Vaccine therapy for malignant melanoma (1996)

The incidence of malignant melanoma of the skin continues to rise worldwide at a rate of about five percent per year.1 In the United States and Canada, melanoma has increased at a rate exceeding that of any other tumor except lung cancer in women. According to the American Cancer Society, about 38,300 patients will be diagnosed with melanoma this year and 7,300 will die from recurrent advanced disease.2 With early diagnosis and adequate surgical treatment, the 10-year cure rate is 90 percent for primary melanomas less than 1.5 mm in thickness (American Joint Committee on Cancer [AJCC] stage I). However, once melanoma metastasizes to distant sites (AJCC stage IV), prognosis is discouraging. At present, five-year survival is rare, and median survival remains a dismal four to eight months, depending on the site of metastasis. Although in rare instances complete responses do occur, on the whole chemotherapy has failed to improve overall survival. Among single agents, dacarbazine has produced the highest response rates (15 to 25 percent) in patients with soft tissue metastasis, but responses to dacarbazine are less than 10 percent in patients with visceral metastasis. In most cases, responses last only three to six months, with only four percent being complete and only about one percent lasting more than 30 months. In a large study from the Mayo Clinic, only 10 of 503 patients undergoing various chemotherapeutic regimens achieved complete remission and survived for more than five years.3 Although biochemotherapeutic regimens combining cytotoxic agents with interleukin-2 and/or interferon alfa appear to increase response rates, significantly prolonged survival is still limited to the small group of complete responders. In short, no regimen of chemotherapy has significantly improved the overall median survival of patients with advanced melanoma, and no single agent or combination of agents has proved superior to dacarbazine, the only drug approved by the Food and Drug Administration for the treatment of metastatic melanoma.4,5 Unfortunately, almost all patients with melanoma metastatic to distant sites experience a progressive disease that follows its inextricable course in defiance of all available therapies. Moreover, a depressingly high 60 to 80 percent of patients who have metastasis limited to the regional lymph nodes (AJCC stage III) or primary melanomas thicker than 4 mm die from disseminated disease within five years, depending on the number of tumor-involved lymph nodes. Review of our experience at the John Wayne Cancer Institute indicates that there has been no improvement in the overall survival of AJCC stage III or stage IV melanoma patients receiving standard therapy without melanoma vaccines for almost a quarter of a century (Fig. 1).6 Thus, there is an urgent need for new approaches to the management of melanoma that has metastasized to the regional nodes or distant sites or is at high risk of metastasizing. Overall survival of patients with stage III melanoma (regional lymph node metastasis) treated with standard therapy. Data based on experience at the John Wayne Cancer Institute. The development of novel approaches using active specific immunotherapy with therapeutic melanoma vaccines has been prompted by clinical observations suggesting an important role of the immune system in melanoma.7–12 These observations include waxing and waning of melanoma lesions; the highly variable rate of disease progression; the possibility of late relapse; the increased incidence of malignant melanoma in immunosuppressed patients; and the therapeutic efficacy of interleukin-2, which mediates its antitumor effect immunologically. A striking observation is spontaneous regression of malignant melanoma. In the experience at the John Wayne Cancer Institute, almost 30 percent of primary melanomas show some evidence of regression, and about 14 percent of nodal metastases occur without an identifiable primary (presumably due to spontaneous regression of the cutaneous melanoma). Regression of melanoma metastatic to distant sites is a frequently discussed but rarely observed phenomenon usually associated with bacterial infections. Nevertheless, multiple cases have been documented since Bennett's original report in 1899.13 Overall survival of patients with stage IV melanoma (distant metastasis) treated with standard therapy. Reprinted with permission from Barth et al.6 The success of prophylactic vaccines against infectious disease prompted investigation of vaccines against cancer. At present, most cancer vaccines are therapeutic rather than prophylactic; they are administered after the advent of disease. Like vaccines against infectious disease, cancer vaccines are made from attenuated whole cells, cell walls, specific antigens, or nonpathogenic strains of living organisms.14 Active immunotherapy with cancer vaccines is administered to stimulate