Seminars in Surgical Oncology 6:364368 (1990)

lmmunotherapy of Gynecologic Malignancies KENNETH A. FOON, MD

AND

JAMES FANNING,

DO

From the Division of Clinical immunology and Department of Medicine (K.A. F.), and the Department of Gynecologic Oncology, Roswell Park Cancer Institute and the State University of New York at Buffalo (J.F.), Buffalo, New York

Systemic Corynebacterium parvum and BCG have limited activity in gynecologic malignancies. Although intraperitoneal C. parvum is active, its toxicity is prohibitive. Intraperitoneal alpha-interferon is an active second line agent for minimal residual disease following combination chemotherapy. Intraperitoneal interferon trials are ongoing. Alpha-interferon is also active against lower genital tract condyloma acuminata. Sufficient numbers of patients have not been evaluated to determine the activity of interleukin-2(11-2) in gynecologic malignancies. Radioisotope labeled monoclonal antibodies can image gynecologic malignancies and may have a future therapeutic role. The last decade has witnessed a substantial growth in immunotherapy and has demonstrated a role for biologic agents in cancer therapy. Continued improvement in biologic therapies should lead to major advances in gynecologic cancer diagnosis and therapy. KEY WORDS: interferon, IL-2 LAK, monoclonal antibodies

INTRODUCTION Immunotherapy can be divided into two categories, active and passive. Active immunotherapy stimulates the host’s antitumor immunity. Active immunotherapy can be specific (tumor vaccines) or nonspecific (Corynebacterium parvum and BCG). Passive immunotherapy involves the administration of biologically active agents with innate antitumor properties. In the 1970s, active specific and nonspecific immunotherapy were evaluated. With the advent of genetic engineering and hybndoma technology, the 1980s have witnessed a renewed interest in immunotherapy . Biologic response modifiers exert antitumor effects via active and passive mechanisms. Some of the biologic response modifiers currently undergoing investigation are interferons, interleukins, growth factors, and monoclonal antibodies [ 11. ACTIVE NON-SPECIFIC IMMUNOTHERAPY C . parvum is a gram-negative anaerobe in nonviable form that exerts its nonspecific immunostimulation primarily by activating natural killer cells and antibodydependent cell-mediated cytotoxicity [2]. A number of major trials have been conducted of C. parvum in gynecologic malignancies [2- 1 11. A Gynecologic Oncology Group trial [2] of C. parvum and melphalan in the treatment of 45 patients with epithelial ovarian cancer re0 1990 Wiley-Liss, Inc.

ported that the addition of C . parvum resulted in an increased response rate (73% versus 29%) and a doubling of median survival and progression-free survival. However, a follow-up randomized prospective study by the Gynecologic Oncology Group failed to show any benefit of the addition of C. parvum to melphalan in stage I11 epithelial ovarian cancer [3]. Intraperitoneal C.parvum appears active against minimal residual ovarian cancer where a 32% response rate in 16 patients was reported [ 71. However, the clinical usefulness of intraperitoneal C . parvum is limited because of significant toxicity (abdominal pain, fever, nausea, and vomiting). There was no benefit reported when C. parvum was added to radiotherapy in the treatment of 135 patients with cervical carcinoma [6]. BCG is a live attenuated strain of Mycobacterium bovis that stimulates both humoral and cell-mediated immunity. In two prospective randomized trials BCG was added to chemotherapy in stage I11 and IV epithelial ovarian cancer [8-lo]. In the first trial, the addition of BCG to doxorubicin and cyclophosphamide increased response rate and survival. In the second trial, BCG Address reprint requests to Kenneth A . Foon, M.D., Division of Clinical Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.

Immunotherapy of Gynecologic Malignancies

added to cisplatin, doxorubicin, and cyclophosphamide did not significantly increase response rate or survival. The role of C. pawum and BCG in the treatment of gynecologic cancers has not been convincingly established. OK-432 is a streptococcal preparation that augments cytotoxic macrophages, natural killer cells, and killer T-cells. The Cervical Cancer Immunotherapy Study Group of Japan [ 1 11 evaluated the addition of OK-432 to radical surgery or radiotherapy in the treatment of cervical cancer. The addition of OK-432 resulted in an increased 3 year progression-free survival rate from 59% to 72%. No large trials of OK-432 for the treatment of gynecologic malignancies have been evaluated in the United States.

INTERFERONS Interferons are a group of closely related proteins and glycoproteins. Alpha, beta, and gamma interferons are produced by, respectively, leukocytes, fibroblasts, and T-lymphocytes. The exact mechanism of interferon’s antitumor activity is unclear. It appears that interferons produce a direct antiproliferative effect as well as stimulating host effector mechanisms, such as natural killer and monocyte cytotoxicity. Parenteral alpha-interferon produced a 14% response rate in 72 patients with epithelial ovarian cancer [ 12-16]. Intraperitoneal alpha interferon appears active as second line treatment following parenteral combination chemotherapy. Forty-three percent of 14 patients with epithelial ovarian cancer responded to intraperitoneal alpha-interferon and 7 1% of women with minimal residual disease responded to alpha-interferon as “salvage therapy” [ 171. Beta and gamma interferons have been less extensively studied [ 18-20]. Local and systemic interferons have been used to successfully treat resistant condyloma accuminata of the lower genital tract. In a review of 8 trials, a 47% complete response rate (176/373) to interferon versus an 18% complete response rate (44/240) with placebo was reported. Mild toxicity was associated with interferon therapy and consisted mainly of fever, fatigue, and mild myelosuppression . The current direction of interferon research includes combinations with other biologic response modifiers and cytotoxic drugs.

