Active Immunotherapy of Metastatic Melanoma with Allogeneic Melanoma Lysates and Interferon ␣

3696 Vol. 8, 3696–3701, December 2002 Clinical Cancer Research

Ulka Vaishampayan, Judith Abrams, disease for at least 16 weeks. The median time to disease Denise Darrah, Vicky Jones, and progression in evaluable patients was 8 months [95% con- Malcolm S. Mitchell1 fidence interval (CI), 6–13 months]. Median survival time for all of the 47 patients enrolled was 12.5 months (95% CI, Karmanos Cancer Institute, and Division of Hematology/Oncology, Department of Medicine, Wayne State University, Detroit, Michigan 8–15 months) with a median time to disease progression of 48201 [U. V., M. S. M.]; Karmanos Cancer Institute, and Department 4 months (95% CI, 3–7 months). of Biostatistics, Wayne State University, Detroit, Michigan 48201 Conclusion: Despite a low objective response rate, this [J. A.]; and University of California, San Diego Cancer Center, La combination holds great promise because of its tolerability Jolla California 92093 [D. D., V. J.] and the high proportion of prolonged durations of remission or disease stabilization that it elicited. ABSTRACT Purpose: A therapeutic lyophilized melanoma vaccine INTRODUCTION consisting of two mechanically disrupted allogeneic mela- Melanoma has had a rising incidence, with 51,400 esti- noma cell lines and the immunological adjuvant Detox-PC mated cases in the United States in the year 2001 (1). It is the (Melacine) has demonstrated encouraging activity in meta- most lethal skin malignancy with an estimated 7,800 deaths static malignant melanoma, often in regimens containing attributable to it in 2001 (1). The majority of the deaths are pretreatment with low-dose cyclophosphamide. In addition, caused by metastatic melanoma, which is usually resistant to IFN-␣2b (INTRON A; Schering-Plough Corporation, Ken- standard cytotoxic therapy, including highly toxic combinations. ilworth, NJ) has shown efficacy in melanoma refractory to Hence, immunotherapy has become the mainstay of treatment in Melacine. In this Phase II trial, the combination of cyclo- advanced malignant melanoma. Active specific immunotherapy phosphamide, Melacine, and IFN␣ was tested in metastatic (“vaccination”) is a strategy that uses tumor-associated antigens malignant melanoma. to induce an immune response against the tumor. Although both Experimental Design: Eligibility criteria included meas- autologous and allogeneic vaccines have been studied, we have urable disease, no prior systemic therapy for a minimum of favored an allogeneic vaccine that we devised, prepared from 4 weeks, and adequate marrow, renal, and hepatic function. mechanically lysed melanoma cell lines, expressing the range of Cyclophosphamide was administered once at a dose of 300 melanoma-associated antigens as well as alloantigens. A prep- .mg/m2 i.v. on day ؊3 before the first dose of Melacine aration called Melacine (Corixa-Montana) consists of lyophi- Melacine was administered at a dose of 2 ؋ 107 tumor cell lized lysates of two melanoma cell lines, MSM-M-1 and MSM- equivalents per dose admixed with 0.25 ml of Detox-PC s.c. M-2, admixed with the immunological adjuvant Detox-PC once a week on weeks 1–4 and week 6. Melacine mainte- (Corixa-Montana) immediately before use. nance was then given monthly from the 8th week, until Phase I and Phase II studies of these melanoma cell lysates, progression or intolerable toxicity. IFN was started in the in their original form stored frozen at Ϫ80°C (“frozen lysates”) evening after the fourth dose of Melacine at a dose of and also of the lyophilized Melacine preparation have been 5,000,000 units/m2 3 times a week, and continued until pro- performed in stage IV melanoma (2, 3). The Phase I study of gression. 19 patients proved the feasibility of immunization against Results: Forty-seven patients were enrolled, of whom 39 melanoma-associated antigens in 50% of the patients and completed the full course and were considered evaluable. elicited a 29% objective clinical response (2). The Phase II The toxicity of the regimen was minimal and consisted trial of the frozen lysates in 25 patients demonstrated a mainly of pain at injection sites and granulomas caused by response in 5 patients (20%), objective regressions and one Detox-PC, and constitutional symptoms attributable to IFN. long-term stability, which was associated with an increase in In 39 evaluable patients, the overall objective response rate precursors of cytolytic T cells against melanoma cells with was 10.2%, but 64% of patients had stabilization of their clinical benefit (3). In Phase II trials of the lyophilized preparation, Melacine, at a single institution an objective response rate of 15.5% was observed (4). IFN-␣2b (INTRON-A; Schering-Plough Corporation, Kenil- Received 12/12/01; revised 6/3/02; accepted 7/3/02. worth, NJ) has been tested in metastatic and adjuvant settings in The costs of publication of this article were defrayed in part by the melanoma (5–7). One large randomized trial demonstrated a payment of page charges. This article must therefore be hereby marked persistent 11% overall survival benefit with adjuvant IFN ther- advertisement in accordance with 18 U.S.C. Section 1734 solely to apy in resected high-risk melanoma (7). A study was conducted indicate this fact. ␣ 1 To whom requests for reprints should be addressed, at 5 Hudson, with the administration of IFN- in metastatic melanoma pa- Harper Hospital, 3990 John R, Detroit, MI 48201. Phone: (313) 745- tients who had demonstrated refractoriness to Melacine. This 2749; Fax: (313) 993-0559; E-mail: [email protected]. trial had a very promising 44% objective response rate. The