the patient's immune system to destroy tumor cells and thereby overcome the immunosuppression produced by tumor-derived factors. Active immunotherapy also attempts to enhance the ability of tumor-associated antigens to stimulate a clinically beneficial immune response. Our early attempts to develop vaccines against melanoma were based on the observation that serum from melanoma patients contains antibodies that react with antigens on autologous melanoma cells.10 These early vaccines were crude mixtures of whole or fractionated, autologous or allogeneic melanoma cells. Most were unsuccessful. However, the application of modern techniques of molecular biology and immunology has allowed definition of a large number of melanoma-associated antigens (MAA) that can induce an immune response in patients with melanoma. Although early investigators doubted the existence of such antigens, their clear demonstration has awakened new interest in development of vaccines that can upregulate a patient's immune response to melanoma. Common MAA shared by melanomas from different patients (i.e., allogeneic melanomas) are the basis for “generic” melanoma vaccines. These common MAA were defined initially by their reaction with polyclonal antibodies from melanoma patients and later by their reaction with highly specific human monoclonal antibodies and cytotoxic T cells (Table 1).15–30 The ability to quantitate the humoral and cell-mediated immune responses to these MAA has transformed melanoma vaccine research from a series of interesting clinical observations to an exciting scientific discipline. The success of prophylactic vaccines against infectious disease prompted investigation of vaccines against cancer. The timing of the response to therapeutic cancer vaccines is quite different from the response to chemotherapy (Table 2). Chemotherapeutic agents are cytotoxic: they kill tumor cells immediately and therefore can cause clinical regression within two to four weeks. By contrast, cancer vaccines have no direct cytotoxic effect on existing metastatic disease. Instead, they elicit humoral and cell-mediated immune responses, which evolve over a period of 12 to 14 weeks and may require six to eight months to induce complete regression.31 After the initial immunization, disease may show progression for four to eight weeks before the growth rate slows and is followed by a period of tumor stability and subsequently by signs of regression. The delayed response to cancer vaccines is somewhat analogous to the delay of six to eight weeks commonly observed with the responses to hormonal therapy of breast cancer. Although a therapeutic cancer vaccine usually requires three to four months to induce clinical regression or slowing of tumor growth, the response is usually durable, lasting from months to years. This is in marked contrast to the short-term response to most chemotherapy regimens. Because MAA are weak antigens, melanoma patients receiving therapeutic vaccines are usually immunized repeatedly for prolonged periods. A melanoma vaccine's success (i.e., its ability to prolong survival) can be predicted by quantitating the patient's immune response during this time. The induction of humoral antibodies and the development of cell-mediated responses are directly related to the duration of survival.31 Attempts have been made to enhance the efficacy of melanoma vaccine therapy by administering a vaccine with nonspecific adjuvants, such as bacille Calmette-Guérin (BCG), or with immunomodulators, such as cyclophosphamide, cimetidine, or indomethacin. These agents may help counteract the tumor-associated immunosuppression induced by T-suppressor cells. Adjuvants can enhance and often modify a patient's immune response to cancer vaccines by providing carriers, immune stimulants, and antigen targeting to particular cells or organ sites. In addition to BCG, currently used adjuvants in human melanoma include DETOX, QS-21, and MF-59. The increasing interest in subunit vaccines (e.g., peptides) will increase the need for effective adjuvants. Recently, investigators have also begun to use DNA sequences from BCG to augment immune responses. In this brief review, we will summarize the present status of melanoma vaccines as therapy for distant metastatic disease (AJCC stage IV) and as adjuvant therapy following surgical resection of regional lymph node metastasis (AJCC stage III). Because we are most familiar with our work, much of this review will concentrate on our own experience during 30 years of research to develop an effective therapeutic vaccine against melanoma. Despite new treatment options, the prognosis of patients with melanoma metastatic to distant sites has not changed significantly over the past two decades (Fig. 1).6 Median overall survival is 7.5 months, and the five-year survival rate is less than five percent. At the John Wayne Cancer Institute, we have developed a living whole-cell melanoma vaccine