INTERLEUKIN-2 (IL-2) IL-2 is a glycoprotein that is released from T-cells following antigen recognition and presentation. IL-2 causes lymphoid proliferation and activates the lytic mechanisms of peripheral blood lymphocytes and tumor infiltrating lymphocytes. IL-2 also causes a release of gamma interferon and tumor necrosis factor. Although IL-2 had activity in renal cell cancer and melanoma, there were no responses among nine women with ovarian

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epithelial cancer 122-241. The toxicity of systemic high dose IL-2 is substantial and includes fever, diarrhea, hypotension, erythema, hepatic and renal dysfunction, neuropsychiatric conditions, and rarely colonic perforation. IL-2 can also cause a “capillary leak syndrome” resulting in pulmonary edema. This may result from direct lymphokine-activated killer cell adherence and cytotoxicity to endothelial cells or IL-2-induced endothelial cell activation. Intrapentoneal IL-2 appears less toxic than high-dose systemic IL-2, but intraperitoneal fibrosis has been reported [ 11.

ADOPTIVE IMMUNOTHERAPY Adoptive immunotherapy is the direct administration of cells with antitumor activity. Two main types of adoptive immunotherapy of current interest involve the administration of lymphokine-activated killer cells (LAK) and tumor-infiltrating lymphocytes (TIL). LAK cell therapy begins by treating patients with IL-2 systemically to stimulate the expansion of in vivo LAK cells. Patients are then leukopheresed and the white cells are incubated with IL-2 for 3-5 days ex vivo. LAK cells are then infused back into the patient with additional IL-2. Alternatively, lymphocytes can be obtained directly from tumor specimens and expanded in IL-2 (TIL). TIL are then administered to the patient with IL-2. In animal models, TIL are 50-100 times as effective as LAK cells [25]. Two of three partial responses were obtained in gynecologic malignancies following intravenous IL-YLAK cell therapy and two of eight partial responses were obtained with intraperitoneal treatment [26-301. No significant toxicity was associated with the administration of LAK cells or TIL. The major toxicities were those associated with IL-2. Although IL-2/LAK and IL-2/TIL are promising treatment modalities, improvement is needed. Current investigations involve optimizing the dose and delivery of IL-2, regional therapy, combination with chemotherapy and/or other biologic response modifiers, and targeting of TIL or LAK cells with monoclonal antibodies.

MONOCLONAL ANTIBODIES Monoclonal antibodies are homogeneous immunoglobulins with unique specificity for a desired antigen. Monoclonal antibodies are produced by the hybridoma technology developed by Kohler and Milstein 2311. Following immunization of mice, the spleen is removed and prepared in a single cell suspension. Antibody-producing B lymphocytes are fused with murine myeloma cells to form hybridoma cells that express both genomes. Hybridomas that produce the desired monoclonal antibody can be identified and cloned. The advantage of monoclonal antibodies are that they are highly specific for single antigens, can be produced in large quantities with a high degree of purity with little batch-to-batch varia-

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tion, and can be coupled with isotopes, drugs, or toxins. Monoclonal antibodies have tremendous potential for detecting serum tumor-associated antigens, immunohistochemical and immunocytochemical detection of malignant cells, and as immunoconjugates for diagnostic imaging and therapy. There are several critical factors for successful monoclonal antibody therapy. The tumor-associated antigens should be distributed densely and homogeneously on the surface of the tumor cells. The monoclonal antibodies should have minimal cross reactivity with normal tissues. They should bind to the antigen with high affinity. The antigen antibody complex should not dissociate from the cell surface membrane. The presence of tumorassociated antigens in the blood stream could bind the monoclonal antibody and prevent tumor localization. The development of human antimouse antibodies (HAMA) is also a major clinical problem. HAMA can theoretically form immune complexes with resultant tissue damage and can neutralize the monoclonal antibody and prevent it from binding to tumor cells. Most HAMA crossreact with almost all other mouse antibodies. Clinical trials with unlabeled monoclonal antibodies have resulted in only minor responses [ 11. This was not surprising because most murine monoclonal antibodies do not adequately activate the human immune effector system and do not have direct cytotoxic effects. Therefore, immunoconjugates have been formed by coupling monoclonal antibodies to radioisotopes, toxins, and cytotoxic drugs. The advantage of radioisotopes is that they do not need to be internalized and they can radiate beyond the antibody binding cells. The advantage of toxins is their extreme potency; frequently a single molecule can destroy a cell. Cytotoxic drugs have a proven track record with defined activity and toxicity. Radioisotope immunoconjugates can be used for diagnosis and treatment. The predominant isotopes used for monoclonal antibody imaging in gynecologic oncology are 1311, 1231,and "'In. The monoclonal antibodies most frequently used are OC125 and HMFG2. Four hundred and five patients with gynecologic malignancies imaged with monoclonal antibody radioisotopes have been reported. The majority of patients had epithelial ovarian cancer. There was an 87% sensitivity (253/292) and a 67% specificity (76/113) [3248]. The smallest lesions detectable were 1-2 cm. There does not appear to be a significant improvement in imaging following intraperitoneal administration. Although imaging with radioisotope monoclonal antibodies is feasible, improved localization of the radioimmunoconjugate is needed before isotope imaging will make a significant impact on the diagnosis of primary or recurrent gynecologic malignancies. Radioisotope immunoconjugates have also been used for the treatment of gynecologic malignancies. Thirty-

four epithelial ovarian cancer patients were treated with intraperitoneal radioimmunoconjugates. Twenty-eight patients were treated with 13'1 conjugated to HMFG1, HMFG2, or H17E2 [49]. The objective response rate was 18% (5/28). There were two partial responses in patients with small residual disease (

Immunotherapy of gynecologic malignancies.

Systemic Corynebacterium parvum and BCG have limited activity in gynecologic malignancies. Although intraperitoneal C. parvum is active, its toxicity ...
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