median survival of responders was 36 months with a median Treatment Plan. Cyclophosphamide was administered duration of response of 11 months (8). Responses were elicited at a dose of 300 mg/m2 i.v. 3 days before the first dose of in visceral metastatic sites as well as s.c. tissue and lung. On the Melacine. This low dose of cyclophosphamide was intended to basis of these encouraging results, a Phase II trial of Melacine down-regulate suppressor T-cell activity, which has been dem- and IFN-␣ in combination was performed in metastatic mela- onstrated experimentally (9–11). Melacine was administered at noma. The results of this study are the subject of this report. a dose of 2 ϫ 107 tumor cell equivalents per dose admixed with 0.25 ml of Detox-PC s.c., divided between two sites once a week on weeks 1–4 and week 6. This course was repeated if PATIENTS AND METHODS there was no evidence of disease progression at week 8. Main- Eligibility Criteria. Eligible patients were required to tenance therapy with Melacine was given monthly thereafter, have a histologically proven diagnosis of melanoma and until progression or excessive toxicity occurred. IFN-␣ was measurable or evaluable metastatic disease. If patients had started in the evening after the fourth Melacine injection at a been previously treated, they were not eligible for enrollment dose of 5,000,000 units/m2 s.c. three times a week until pro- until 4 weeks had elapsed from the time of previous treat- gression occurred. This dose level was based on previous im- ment, such as radiation therapy, chemotherapy, or immuno- munological and therapeutic studies with this preparation (8, therapy. Good performance status (Karnofsky scale, Ն70%) 12). The dose of IFN-␣ was reduced to 2,500,000 units/m2 three was required for enrollment, with adequate bone marrow, times/week if any grade 3 or 4 toxicity occurred. No dose 3 hepatic, and renal function (WBC count, Ն3000/mm ; plate- re-escalation was permitted. If IFN-␣ was not tolerated despite 3 let count, Ն100,000/mm ; serum bilirubin, Յ2 mg/dl; and dose adjustment, it was discontinued. Detox-PC was omitted at serum creatinine, Յ2 mg/dl). Patients with brain metastases the first sign of severe granulomas, but the melanoma lysate were allowed to enroll if the metastases were controlled for at portion of Melacine was continued. least 6 weeks by surgery or radiotherapy. Exclusion criteria Statistical Methods. The primary end point originally included allergy to eggs (because the adjuvant was cultured selected for this Phase II trial was objective response rate. in chicken egg extract), concurrent treatment with cortico- Response to therapy was assessed every 8 weeks. Patients were steroids or antihistamines, and the absence of a delayed taken off the protocol if there was disease progression, a treat- hypersensitivity reaction to at least one of a standard battery ment delay of more than 4 weeks, or administration of any other of microbial skin test antigens. These comprised Streptokinase/ antitumor therapy, or if the patient refused further treatment. Streptodornase, Candida, Mumps, Trichophyton (Hollister- Patients were evaluable for response if they completed the first Stier Laboratories), and intermediate strength purified pro- course of therapy, i.e., 8 weeks of