called CancerVax. CancerVax is an irradiated mixture of three allogeneic melanoma cell lines selected for their high content of immunogenic MAA, including all antigens listed in Table 1. Since 1984, we have been investigating the response to CancerVax in patients with melanoma metastatic to distant sites (AJCC stage IV). In 1992, a first analysis of our phase II experience with 75 patients revealed a response rate of 22 percent.31,32 Median survival was significantly longer in 75 patients treated with CancerVax than in 1,275 historical controls receiving other types of treatment (23 months versus 7.5 months, p=0.0001). This series has recently been updated and now includes 157 CancerVax patients and 1,521 controls.33 Median survival is still an impressive 23 months, with a five-year survival rate of 25 percent (Fig. 2). In a series of melanoma patients undergoing treatment for pulmonary metastasis, median overall survival following CancerVax therapy was 13 months, compared with eight months following other treatments, such as chemotherapy or BCG immunotherapy.34 The survival benefit is highest among patients who have undergone complete resection of metastatic disease (often to multiple sites) prior to CancerVax therapy. For example, patients with visceral metastasis (AJCC stage IV M1b) who were rendered free of disease prior to vaccine therapy experienced a five-year survival rate of 33 percent compared with 10 percent for similar patients undergoing surgical resection followed by non-CancerVax therapy (Fig. 3). Survival of 157 patients with AJCC stage IV melanoma treated with CancerVax versus 1,521 historic controls treated with nonvaccine therapies. Five-year survival was 25 percent for the CancerVax patients versus six percent for the historic controls (p=0.0001). Although 15 to 20 percent of patients with evaluable disease undergo partial or complete regression of metastasis following immunotherapy with CancerVax,33 vaccine-induced regression occurs primarily in patients with metastases less than 2 cm in diameter (Fig. 4).31 A much more frequent clinical response to CancerVax is slowing of tumor growth, which can be measured by an increase in tumor doubling time or a period of prolonged stability in tumor size (Fig. 5).31,34–36 In addition to its effect on macroscopic disease, CancerVax appears to inhibit blood-borne micrometastasis. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques indicate that up to 95 percent of patients with metastasis to distant organ sites have tumor cells circulating in the bloodstream, at least some of which will be able to induce secondary metastasis.37 Cytotoxic T cells and antibodies can attack these tumor cells at some step in the metastatic process, including intravasation into the microcirculation, circulation in the bloodstream, and extravasation into the interstitial space. The ability to inhibit the metastatic process may be an important benefit of active immunotherapy because our data indicate more than a doubling in the survival rate of patients who respond to vaccine therapy by formation of cytotoxic T cells38 or IgM antibodies with specificity for melanoma cell-surface antigens.31 Survival of melanoma patients receiving CancerVax versus other adjuvant therapies after complete resection of visceral metastasis (AJCC stage IV M1b disease). Other adjuvant therapies were immunotherapy with bacille Calmette-Guérin and/or chemotherapy. Our studies of brain metastasis in AJCC stage IV melanoma show that as many as 65 to 75 percent of patients have central nervous system involvement at the time of death.39 The brain is the initial site of distant metastasis in about 20 percent of patients, whereas about 50 percent exhibit initial metastasis to noncerebral sites and later develop secondary cerebral metastasis. However, the incidence of secondary brain metastasis in patients receiving CancerVax is only 22 percent, even though their survival is twofold the survival of control patients from our historical data base who had an incidence of 49 percent for secondary brain metastasis (Table 3). We believe that CancerVax may inhibit the metastatic cascade by activating cytotoxic T cells and antibodies that attack melanoma tumor cells which have entered the blood-stream during transit to the brain and thereby delay or inhibit the development of blood-borne cerebral metastasis. Thus, even in the absence of a quantifiable lesion response, vaccine treatment may be beneficial by preventing secondary metastasis and improving the response to chemotherapy or biotherapy in patients whose disease progresses on immunotherapy alone.40,41 Because of our encouraging results with CancerVax in stage IV disease, we will shortly begin a randomized, multicenter phase III trial of this vaccine. In several phase I/II studies, Mitchell's group tested preparations of two mechanically disrupted melanoma cell lines (Melacine) injected subcutaneously in combination with