancer
Center are working together to develop new strategies for
the treatment of patients with melanoma. For the future, new
immunotherapeutic trials are being developed based on basic
and clinical research that is currently ongoing at the University
of Michigan.
References
1. Balch CM, Reintgen DS, Kirkwood JM, et al: Cutaneous
melanoma, in DeVita VT Jr, Hellman S, Rosenberg SA (Eds):
Cancer: Principles and Practice of Oncology. Philadelphia,
PA, Lippincott-Raven, 1997, pp 1947-1994.
2. Hill GJ 2d, Krementz ET, Hill HZ: Dimethyl triazeno
imidazole carboxamide and combination therapy for melanoma:
IV. Late results after complete response to chemotherapy (Central
Oncology Group protocols 7130, 7131, and 7131A). Cancer 1984;53:1299-1305.
3. Falkson CI, Ibrahim J, Kirkwood J, et al: Phase III
trial of dacarbazine versus dacarbazine with interferon-2b
versus dacarbazine with tamoxifen versus dacarbazine with
interferon-2b and tamoxifen in patients with metastatic malignant
melanoma: An Eastern Cooperative Oncology Group study. J Clin
Oncol 1998;16: 1743-1751.
4. Chapman PB, Finhorn LH, Meyers ML, et al. Phase III
multicenter randomized trial of Dartmouth regimen versus dacarbazine
in patients with metastatic melanoma. J Clin Oncol 1999;17:2745-2751.
5. Schwartzentruber D, Hom SS, Rosenberg SA, Topalian
SL. In vitro predictors of therapeutic response in melanoma
patients receiving TIL and IL-2. J Clin Oncol 1994;12: 1475-1480.
6. Atkins MB, Lotze MT, Dutcher JP, et al. High dose recombinant
interleukin-2 therapy for patients with metastatic melanoma.
Analysis of 270 patients treated between 1985 and 1993. J
Clin Oncol 1999;17:2105-2116.
7. Richards JM, Mehta N, Ramming K, et al. Sequential
chemoimmunotherapy in the treatment of metastatic melanoma.
J Clin Oncol 1992;8:1338-1343.
8. Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy
regimen with concurrent administration of cisplatin vinblastine,
dacarbazine, interferon alfa, and interleukin-2 for patients
with metastatic melanoma. J Clin Oncol 1998;16: 1752-1759.
9. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.
Prospective randomized trials of the treatment of patients
with metastatic melanoma using chemotherapy with cisplatin,
dacarbazine, and tamoxifen alone or in combination with interleukin-2
and interferon alfa-2b. J Clin Oncol 1999;17:968-975.
10. Inoba K, Metlay JP, Crowley MT, et al. Dendritic cells
pulsed with protein antigens in vitro can prime antigen specific,
MHC restricted T cells in situ. J Exp Med 1990;172:631-640.
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