treatment. Disease response tein derivative. Patients with a prior malignancy other than was assessed using standard criteria for solid tumors (13). Time- nonmelanoma skin cancers were accepted, but had to have to-disease progression was calculated from the date of registra- been disease free for a minimum of 5 years. A signed in- tion to the date of progressive disease or death. Secondary end formed consent was obtained from every individual enrolled points included assessment of toxicity, time to treatment failure, on the protocol. and overall survival. Exact binomial methods were used to Preparation of Lysates and Melacine. The lysates were calculate CIs around response rates. Kaplan-Meier product limit derived from two distinct melanoma cell lines cultured from the methods were used to estimate median survival and cumulative s.c. nodules of two female patients. Both cell lines have been survival proportions. deposited with the American Type Culture Collection. MSM- M-1 (abbreviated M-1) was obtained in 1980, is amelanotic, nearly tetraploid, grows slowly and expresses HLA-A2, HLA- RESULTS B12, HLA-B62, and HLA-C3 and HLA class II antigens DR4, Characteristics of the Patients. Between October 1994 DR10, DRw53, and DQ8. It also expresses ganglioside GD3 but and May 1996 a total of 57 individuals were screened for this not GD2. The second cell line (MSM-M-2 or M-2) is diploid study, 10 of whom were found to be ineligible after registra- with a small percentage of hypodiploid cells and trisomy of tion but before treatment. Ineligibility was attributable to chromosome 7. It is highly pigmented, rapidly growing and incorrect diagnosis, patient’s changing his/her mind about expresses HLA-A28 (now called HLA-A*6802), -A31, -B51, enrolling, rapid progression of the disease before the protocol -B60, -C2, and -C6 and is devoid of HLA Class II antigens by could be started, or refusal of the insurance company to pay serological assays. However, the genes coding for HLA Class II for the study. Reasons for inevaluability included failure to antigens are present in this cell line. complete 8 weeks of treatment (eight patients) because of Mechanical disruption of the melanoma cells for this rapid progression of disease before the first evaluation point study was performed at Corixa-Montana with a Polytron in six patients and failure to comply with the protocol and stainless steel high-speed tissue homogenizer (Tekmar, Cin- request to be removed from the study in one patient each cinnati, OH) and three cycles of freeze thawing. By serolog- (Fig. 1). The median age of enrolled patients was 61 years ical assays, this preparation contains the common melanoma (range, 23– 84 years); 16 participants were female and 31 antigens tyrosinase, gp100, and MART-1/Melan A. Melacine were male (Table 1). Approximately 25% of the patients had (Corixa-Montana), the lyophilized version of this lysate prep- lung metastases only, whereas 57% of the group had meta- aration, stored at 4°C, was used in this study. The lyophilized static disease in visceral sites and bone. lysates were mixed with the immunological adjuvant Treatment. Forty-seven patients were treated per proto- Detox-PC (Corixa-Montana) within 30 min before injection. col, and the median duration of therapy was 17 weeks. Thirty-