the adjuvant DETOX. Median overall survival of the 106 patients was 12.2 months, but 20 patients (19 percent) had objective clinical regression of tumor masses, five with complete responses.42 The median duration of response was 46 months. Clinical response correlated with an increase in the level of cytotoxic T-cell precursors in the blood as well as a partial match of the patient's HLA phenotype with vaccine cell A phase III trial of AJCC stage IV melanoma patients was recently with patients receiving vaccine (Melacine) or combination chemotherapy analysis revealed that median survival was not significantly different among evaluable patients receiving versus chemotherapy Although were significantly less frequent with the response rate among evaluable patients was significantly with chemotherapy percent percent and percent than with the vaccine percent, two percent, and percent, survival analysis is available as melanoma metastases on before and four months after of CancerVax show that melanoma cells as regression This remains free of disease at 7.5 years of Reprinted with permission from et of interferon at a of three per induced responses in eight of patients who failed treatment of their HLA on these a phase III trial will with This trial will include patients and is to begin this monoclonal antibodies high molecular have been developed by antibodies can stimulate that are to the antigen and thereby induce humoral and immune response. of the have been used in phase I/II clinical studies of patients with stage IV to and with BCG as an these antibodies against in 60 percent of the The that these antibodies are IgM and a immune response to the of was associated with significantly increased doubling time a of the rate of tumor growth, is during most of the growth of clinically pulmonary after of CancerVax a rate of tumor cell growth or increased cell the tumor only 75 to its after of The longer the the less the Reprinted with permission from Barth et group has used a vaccine made from autologous tumor with BCG as an Because melanoma cells are not the number of is of patients to treatment with autologous melanoma four responses were percent of the patients with tumor regression to autologous group has autologous melanoma cells to to enhance their active immunotherapy to of a cancer vaccine after surgical resection of all clinically In patients with AJCC stage III melanoma, adjuvant immunotherapy is to the of after of tumor-involved regional lymph nodes. Our studies indicate the of circulating tumor cells in about percent of AJCC stage III Active immunotherapy is more in these patients than in with a tumor because a tumor of even cm in diameter contains up to one tumor cells that have the patient's immune Moreover, without adjuvant an 60 to 80 percent of AJCC stage III patients will experience and within five years after depending on the initial number of tumor-involved regional lymph However, the median time to is one to two years, a period to the induction of a clinically beneficial response to vaccine immunotherapy for patients with AJCC stage III melanoma has undergone investigation in of specific melanoma nonspecific immune such as BCG and and response such as the all of these have been or of The treatment of melanoma was significantly changed in et from the that significantly prolonged and overall survival following surgical resection of primary melanoma (AJCC stage or regional lymph node metastasis (AJCC stage III). administered for four weeks and subcutaneously three a for weeks increased median survival by one to years and median overall survival by to years compared with treatment also increased the five-year survival rate by percent. This important study was the first randomized, trial to show a benefit of adjuvant therapy in and overall survival of melanoma on its the approved for adjuvant therapy in melanoma patients at high risk for However, one year of interferon therapy about and In the in 65 percent of patients, percent during the induction phase and 46 percent during therapy. Other investigators have been less and less and for of adjuvant and at the have the study melanoma patients with regional lymph node metastases were to an observation or to treatment with for three years. The most report of their results no in or overall which indicates that less is not as effective as the regimen used in the to adjuvant therapy was by the Cancer and recently by et This trial compared three per for 12 with observation in patients with primary melanomas and patients with regional nodal metastasis. Although there was no in or overall analysis improvement in the survival of patients with nodal metastasis. In of interferon for a period or high for a period to be less effective than for about one However, the and of interferon this regimen less than active immunotherapy to of a cancer vaccine after surgical resection of all clinically In the early we a study of a living allogeneic melanoma vaccine CancerVax in AJCC stage III melanoma patients undergoing resection of lymph node Although vaccine to have a five-year survival rate percent) than patients in the observation group this was not due to the small who developed a high of IgM antibodies against MAA experienced prolonged but because of the vaccine's only one of patients were responders. and overall survival of melanoma patients to bacille Calmette-Guérin or as adjuvant therapy following resection of regional nodal metastasis (AJCC stage III disease). Reprinted with permission from et Overall survival of melanoma patients to melanoma or as adjuvant therapy after resection of regional nodal metastasis (AJCC stage III disease). therapy was associated with a increase in overall survival Reprinted with permission from et survival of melanoma patients receiving adjuvant CancerVax versus other adjuvant therapies or no adjuvant therapy following resection of regional nodal metastasis (AJCC stage III disease). Other adjuvant therapies were immunotherapy with bacille Calmette-Guérin and/or chemotherapy. indicate the number of patients observed and at risk for observation Since that we and have phase II of vaccines as adjuvants in melanoma (Table These have irradiated whole cell melanoma cell antigen vaccine autologous vaccine and melanoma vaccine Because the phase II data a survival results of III) have been with In the phase III trial by et patients with AJCC stage III melanoma with BCG or BCG after with After a median of months, there was no in and overall survival the two treatment (Fig. However, patients with an level were from the there was a improvement in survival. In the phase multicenter trial by et patients with AJCC stage III melanoma melanoma or for one After a of 30 months, analysis no in and overall survival (Fig. analysis revealed an improvement of percent in overall survival for patients treated with which increased to 30 percent for than years with one to five lymph nodes A analysis with longer is in the of tumor-involved lymph nodes in AJCC stage III melanoma patients receiving CancerVax versus other adjuvant therapies. We recently the updated results of our adjuvant phase II trial of CancerVax for AJCC stage III melanoma. CancerVax was administered in a of living irradiated cells, as years after percent of the melanoma patients receiving CancerVax were disease free compared with percent of historic control patients receiving other adjuvant therapies (Fig. Median survival was months for the control group versus than 90 months for patients receiving CancerVax Although we not the in an historical data we its by a large number of patients and by vaccine and control to the number of lymph which is the most important in AJCC stage III melanoma (Fig. The results were highly of a therapeutic studies revealed that a reaction and/or increased cytotoxic T-cell were of a of these phase II a phase III trial of adjuvant therapy will shortly be to CancerVax against The of vaccine for malignant melanoma the development of modern tumor immunology and molecular Although have been many Among these are the clinical of MAA, the the and the role of the various A is a melanoma vaccine be a of a single or a mixture of living whole cells. vaccines such as CancerVax a of MAA, some and which usually include many antigens present on cells of the patient's and control of vaccines are but However, of specific immune responses requires against multiple there is an HLA living cell vaccines have the of being able to present their antigens to the patient's T cells as well as vaccines are well defined and can usually be produced in large without control and of a specific immune response less of a However, not all human melanomas will a specific melanoma antigen or a HLA and therefore only a of all melanoma patients may benefit from such a vaccine. Although the data from vaccine studies indicate that in patients who do not develop a or humoral immune response and in who develop one or types of response, is still an vaccine primarily induce a response, a humoral response, or will to these important the last 25 years, active specific immunotherapy with vaccines has as a new in the treatment of malignant melanoma. II studies have the and the of vaccine approaches in the adjuvant and metastatic Although early results from phase III have not an survival benefit for adjuvant vaccine this the results at present be a rather than a to the of that have the to a small therapeutic a therapeutic benefit be by the of cancer vaccines. The for melanoma and other cancer vaccines is because of their approaches using or vaccine cell lines that have been with an allogeneic HLA the of a or the have now entered clinical These increase the of melanoma vaccine therapy and new for patients with this disease. After many years without we are now at the of the and can be about the of therapeutic vaccines for melanoma and other types of cancer.