Table 2 Response rates with Melacine ϩ IFN-␣ therapy in stage IV melanoma Evaluable Total no. of Response patients (n ϭ 39) patients (n ϭ 47) CR 2 (5.1%) 2 (4.2%) PR 2 (5.1%) 2 (4.2%) S.D. 25 (64.1%) 25 (53.1%) PD 10 (25.6%) 18 (38.2%)

Response and Survival. Of 39 evaluable patients, CRs2 and PRs were observed in two patients each (10.2%); four (10%) had a minimal response (measurable shrinkage of tumor masses but less than PR or CR) (Table 2). On the basis of these Fig. 1 Disposition of the patients who were screened for the clinical data, we estimate, with 95% confidence, that the objective study. Of 57 patients, 47 were entered, of whom 39 were treated for the response rate of patients receiving this therapy is between 10 full 8 weeks and were fully evaluable. and 35%. Moreover, ϳ74% of patients had either an objective remission or a stabilization of their disease. With 95% confidence, we estimate that at least 56% and at most 87% of patients Table 1 Patient characteristics receiving this therapy might expect response or stabilization of Characteristic n (%) their disease. Twenty-one patients (53.8%) demonstrated dis- Age ease stabilization for at least 4 months (Table 2). Յ70 yr 31 (66) Follow-up was complete as of February 2001. The median Ͼ70 yr 16 (34) survival for all of the 47 patients was 12.5 months (95% CI, 8.3, Metastatic sites 15.0); 1- and 2-year overall survival rates were 53 and 17%, Pulmonary only 11 (23) Visceral and/or bone 27 (57) respectively (Fig. 2). When analyses were restricted to evaluable Lymph node only 5 (11) patients, median survival was 14.3 months (95% CI, 9.8, 19.5) Skin/soft tissue only 4 (9) with 1- and 2-year survival rates of 64 and 21%, respectively No. of metastatic sites (Fig. 3). In the evaluable patients, the median time to failure was 1 19 (40) 2 18 (38) 6 months (95% CI, 3, 8), with 1- and 2-year progression-free 3 7 (15) survival rates of 28 and 10%. The median duration of disease Ն4 3 (7) response or stabilization was 8 months (95% CI, 6, 13 months). Prior therapy Median time to treatment failure for all of the 47 patients was None 35 (75) 4.0 months (95% CI, 3, 7) with 1- and 2-year progression-free Immunotherapy 3 (6) Chemotherapy 3 (6) survival rates of 23 and 9%, respectively (Fig. 2). All four of the Radiation therapy 4 (9) patients with an objective response, and four with disease sta- Chemotherapy and radiation 2 (4) bilization beyond 1 year, survived more than 2 years. Cumula- tive disease stabilization rates were 38% at 1 year and 14% at 2 years.

nine patients (83%) completed the first 8 weeks of therapy, and DISCUSSION 31 patients completed 16 weeks of therapy; 24 of these received The previously observed objective response rate of 44% subsequent monthly maintenance treatment. One patient com- with IFN-␣ administered after Melacine failure was not dupli- pleted 8 weeks, three completed 9 weeks, and one each com- cated in this study of concomitant therapy (Table 3). Concom- pleted 11, 12, 14, and 15 weeks of therapy. The median duration itant rather than sequential treatment was chosen here to reduce of maintenance therapy was 19 weeks, (range, 1–288 weeks). the time required to administer the treatment regimen and to Two patients had a sustained remission and, thus, received avoid the risk of having the patient not respond to Melacine treatment beyond 2 years. before affording him or her the potential benefit of the IFN-␣. Toxicity. Melacine was extremely well tolerated. The Although the combination of Melacine and IFN resulted in few predominant toxicity noted was local pain at the site of objective clinical responses, meaningful disease stabilization injection for no longer than 24 h after the injection. No severe was achieved in more than one-half of the patients. The possible granulomas or sterile abscesses occurred, because the Detox explanations for this phenomenon are several. It has been shown portion of the vaccine, which we have found to be responsi- that the HLA phenotype of the tumor is a significant predictor of ble for these delayed hypersensitivity reactions, was discontinued at the first sign of a significant granuloma. The IFN- related toxicities were mainly constitutional, such as an influenza-like syndrome. There were no treatment-related 2 The abbreviations used are: CR, complete remission; PR, partial re- hospitalizations or mortalities. mission; S.D., stable disease; CI, confidence interval.

Table 3 Summary of Melacine-based trials in metastatic malignant melanoma No. of Med duration Study (Ref.) patients CR PR S.D.a Clinical benefit MS of CR/PR/S.D. Phase I (2)b 17c 2 3 3 8 (47%) NR NR Phase II (3) 25c 1 3 1 5 (20%) NR 17 mo Melacine3IFN (8)b 18c 5 3 0 8 (44%) 10.1 mo 11 mo Melacine ϩ IFN (current study) All patients 47 2 2 25 29 (61.7%) 12.5 mo 4 mo Evaluable 39c 2 2 25 29 (74.3%) 14 mo 8 mo a MS, median survival; Med, median progression-free survival; NR, not reported. b Low-dose cyclophosphamide pretreatment given to six patients. c Number of evaluable patients.

Fig. 3 Survival curves (Kaplan-Meier) of the 39 evaluable patients Fig. 2 Survival curves (Kaplan-Meier) of all of the 47 patients entered entered on study. into the study.

response to Melacine in patients with metastatic melanoma (14) biochemotherapy regimens (17–21). Melacine-based regimens and, more recently, with prolonged disease-free response in had no reported treatment-related mortalities or hospitalizations. Stage II melanoma (15). Several HLA Class I phenotypes such The low incidence of systemic toxicity and local toxicity, if as HLA-A2, -B12 and -C3 were associated with a higher re- careful attention is paid to reducing or eliminating the adjuvant sponse rate to treatment with Melacine alone, perhaps because before severe granulomas occur, makes this therapy widely those alleles presented important immunodominant melanoma acceptable to patients. epitopes. This could explain the variation in the response rates The advent of biological therapy in the oncology therapeu- seen among the three trials (2, 3, 8) of Melacine therapy. Patient tics arena, necessitates an appreciation of the concept of tumor selection can also play a large role in explaining the differences containment without size reduction. When that translates into a in response rates across Phase II trials. Some prognostic factors likelihood of extending survival, the regimen may effect a such as serum lactic dehydrogenase levels, performance status, therapeutic benefit often exceeding that of cytotoxic therapies. and sites of metastatic disease influencing survival have been This may be analogous to the control of a disease such as reported (16). There are also likely to be a number of other hypertension by medication without the elimination of the un- characteristics of the patients that are yet unknown but that may derlying condition. Stabilization or nonprogression of disease in be important in determining the response to vaccine treatment. a substantial proportion of patients has been observed through- The most striking feature in our studies of Melacine in combi- out Phase I-III clinical trials with Melacine (22), and other nation with IFN-␣2b was that there was a distinct clinical vaccines such as Theratope in breast cancer. In a Phase II benefit and prolonged survival despite the lack of an overt multicenter study of 139 patients, Elliott et al. (23) observed an clinical response. This may reflect the distinct mode of action of improved survival (median, 22.3 months) for all patients who biological therapies such as vaccines, which may permit a had stabilization of disease for at least 6 months. In that trial, the stalemate with the tumor, whereby the growth of the latter is objective response rate was 8%, but 23% of patients with S.D. controlled but the tumor mass is not significantly reduced. derived therapeutic benefit also. Unlike cytotoxic chemother- Although the results of this Phase II trial and those of bioche- apy, vaccines may permit the host to reach a state of balance motherapy are not directly comparable, the median survival with the tumor, in which the net result of tumor growth and achieved with our minimally toxic regimen of melanoma vac- destruction is zero. That might lead to a more useful increase in cine and IFN-␣2b was little different from that achieved by survival than rapid destruction and rapid regrowth of the tumor

Fig. 4 Schema of the present multicenter trial of Melacine ϩ IFN-␣ versus high-dose IFN-␣ in resected Stage III melanoma.

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Ulka Vaishampayan, Judith Abrams, Denise Darrah, et al.

Clin Cancer Res 2002;8:3696-3701.

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